tag:blogger.com,1999:blog-4184507017780725122024-03-13T01:35:10.755-07:00Cancer BiologyA forum for all things cancer related. Brought to you by the Bio 179 students at Santa Clara University.IslasLabhttp://www.blogger.com/profile/09749065924061485019noreply@blogger.comBlogger351125tag:blogger.com,1999:blog-418450701778072512.post-44072428244580687582014-06-11T13:27:00.000-07:002014-06-11T13:27:14.745-07:00Could LxxLL be a key to a New Site for Target Drugs?<span style="font-family: Arial,Helvetica,sans-serif;">We have mapped the entire human genome. We have discovered specific site targeting drugs that have been a huge success in killing cancer. What is next? Of course to further embark on this newly discovered path and target other genes for success! </span><br />
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<span style="font-family: Arial,Helvetica,sans-serif;">How do these targeting drugs work? Lets look at the human papillomavirus (HPV) vaccine. This vaccine is preventing strains 16 and 18 from infecting women.These strains are the cause of at least 70% of cervical cancer cases. When HPV infect someone, it acts as a retrovirus. It copies into human DNA. Then, it makes an E6 protein. This protein is not equivalent to the human one, but from HPV. This E6 protein floats around cells and attaches with ubiquitin ligase, a protein that degrades genes from doing their job. There is a domain on this E6 protein that start with Zinc C domain and terminates with a Zinc N domain. In between is a linker helix domain that is very hydrophobic. This makes up the LxxLL sequence with L being acidic Leucine and x being other hydrophobic amino acids. This hydrophobic pocket then binds with extreme ease to proteins like p53 and RB. When they are in contact, ubiquitin ligase then deregulates the protein E6 is bound to. In turn, this then causes no tumor suppression or cell death and cancer develops. Because HPV is sexually transmitted almost all of these cases result in cervical cancer. </span><br />
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<a href="http://4.bp.blogspot.com/-7yKazYiG6cU/U4_70ttLk5I/AAAAAAAAABw/YuyPHgq7RJU/s1600/Screen+Shot+2014-06-02+at+4.15.14+PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-7yKazYiG6cU/U4_70ttLk5I/AAAAAAAAABw/YuyPHgq7RJU/s1600/Screen+Shot+2014-06-02+at+4.15.14+PM.png" height="320" width="246" /></a></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: x-small;"><span style="font-size: xx-small;">Figure 1:<b> E6 protein structure when bound with ubiquitin ligase.</b></span></span></span><br />
<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: x-small;"><span style="font-size: xx-small;">The top image shows the structure of the folding of the E6 protein, in yellow is the first Zinc domain, in grey is the linker helix domain and in purple is the terminal Zinc domain. The bottom images shows the hydrophobic LxxLL pocket. </span></span></span><br />
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<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: x-small;"><span style="font-size: xx-small;"><span style="font-size: small;">A crucial point to notice in this process is that the LxxLL pocket can bind with a plethora of different proteins. Targeted therapies do just this. If we could make a drug/ structure that has a pocket like LxxLL that could go in and bind to proteins that are mutated, we could used this process to treat cancer. This is especially important because proteins like RB and p53 are in almost all cases of cancer and there has not been much research done on these oncoproteins. Targeting drugs have proven in the past to be very successful in curing targeted cancer. This specific pocket could be useful for further research in this field.</span></span></span></span><br />
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<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: x-small;"><span style="font-size: xx-small;"><span style="font-size: small;">Even though this started with the HPV vaccine which does not cure cancer, it prevents it, if science found the technology to to build a protein that when inserted into a cancer cell could latch onto mutated proteins and regulate them again, we could help cure many forms of cancer. Evidence shows through the HPV that it really does work. Our next step is to instead of using it as a prevention, we use this technology as a cure. By knowing how HPV attacks proteins we can do the same with an artificial structure. If we went after proteins as common in mutations as p53 and RB we could change many lives. I would love to see further research on this LxxLL pocket. I feel that having a technology break through would come best with furthering our knowledge on targeting mutations on proteins that influence all cancers. This pocket could be the start of a new era in cancer research. </span> </span></span></span><br />
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<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: x-small;">Work Cited:</span></span><br />
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<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: x-small;">Zanier, K., S. Charbonnier, A. O. M. O. Sidi, A. G. Mcewen, M. G.
Ferrario, P. Poussin-Courmontagne, V. Cura, N. Brimer, K. O. Babah, T.
Ansari, I. Muller, R. H. Stote, J. Cavarelli, S. Vande Pol, and G.
Trave. "Structural Basis for Hijacking of Cellular LxxLL Motifs by
Papillomavirus E6 Oncoproteins." <i>Science</i> 339.6120 (2013): 694-98. Web. 12 May 2014. <<a class="wiki_link_ext" href="http://www.sciencemag.org/content/339/6120/694.full" rel="nofollow">http://www.sciencemag.org/content/339/6120/694.full</a>>.</span></span>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-75156393447907673272014-06-07T23:45:00.003-07:002014-06-07T23:45:35.346-07:00Epithelial-Mesenchymal Transition on CTCs<!--[if gte mso 9]><xml>
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<span style="font-family: "Times New Roman","serif"; font-size: 12.0pt;">In
<a href="http://islaslab.blogspot.com/2014/05/delving-further-into-circulating-tumor.html" target="_blank">my previous blog post</a> I mainly addressed the issue of factors that affect
circulating tumor cell count in blood samples. As previously mentioned, this
could lead to an under or overrepresentation of the cumulative CTC total within
the patient. As such, it is important to account for these factors during
quantification and ultimate prognosis using CTCs. In my previous post I focused
more on the factors of clustering and filtration. The factors that followed,
such as cloaking had to do with molecules from within the circulatory system
masking CTC presence and as a result prevented accurate analyses to the point
where it was deemed another factor in distorting CTC measurement. However one
of the factors that was in the article mentioned, but was never given a greater insight to is
G in the image below labeled “(partial) EMT”. </span></div>
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<span style="font-family: "Times New Roman","serif"; font-size: 12.0pt;">The
above image is from the article “<a href="http://www.sciencemag.org/content/341/6151/1186.full" target="_blank">Circulating Tumor Cells</a>” by Vicki Plaks and
was also shown in my previous post. Within these factors is (partial) EMT which
was vaguely addressed by the article in a generalized manner.
Afterwards I found an article titled “<a href="http://www.jci.org/articles/view/39104" target="_blank">The Basics of Epithelial-mesenchymalTransition</a>” that highlighted EMTs and the process that it encompasses. The
article showed that epithelial-mesenchymal transition (EMT), was actually the
process in which an epithelial cell that normally interacts with the membrane
that it is on, undergoes biochemical changes that allows
it to gain mesenchymal cell properties. This essentially means that the cells gain
enhanced migratory capabilities and overall seem to gain cancerous cell-like
qualities, such as increased invasiveness in the organism.At this point, the possible skewing of data in a theoretical sense was realized; if these epithelial cells are being released from the initial carcinoma site, then these cells are more than just the new characteristics they have acquired: they are also products from the irregular cancerous growth.</span></div>
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<span style="font-family: "Times New Roman","serif"; font-size: 12.0pt;">The additional loss of traits that define the tethering potential in normal epithelial cells to the underlying structures could adversely affect CTC count because now the number of site that are used to target CTCs has substantially decreased. As a result, it is believed that the release of epithelial cells that were within proximity of the initial outgrowth of may fulfill the criteria to be detected by popular detection methods such as the CellSearch system, which according to <a href="http://jco.ascopubs.org/content/32/11/1104.short" target="_blank">this article</a> by Terence W. Friedlander, is reliant on the implementation of antibodies that are directed against the epithelial cell adhesion molecule (EpCAM), which is expressed on cells derived from the epithelium. However the process isn't solely associated with more targets, but also potential loss of these transmembrane proteins leading to less targets for the CellSearch system. This, alongside the previous accepted assumption that neighboring cells that haven't necessarily gained the function of cancerous cells in that general region, may still have a manner of being quantified and accounted for by the CellSearch system. This could result in an overrepresentation of the current metastasizing potential of the cancerous growth.</span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjch1E5gcVykcxXfXjmKtPGL39wo_l2vejr3TxXoNrEQab76cgdkRuVrRyPT5Jo-4u-EBI-QjBjyID5ioawxa0_2rM0Q0otlMXLSIDZHdsSs5IpBlUsIuf8a5QYjilvhOlqCfK6bF11uUc/s1600/JCI39104.f2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjch1E5gcVykcxXfXjmKtPGL39wo_l2vejr3TxXoNrEQab76cgdkRuVrRyPT5Jo-4u-EBI-QjBjyID5ioawxa0_2rM0Q0otlMXLSIDZHdsSs5IpBlUsIuf8a5QYjilvhOlqCfK6bF11uUc/s1600/JCI39104.f2.jpg" height="306" width="400" /></a></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhIU0MnJ_XK8-JNapr058YFTNnEQEv2b__SCd3Fi3xc_gV-Wkc7KZOtGYPyYhsaV-R-Eihz1A2xUx-dlKBOGhtVI0BNE7wc3e5ZHpz8e3lrYJtqTCTMrrT4aTT6Jk3kQYoPRVxLki4ouMzQ/s1600/JCI39104.f5.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhIU0MnJ_XK8-JNapr058YFTNnEQEv2b__SCd3Fi3xc_gV-Wkc7KZOtGYPyYhsaV-R-Eihz1A2xUx-dlKBOGhtVI0BNE7wc3e5ZHpz8e3lrYJtqTCTMrrT4aTT6Jk3kQYoPRVxLki4ouMzQ/s1600/JCI39104.f5.jpg" height="75" width="400" /></a></div>
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Above are two images from Raghy Kalluri's <a href="http://www.jci.org/articles/view/39104" target="_blank">article</a> and they mainly serve to show the general process of EMT. As read in the article, it seems that though the general steps within the process are known, it is unclear as to what dictates this process with respect to the carcinomas genetic information. There is one particular point within this section in the article that caught my attention and that was when it stated, "...activation of an EMT program has been proposed as the critical mechanism
for the acquisition of malignant phenotypes by epithelial cancer cells." and that made me question how EMT results in the acquisition of these phenotypes. After continued research, it seems that this is largely an assumption made by deductive reasoning without any convincing concrete evidence that supports it. Yet another topic of interest that I researched more into was what dictated the determining of a location where irregular growth resulting in a cancerous outgrowth would begin. However, like many other sections of research within this complex area of study, this too didn't lead to any significant findings indicating a pathway or factor that dictates this function. I personally believe the most reasonable assumption that can be made at the moment is that it seeks the location where it will most likely experience optimal to its proliferation. The manner it does so however, is beyond the research I have made.<br />
<br />
With the current limited knowledge, I believe that the future of CTC analysis lies in developing a manner of analyzing CTCs that is reliant on mutations that arise because of the previously mentioned EMT process. I largely believe that this is would be a more accurate manner of targeting and defining CTC cells because analysis of transmembrane glycoproteins is quite circumstantial in that it relies heavily on the presence of surface protein targets. Genome targeting, however would focus on more specialized characteristics that occurs within a structure that all active tumor cells have. There is however, issues with this form of analysis, the first being the manner of making markers that target for these mutated forms of genetic information within the tumor cells that are likely to undergo EMT and enter the bloodstream, while not affecting normal cells that are proximal to the tumor site. <br />
<br />
Interestingly enough, this is where we come back around to Plak's article. As shown in the first image, box J shows a panel labeled "single-cell 'omics'." After going back through Plak's article once more it seems that prevalent research has been done in terms of targeting these tumor cells through their genome. However, the main recurring theme that keeps on affecting CTC count and hinders many advances in cancer research is the fact that cancer is not static and there is not a set recurring characteristic amongst all cancers that allow them to be targeted at a molecular level. Overall, I personally believe that CTC quantification, as with other procedures within the cancer field that we have identified in class, is taking an approach that is too "static" and isn't paralleling the dynamic nature of cancer as a whole. Accepting the fact that treatments will most likely continue with their static nature, I believe that it is necessary to modify the set static form of analysis in order to better identify a dynamic nature. However, such a process is easier said than done, but noting that the continuous progress in the field has shown promising results, it wouldn't do the research justice to say that continual funding for improvement in CTC analysis is an inefficient use of resources.</div>
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<span style="font-family: "Times New Roman","serif"; font-size: 12.0pt;">References</span></div>
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<span style="font-family: "Times New Roman","serif"; font-size: 12.0pt;"></span>Kalluri, Raghu, and Robert A. Weinberg. "The Basics of Epithelial-mesenchymal Transition." <i>Journal of Clinical Investigation</i> 119.6 (2009): 1420-428. Web. 4 June 2014.</div>
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Plaks, V., C. D. Koopman, and Z. Werb. "Circulating Tumor Cells." <i>Science</i> 341.6151 (2013): 1186-188. Web. 4 June 2014. </div>
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Carlos Riverahttp://www.blogger.com/profile/11631447224226768437noreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-64615164917024191922014-06-07T21:33:00.000-07:002014-06-07T21:33:00.283-07:00Mechanisms For Trastuzumab Resistance<div class="MsoNormal">
<span style="color: black; mso-bidi-font-family: "Times New Roman";">My cancer project looked at a possible mechanism for Trastuzumab
resistance, this being AMF causing HER2 phosphorylation leading to
intracellular signaling. While this idea is interesting it is fairly new so I
wanted to do more research on what is widely accepted today as the mechanism
for Trastuzumab resistance. Trastuzumab is a monoclonal antibody that
specifically targets the HER2 receptor. A monoclonal antibody is a synthetic
molecule whose primary role is to attack a certain defect in a cancer cell. These
antibodies also cause cancer cells to become more visible to the immune system,
thereby causing an immunogenic response. Trastuzumab binds to HER2 extracellularly
and this causes HER2 to become deactivated. This ceases all signal
transduction, which leads to inhibition of both the MAPK pathway and the pi3k
pathway. However, the majority of patients with metastatic breast cancer
develop a resistance to Trastuzumab within a year. How does this happen?<o:p></o:p></span></div>
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<span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">While the exact mechanisms
for Trastuzumab are still being researched there are some molecular and
cellular mechanisms that have been reported in the literature. The first
mechanism by which Trastuzumab resistance occurs is through disruption of the
interaction between the therapeutic drug and the target receptor. MUC4 is a
high molecular weight glycoprotein. It is known for it's anti-adhesion
properties, as well as its direct link to metastasis. This membrane-bound
glycoprotein was shown to bind to HER2 and cause steric hindrance, leading to
an inability for Trastuzumab to bind to the receptor. MUC4 interacts directly
with HER2, and subsequently this interaction is <span style="background: white;">dependent upon an epidermal growth factor (EGF)-like domain on the
ASGP-2 subunit of MUC4. Due to this interaction MUC4 acts as a ligand for the
HER2 receptor and causes phosphorylation, and therefore the downstream
signaling cascades. Another conclusion researchers were able to make was that
levels of MUC4 are inversely correlated with Trastuzumab binding
capabilities. </span><o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="background: white; color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">Trastuzumab
resistance has also been credited to increased signaling from the insulin-like
growth factor I-receptor(IGF-IR). Increased IGF-IR levels were shown to reduce
Trastuzumab effectiveness, and, similar to MUC4, IGR-IR also interacts directly
with HER2 and causes phosphorylation. Another side effects is that in
Trastuzumab resistant cells, IGF-IR causes a more rapid stimulation of Pi3k and
MAPK pathways. The researchers also observed down-regulation of p27kip1</span><span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><o:p></o:p></span></div>
<div class="MsoNormal">
<span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">in cells which had
increased levels of IGF-IR. <span style="background: white;">They concluded
that, "p27kip1 is a critical mediator of Trastuzumab response, and
that its down-regulation may occur subsequent to increased signaling from
growth factor receptors such as IGF-IR, promoting resistance to
Trastuzumab."(Nahta 2006). </span><o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="background: white; color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">Trastuzumab
resistance is a major problem, and understanding the biological and molecular
reasonings for this resistance is vital in finding a solution to this
resistance. There are some therapies, which tackle the problems stated above.
Firstly, there is Pertuzumab, which is similar to Trastuzumab in that it is
also a monoclonal antibody, and is a dimerization inhibitor. However,
Pertuzumab disrupts the interaction between IGF-IR and HER2 in Trastuzumab
resistant cells. Pertuzumab binds to domain I,II, and III, while Trastuzumab
binds to domain IV of the extracellular domain. While all this information is
promising there still seems to be a significant number of patients who become
resistant to Pertuzumab and Trastuzumab. The researchers believe that
downstream signaling may be causing the resistance. More research would be
needed in figuring out the mechanism by which cancer cells gain resistance to
Pertuzumab. </span><span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="color: black; mso-bidi-font-family: "Times New Roman";">As Trastuzumab resistance becomes a more important
issue, and as recent research strongly supports the role for Trastuzumab not only in
management of metastatic cancer but also as an adjuvant therapy in HER2
positive breast cancer. Detecting the molecular and biological
mechanisms that lead to Trastuzumab resistance is of vital importance. Not
until we find a therapy that specifically targets these mechanisms can we
produce a Trastuzumab therapy that lasts a sufficient amount of time.
<o:p></o:p></span></div>
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<br /></div>
<div class="MsoNormal">
<span style="mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">Sources:<o:p></o:p></span></div>
<div class="MsoNormal" style="background: white; line-height: 14.65pt; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto;">
<span style="color: black; mso-bidi-font-family: Arial; mso-fareast-font-family: "Times New Roman";">Hudis, Clifford A.
"Trastuzumab — Mechanism of Action and Use in Clinical Practice." New
England Journal of Medicine 357.1 (2007): 39-51. Web.<o:p></o:p></span></div>
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<span style="color: black; mso-bidi-font-family: Arial; mso-fareast-font-family: "Times New Roman";">Nahta, Rita. Esteva, Francisco. “HER2
therapy: </span><span style="mso-bidi-font-family: Arial; mso-fareast-font-family: "Times New Roman";">Molecular mechanisms of Trastuzumab resistance.”
Biomed Central Study. (2006):</span><span style="mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"> <a href="http://dx.doi.org/10.1186%2Fbcr1612"><span style="background: white; color: windowtext; mso-bidi-font-family: Arial; text-decoration: none; text-underline: none;">0.1186/bcr1612</span></a>. Web.<o:p></o:p></span></div>
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Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-82755516542932838842014-06-07T21:22:00.002-07:002014-06-07T21:24:31.815-07:00Cholesterol and Cancer Inhibition<br />
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<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 150%;">For
our project, Matt and I focused on cholesterol and its metabolite’s promoting
effects on breast cancer. However, as
Matt mentioned in our presentation, there is a tumor suppressing metabolite of
cholesterol. It is still very much in
the works, but research seems to support the suppression of this metabolite,
called Dendrogenin A (DDA). This
molecule is an <a href="http://physrev.physiology.org/content/80/1/361">amino-oxysterol</a>
metabolite that “arises from cholesterol-5,6-epoxides and histamine in mammals”
(Silvente-Poirot). Very little is
actually known about this molecule and its inhibitive abilities, and a Google
search turned up this study and one other that identified DDA as a product of
cholesterol. It has recently been
discovered to be a natural metabolite occurring in mammals, having been previously
synthesized synthetically. The fact that
this molecule may be a successful inhibitor of cancer makes it very
exciting. The fact that it is naturally occurring
makes it even better. <o:p></o:p></span></div>
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<span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">What was very cool about this
molecule is that in vitro, DDA was able to induce cell differentiation and
eventually death(Medina).</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">As a result,
the researchers decided to test this result in mice.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">They took mice with functioning immune
systems and infected(grafred) them with either mammary tumors, or
melanoma.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">The same day they were treated
with DDA or the vehicle control(Medina).</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">
</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">The results were incredible.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">In
Figure 1 A,C,E, and F, we can see that the tumor suppression brought about by
DDA are great.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">Each treatment with DDA
shows the least amount of growth in the differing systems (which mainly meant
the type of cells used to grow the tumors were different).</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">When analyzing the two Kaplin-meyer plots, we
see that the mice injected with DDA show a greater mean survival rate, doing
considerably better than those treated with the vehicle (Figure 1 B and D).</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">Also, those mice injected with 0.37 ug/kg of
DDA did a little better than those injected with 0.037 ug/kg DDA, a seemingly
minor point that will lead to eventual dosing calculations.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">Later on in the paper, they discuss how this
may be due to the immune response to cells containing higher levels of
DDA.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;">They believe this is the result of
DDA somehow allowing the immune system to recognize the tumors better and eradicate
them from the body (Medina).</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span></div>
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<tr><td style="text-align: center;"><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674249/bin/ncomms2835-f4.jpg" imageanchor="1" style="clear: right; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img alt="An external file that holds a picture, illustration, etc.
Object name is ncomms2835-f4.jpg" border="0" src="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674249/bin/ncomms2835-f4.jpg" height="246" style="font-family: 'Times New Roman', serif; font-size: 16px;" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="font-size: 13px; text-align: center;"><strong style="background-color: white; font-family: 'Times New Roman', serif; font-size: 16px; line-height: 21.998762130737305px; text-align: left;">Figure 1: DDA inhibited the growth of B16F10 melanoma and TS/A mammary tumours implanted into immunocompetent mice and enhanced animal survival.</strong><br />
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Immunocompetent mice were implanted s.c. with (<strong>a</strong>) B16F10 cells or (<strong>b</strong>,<strong>c</strong>) TS/A cells and animals (<em>n</em>=10<img alt=" " border="0" src="http://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcents/x2009.gif" style="border: 0px; max-width: 100%;" title="" />mice per group) were treated every 5 days starting on the day of tumour implantation with the indicated doses of either dacarbazine (intraperitoneally (i.p.)), DDA (s.c.), C17 (s.c.), vehicle (s.c.) or Tam (i.p.). Animals were monitored for tumour growth (<strong>a</strong>,<strong>c</strong>), *<em>P</em><0.05; **<em>P</em><0.01 (analysis of variance (ANOVA), Dunnett’s post test), and survival (<strong>b</strong>,<strong>d</strong>), *<em>P</em><0.05; ***<em>P</em><0.0001 (log-rank tests). Immunocompetent mice were implanted s.c. with (<strong>e</strong>) B16F10 cells or (<strong>f</strong>) TS/A cells, and when the tumour reached a volume of 50–100<img alt=" " border="0" src="http://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcents/x2009.gif" style="border: 0px; max-width: 100%;" title="" />mm<span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, animals (<em>n</em>=10<img alt=" " border="0" src="http://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcents/x2009.gif" style="border: 0px; max-width: 100%;" title="" />mice per group) were treated once per day with the indicated doses of dacarbazine (i.p.), DDA (s.c.), C17 (s.c.), vehicle (s.c.) or Tam (i.p.) and were monitored over time for tumour growth, *<em>P</em><0.05; **<em>P</em><0.01 (ANOVA, Dunnett’s post tests). The mean tumour volume±s.e.m is shown. The data are representative of three independent experiments.</div>
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<span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 150%;"> </span></div>
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<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 150%;">Now this information is very
interesting, but the best part of this development is its usefulness to the
treatment of all cancers. The anti-tumor
abilities have already been applied to two very different cancers, showing inhibiting
effects. This gives researchers great
hope that this may help in many different cancers as well. And the fact that it is naturally occurring is
very big as well. So now the research will
focus on finding a way to boost the levels of DDA in the tumor cells safely and
effectively. Then they have to see if
these changes in body chemistry happen to cause any adverse side effects. With the many side effects of the current
treatments, it seems as though it is a possibility. However, I feel that the fact that it
naturally occurs in the body, it would not have as many side effects as seen by
other drugs. If this is able to be done,
theoretically it could help to treat many different forms of cancer. This research is very new and is still only
in the early stages of mouse testing. I
feel that in a couple of years, we will see this DDA research being applied to
clinical trials. The multi-cancer
treatability of this molecule will make it a goldmine for drug companies. It is the treatment of the future. </span></div>
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<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"><b>Works
Cited </b><o:p></o:p></span></div>
<div class="MsoListParagraphCxSpFirst" style="margin-left: 39.35pt; mso-add-space: auto; mso-list: l0 level1 lfo1; text-align: justify; text-indent: -.25in;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%; mso-fareast-font-family: "Times New Roman";">1.<span style="font-family: 'Times New Roman'; font-size: 7pt; line-height: normal;"> </span></span><span lang="EN-US" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;">Medina, Philippe De, Michael R. Paillasse, Gregory Segala, Maud
Voisin, Loubna Mhamdi, Florence Dalenc, Magali Lacroix-Triki, Thomas Filleron,
Frederic Pont, Talal Al Saati, Christophe Morisseau, Bruce D. Hammock, Sandrine
Silvente-Poirot, and Marc Poirot. "Dendrogenin A Arises from Cholesterol
and Histamine Metabolism and Shows Cell Differentiation and Anti-tumour
Properties."<span class="apple-converted-space"> </span></span><i style="box-sizing: border-box; text-align: start;">Nature Communications</i><span class="apple-converted-space"><span style="background-color: rgba(255, 255, 255, 0.0980392); text-align: start;"> </span>4 (2013): 1840. Web.</span><span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"><o:p></o:p></span></div>
<br />
<div class="MsoListParagraphCxSpLast" style="margin-left: 39.35pt; mso-add-space: auto; mso-list: l0 level1 lfo1; text-align: justify; text-indent: -.25in;">
<!--[if !supportLists]--><span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%; mso-fareast-font-family: "Times New Roman";">2.<span style="font-family: 'Times New Roman'; font-size: 7pt; line-height: normal;"> </span></span><span lang="EN-US" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;">Silvente-Poirot, S., and M. Poirot. "Cholesterol and Cancer,
in the Balance."<span class="apple-converted-space"> </span></span><i style="box-sizing: border-box; text-align: start;">Science</i><span class="apple-converted-space"><span style="background-color: rgba(255, 255, 255, 0.0980392); text-align: start;"> </span>343.6178 (2014): 1445-446. Web.</span><span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"><o:p></o:p></span></div>
Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-3496758970740230492014-06-07T14:58:00.001-07:002014-06-11T10:52:15.457-07:00We Are All MutantMel Greaves' <a href="http://www.nature.com/nrc/journal/v14/n4/full/nrc3703.html#ref-link-6" target="_blank">article</a> "Does everyone develop covert cancer?" discusses that while around 1 in 3 individuals will develop overt cancer, there is increasing evidence that most, if not all, people in their lifetimes develop covert cancer. Greaves begins by defining covert cancer as cancer that is "hidden and subclinical" but that can be "uncovered by more incisive interrogation," as opposed to overt cancer, or full-blown, malignant growths or tumors. The evidence for these covert cancers is primarily gathered from autopsies of individuals who died for non-cancerous reasons. Most autopsy reports show a substantially higher frequency of pre-malignant lesions, or carcinoma <i>in situ</i> (CIS), than of clinical cancer frequencies or cumulative life-time risk of developing overt cancer. This suggests a much higher frequency of CIS than is commonly believed or recorded.<br />
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<tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-U-Bfg--FNCE/U5OB_r3wewI/AAAAAAAAACQ/BEV-qZTG7P4/s1600/Screen+Shot+2014-06-07+at+2.19.18+PM.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://4.bp.blogspot.com/-U-Bfg--FNCE/U5OB_r3wewI/AAAAAAAAACQ/BEV-qZTG7P4/s1600/Screen+Shot+2014-06-07+at+2.19.18+PM.png" height="313" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 1. Average incidence of cancer by age.</b></td></tr>
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We discussed this graph in class numerous times. It is widely accepted that the risk of overt cancer increases with age; this figure clearly depicts that. However, it can be asserted that the risk of covert cancer increases with age as well. As many as 1 in 5 newborns have covert, pre-malignant cancer. If the rates of CIS are this high in individuals at birth, then it is not much of a stretch to think that most people develop CIS in their lifetime.</div>
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Upon looking at mutation rates of DNA, the high frequency of CIS is unsurprising. DNA is extremely vulnerable to error-prone replication and damage, and it often "lacks perfect fidelity of repair" (Greaves). Couple that with the immense number of cells replicated per day, and the numbers are in favor of CIS. Our bone marrow and intestinal epithelia produce <span style="font-family: Times, 'Times New Roman', serif;">10</span><span style="font-family: Times, 'Times New Roman', serif; vertical-align: 3pt;"><span style="font-size: xx-small;">11 </span></span>cells per day, and mutation rates average around<span style="font-family: Times, Times New Roman, serif;"> 10<span style="font-size: xx-small;"><span style="vertical-align: 3pt;">−</span><span style="vertical-align: 3pt;">8</span></span>–10<span style="font-size: xx-small;"><span style="vertical-align: 3pt;">−</span><span style="vertical-align: 3pt;">9</span></span> </span>per base pair per cell cycle (Greaves), so it is inevitable that mutations arise. </div>
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In addition to these natural functions, our bodies are constantly surrounded by environmental factors that are "mismatched with our genetic heritage" (Greaves). Exposure to carcinogenic tar from tobacco, excessive UV rays, and persistent hormonal drive due to early pregnancy and prolonged breastfeeding are unnatural, and hugely increase DNA mutation rates .</div>
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With that, we can assume that mutations naturally arise all the time due to endogenous processes and exogenous influences. Longer lifespans caused by increased technology and medical care provide more time for these mutations to occur. </div>
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An issue with this high prevalence of CIS is how to differentiate the ones that have a higher propensity for developing into malignant cancers that merit higher degrees of intervention. A measure that is currently being used is limiting the progressive ability of the CIS, with the help of non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs have been found to reduce the risk of overt cancer very effectively. It is ironic that the most effective way to prevent overt cancer from forming is with the use of the most common household drug, aspirin. </div>
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I found this article to be very thought-provoking. Everyday you hear of another thing that purportedly increases our risk of cancer. With so many negative environmental factors that we come in contact with everyday, it is not surprising that CIS is so common. It is something that everyone should be aware of, although it is not something that everyone should fear. I think this article was a little dramatic in this way. Yes, CIS is very common, but oftentimes there is very little associated risk. I would have appreciated more data on the numbers of CIS that develop into overt cancer; I would assume these numbers to be relatively low. Overall, though, I think this article raised good points and presented logical data for the topic.</div>
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<span style="font-family: Times, Times New Roman, serif;"><u>Source:</u></span><br />
<span style="font-family: Times, Times New Roman, serif;"><span style="background-color: rgba(255, 255, 255, 0.0980392); line-height: 24px; text-indent: -40px;">Greaves, Mel. "Does Everyone Develop Covert Cancer?" </span><i style="box-sizing: border-box; line-height: 24px; text-indent: -40px;">Nature.com</i><span style="background-color: rgba(255, 255, 255, 0.0980392); line-height: 24px; text-indent: -40px;">. Nature Publishing Group, 13 Mar. 2014. Web.</span></span>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-34284126823078573122014-06-07T12:41:00.002-07:002014-06-07T12:41:16.444-07:00Panitumumab versus Cetuximab - Treatment in Metastatic Colorectal CancerThroughout all our research about anti-EGFR treatment in metastatic colorectal cancer, my partner Tien Lu and I often discovered panitumumab and cetuximab as main-line therapies (More in our <a href="http://islaslab.wikispaces.com/The+Effect+of+KRAS+Mutations+on+Anti-EGFR+Therapies">wiki</a>). Both of these drugs are anti-EGFR treatments. EGFR is the epidermal growth factor receptor, which contains many pathways that lead to cell proliferation and survival. Therefore, it is no surprise EGFR as been important in the study of cancer, as malfunction in its pathways can lead to uncontrollable cell growth, differentiation, and migration. Typically, EGFR ligands bind to the EGFR cell surface receptor to induce cell signaling down the pathway, leading to cell replication. Monoclonal antibodies are anti-EGFR treatment, and bind to the EGFR receptor instead, blocking the downstream signaling and stopping cell proliferation.<br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_WvK7ubNcvG9JvMiuMGCwalZ2fh_LqyP6ClUgbNTYS_KI2Hq3wE5UHTa8F885UCQYk6pDbbUSmycb0pxynAYlEpEhfoJQr322FqeEMSrgno7dgrOmwIEjFG1wcEt8oYcrbZkMcpguYfrm/s1600/F1.medium.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_WvK7ubNcvG9JvMiuMGCwalZ2fh_LqyP6ClUgbNTYS_KI2Hq3wE5UHTa8F885UCQYk6pDbbUSmycb0pxynAYlEpEhfoJQr322FqeEMSrgno7dgrOmwIEjFG1wcEt8oYcrbZkMcpguYfrm/s1600/F1.medium.gif" height="284" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure 1. Similarity in anti-EGFR treatments in disrupting MAP Kinase pathway.</td></tr>
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Figure 1 illustrates the mechanism of the anti-EGFR drugs cetuximab and panitumumab. The pathways affected by the drugs are highlighted in red. In fact, panitumumab and cetuximab use the same mechanism and are virtually interchangeable. Both can bind to either EGFR receptor and inhibit the downstream signaling. Despite the same mechanisms used by cetuximab and panitumumab, a trial showed that patients given both drugs acquired resistance to cetuximab first (Bardelli, et al. 2010). Interestingly, when cetuximab resistance was found after prolonged exposure to the drugs, panitumumab still retained some function. However, this does not lead to panitumumab being a more effective drug because similar resistance can occur in Panitumumab first (Helwick, et al. 2013).<br />
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Furthermore, there was a phase 3 <a href="http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70118-4/abstract">study</a> conducted to determine if there was a difference between cetuximab and panitumumab on KRAS wild-type patients with metastatic colorectal cancer. As my partner and I noted in our <a href="http://islaslab.wikispaces.com/The+Effect+of+KRAS+Mutations+on+Anti-EGFR+Therapies">wiki</a>, KRAS mutations can have negative impact on anti-EGFR therapy, so all participating patients were wild-type KRAS. All 999 patients that were part of the final analysis had chemotherapy-refractory cancer. 499 patients received panitumumab and 500 received cetuximab. The primary analysis was overall survival, defined as the percentage of surviving patients from the start of treatment onward.<br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiD22zi0xJeaSYSQxweJnsHNO7T3pwKsB6z1cw4Dw1BTa1r7M9CYBxfQggztOT-QSRbXyh9XomX5jyo14bMM3UI62gaizOXQtYXI9uKWR0oSPi5QtCvm1JFN9qj2LyZGsxj1EqvxLdpQ9eq/s1600/PvsCmab.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiD22zi0xJeaSYSQxweJnsHNO7T3pwKsB6z1cw4Dw1BTa1r7M9CYBxfQggztOT-QSRbXyh9XomX5jyo14bMM3UI62gaizOXQtYXI9uKWR0oSPi5QtCvm1JFN9qj2LyZGsxj1EqvxLdpQ9eq/s1600/PvsCmab.jpg" height="183" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure 2. Kaplan-Meier plot of overall survival by treatment group.</td></tr>
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In the study, the median overall survival was 10.4 months for panitumumab and 10 months for cetuximab (95% CI). The researchers concluded that there is no significant difference in panitumumab and cetuximab treatment. Therefore doctors do not have a particular drug that should be favored over the other when prescribing an intervention for a patient with metastatic colorectal cancer. Going forward it may be best to give patients a cocktail of the two drugs, in case resistance is acquired in one.<span style="background-color: white;"> Or, as is more common, give the drugs in sequential order; prescribing the other drug when resistance is acquired in the first. </span><br />
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However, it is worth noting that panitumumab is given in 7 doses versus the 14 doses for cetuximab in the study.The minuscule difference in drug response may be attributed to the larger but less frequent doses of panitumumab having more efficacy. Regardless, the researchers concluded that the monoclonal antibody drugs are nearly identical in efficacy and safety (Price, et al. 2014). Yet the issue remains of how one drug's resistance does not occur simultaneously with the others (when the two are given together). If the monoclonal antibodies abide by the same mechanism, the discrepancy in resistance acquisition is possibly due to cetuximab and panitumumab binding to distinct epitopes. That is, the antibodies are binding to different antigen domains, leading to slightly different EGFR-binding capacities. Consequently, the EGFR-binding suppression occurs differently in the two drugs. Nevertheless this is only a hypothesis, and further work is being conducted to discover the difference in panitumumab (brand name Vectibix) and cetuximab (brand name Erbitux).<br />
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<u>References</u><br />
<div class="citation_text mla7" style="background: rgba(255, 255, 255, 0.0980392); box-sizing: border-box; font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; margin-left: 2.5em; margin-top: 5px; text-indent: -2.5em; word-wrap: break-word;">
"Journal of Clinical Oncology." <i style="box-sizing: border-box;">Molecular Mechanisms of Resistance to Cetuximab and Panitumumab in Colorectal Cancer</i>. Journal of Clinical Oncology, n.d. Web. 07 June 2014. http://jco.ascopubs.org/content/28/7/1254/T1.expansion.html</div>
<div class="citation_text mla7" style="background: rgba(255, 255, 255, 0.0980392); box-sizing: border-box; margin-left: 2.5em; margin-top: 5px; text-indent: -2.5em; word-wrap: break-word;">
<span style="font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -2.5em;">"About FDA." </span><i style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -2.5em;">Cetuximab (Erbitux) and Panitumumab (Vectibix)</i><span style="font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -2.5em;">. FDA, n.d. Web. 07 June 2014. </span><span style="background-color: transparent; line-height: 24px;"><span style="font-family: Times New Roman, Times, serif;">http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm172905.htm</span></span></div>
<div class="citation_text mla7" style="background: rgba(255, 255, 255, 0.0980392); box-sizing: border-box; margin-left: 2.5em; margin-top: 5px; text-indent: -2.5em; word-wrap: break-word;">
<span style="font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -2.5em;">"Panitumumab versus Cetuximab in Patients with Chemotherapy-refractory Wild-type KRAS Exon 2 Metastatic Colorectal Cancer (ASPECCT): A Randomised, Multicentre, Open-label, Non-inferiority Phase 3 Study."</span><i style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -2.5em;">Panitumumab versus Cetuximab in Patients with Chemotherapy-refractory Wild-type KRAS Exon 2 Metastatic Colorectal Cancer (ASPECCT): A Randomised, Multicentre, Open-label, Non-inferiority Phase 3 Study : The Lancet Oncology</i><span style="font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -2.5em;">. The Lancet Oncology, n.d. Web. 07 June 2014. </span><span style="background-color: transparent; line-height: 24px;"><span style="font-family: Times New Roman, Times, serif;">http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70118-4/fulltext</span></span></div>
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Anonymoushttp://www.blogger.com/profile/03710620971265452062noreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-31783012004158247282014-06-06T19:28:00.001-07:002014-06-09T20:27:12.303-07:00Five or More Blistering Sunburns Before 20 Increases Melanoma Risk by 80%<div class="MsoNormal">
I thought this post would be particularly fitting with
summer right around the corner.</div>
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<br /></div>
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I was doing some reading and came across <a href="http://www.mdconnects.com/articles/1655/20140530/five-more-blistering-sunburns-before-age-20-increase-melanoma-risk.htm">this article</a>, which
summarized a study that examined the relationship between sun exposure (along
with some other risk factors) and the risk of different types of skin cancers.
In this study, researchers were able to follow 108,916 US women over 20 years and
determined that having five or more blistering sunburns between ages 15 and 20
resulted in an 80% increased risk for melanoma. Moreover, women in the same age
range had a 68% increased risk for basal cell carcinoma and squamous cell
carcinoma after having five or more blistering sunburns. </div>
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<a name='more'></a><br />
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At this point, you may be wondering how many blistering
sunburns you’ve had in the past five years—after all, an 80% increase in risk
for the skin cancer that accounts for the vast majority of skin cancer deaths
may sound downright terrifying (I was certainly shocked to hear the stat). If
you have had five or more blistering sunburns before 20, you may even feel
helpless after hearing this statistic. But not to worry, the risk might not be
as horrifying as statistical evidence makes it seem.</div>
<div class="separator" style="clear: both; text-align: center;">
<a href="http://4.bp.blogspot.com/-7NBuJZ3Wz1g/U5J34Ds5HYI/AAAAAAAAABA/eEa_ntFRNEI/s1600/Screen+Shot+2014-06-06+at+6.19.52+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-7NBuJZ3Wz1g/U5J34Ds5HYI/AAAAAAAAABA/eEa_ntFRNEI/s1600/Screen+Shot+2014-06-06+at+6.19.52+PM.png" height="240" width="400" /></a></div>
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The above graph from the American Cancer Society’s <i style="mso-bidi-font-style: normal;">Cancer Facts and Figures 2013</i> shows the
probability of developing invasive cancers over multiple age intervals. I have
drawn a red box around melanoma. Note that upon looking at the Birth to Death
group, males have a 2.87% chance of developing melanoma in their lifetime and
women have a 1.85% chance. That averages out to a little over 2%, meaning
people in general have slightly more than a 2% chance of developing melanoma.
When 5 or more blistering sunburns before 20 increases this chance by 80%, the
risk of melanoma isn’t even 5%. </div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
In closing, I think this article is a good example of how
statistical evidence can be blown out of proportion. Sure, there is an 80%
increased risk for melanoma after having 5 or more blistering sunburns before
20, but without the context of the probability for getting melanoma (which the
article doesn’t provide), the article makes it seem like 4 out of 5 people with
5 or more blistering sunburns will undoubtedly develop melanoma later in life. But
that’s obviously not the case. Even with the 80% increase, the chances of these
people getting melanoma are still extremely small, and it’s probably even
smaller if you’re not a part of a subset of individuals who have higher risks
of getting melanoma. A 5% risk might still be a little scary, but it certainly
isn’t as terrifying as 80%--that’s enough to make you never want to see the
light of day again. But that doesn’t mean you should avoid taking precautionary
measures against skin cancers. Just remember this: when you’re lying on a beach
somewhere this summer, take the time to use sunscreen and avoid blistering. The
odds will still be in your favor even if you’ve already had many blistering sunburns,
but you certainly don’t want to do anything that will ensure that at some point
in you’re life you become a part of that unfortunate 5%. </div>
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References</div>
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<span style="background: white; color: black; mso-bidi-font-size: 16.0pt;"><br /></span></div>
<div class="MsoNormal">
<span style="background: white; color: black; mso-bidi-font-size: 16.0pt;">"Cancer Facts & Figures 2013."</span><span style="color: black;"> </span><i style="mso-bidi-font-style: normal;"><span style="background: white; color: black; mso-bidi-font-size: 16.0pt;">Cancer Facts
& Figures 2013</span></i><span style="background: white; color: black; mso-bidi-font-size: 16.0pt;">. American CancerSociety, n.d. Web. 27 Feb. 2014.<http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cncer-facts-figures-2013>.</span><span style="mso-bidi-font-size: 10.0pt;"><o:p></o:p></span></div>
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<span style="color: black; mso-bidi-font-size: 16.0pt;"><br /></span></div>
<div class="MsoNormal">
<span style="color: black; mso-bidi-font-size: 16.0pt;">"Five
or More Blistering Sunburns before Age 20 May Increase Melanoma Risk by 80Percent."</span><span style="color: black;"> </span><i style="mso-bidi-font-style: normal;"><span style="color: black; mso-bidi-font-size: 16.0pt;">Mdconnects.com</span></i><span style="color: black; mso-bidi-font-size: 16.0pt;">. N.p., 30 May 2014. Web. 1 June
2014.<http://www.mdconnects.com/articles/1655/20140530/five-moreblistering-sunburns-before-age-20-increase-melanoma-risk.htm>.</span><span style="mso-bidi-font-size: 10.0pt;"><o:p></o:p></span></div>
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Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-62147110420202339132014-06-05T22:21:00.000-07:002014-06-09T20:22:54.603-07:00Cancer and Personalized Medicine<div class="MsoNormal" style="text-indent: .5in;">
If you recall we spent week five of
the course discussing the different treatments available for those who have
cancer. During the week, we discussed the three most common methods of
treatment, those being: surgical oncology, radiation therapy, and medical oncology.
Surgical oncology mainly takes place as a treatment in the form of a resection
of a solid tumor with wide margins to ensure complete removal. Radiation
oncology uses x-rays and carbon ions to directly damage DNA of the cancer cells
in hopes the damage will prevent continued growth. Lastly, we discussed medical
oncology, wherein we discussed chemotherapy. When we discuss personalized
medicine we are generally referring to changing the way in which we use medical
oncology.<br />
<a name='more'></a> </div>
<div class="MsoNormal" style="text-indent: .5in;">
Today if you are in the unfortunate
circumstance that you have cancer, the way in which you are treated for that
cancer doesn’t have a lot to do with who you are. It will vary depending on
what type of cancer you have, yes, but nothing to do with you as a person. The
doctor will give you the same treatment to those who have the same cancer, at
the same stage as you.<span style="mso-spacerun: yes;"> </span>This is due to
the precedents within the “standard of care” which involves finding and
administering the best treatment for the general population. For example,
pre-emptive measures for breast cancer include self-exams until age 40 when
mammograms become the standard and, if diagnosed, surgical oncology and medical
oncology (chemotherapy) are recommended. In many cases this standard of care
may be the safest, most sensible option. However, while you may have the same
type of cancer as the other patient in the waiting room, you are not the same
person as them, and this is what personalized medicine tries to focus on by
incorporating a person’s genetic makeup. </div>
<div class="MsoNormal" style="text-indent: .5in;">
At its core, personalized medicine
is an approach that emphasizes the ways in which your disease risks are unique
and different, based on the predispositions written into your genome at birth.
Its emphasis is then transcribed into an action of prevention, diagnosis, and
treatment that is very specifically designed for you. Because of the human
genome project we have identified every genome in the human sequence. This and
other advancements have made it so anyone can have their personal genomes
scanned and fully sequenced. These genetic tests could lead to successful
medical oncologic treatments (like drugs) rather than surgery. For example,
liver can be BRAF positive and if this is identified then you could take
sorafenib, an FDA approved drug by disabling the BRAF kinase domain. It
does this by preventing ATP from binding and, hence, locking the enzyme in its
active form. In a different case, cystic fibrosis patients have a mutation in
the CFTR gene. This causes the over secretion of mucus, impeding the lungs and
pancreas, leading to labored breathing and the pancreas’s inability to absorb
what it needs from food. Thanks to studies done on the CFTR gene, researchers
have found a mutation that’s found in 4% of cystic fibrosis patients. The mutation
is caused by the amino acid glycine (at 551) being replaced
with an aspartic acid. Specifically for G551D, the protein is brought to the
epithelial cell surface (the correct destination), but protein cannot transport
chloride through the ion channel. Ivacaftor promotes the transport of chloride
through the ion channel by binding to the channel, which increases the chance
that the ion channel remains open.</div>
<div class="MsoNormal" style="text-indent: .5in;">
In the method of prevention, I
think that the prime example stems from breast cancer. Those who are carriers
of a BRCA1 mutation are at a 65% risk of breast cancer and 39% of ovarian
cancer. Generally, it is not until after they find an anomaly in mammogram that
they test for the BRCA1 mutation. However, with the ease of testing now, if
testing for the BRCA1 mutation became apart of one’s first physical it could
warrant starting mammograms before the age of 40 and making them more frequent
than once a year. This would help to catch the breast lump as a carcinoma in
situ, providing a much better outcome for the patient in that he or she might
not need chemotherapy. </div>
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In the case of cancer, great
strides have come from the incorporation of genetics into medicine. We have
seen a couple cases in which genetic testing could be, and has been, used
helped to improve the outcomes of those who have taken the advantages of
personalized medicine. One of its pitfalls is that in a recent study by GfK (a
global research firm), only 4% of those questioned knew what Personalized medicine
was based on the definition “medicine based on genomic makeup”. In addition,
those that do know about its possible positives want to see evidence before you’re
willing to move away from the tried and true methods of treating cancer.</div>
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References:<o:p></o:p></div>
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<span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">McMullan, Dawn. "What Is Personalized Medicine?" <i>Genome</i> Spring
2014 (2014): 34-39. Web. 1 June 2014.<o:p></o:p></span></div>
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<span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">Morton, Carol C. "Dana-Farber/Harvard Cancer Center: The
Future of BRAF Inhibitors." <i>The Future of BRAF Inhibitors</i>.
Harvard University, n.d. Web. 1 June 2014.<o:p></o:p></span></div>
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<span style="color: black; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">Verma, Mukesh. "Personalized Medicine and Cancer." <i>Journal
of Personalized Medicine</i> 2.1 (2012): 1-14. Web.<o:p></o:p></span></div>
Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-13413022082757121682014-06-05T21:11:00.001-07:002014-06-05T21:11:32.415-07:00Will This Man Cure Cancer?While in the passenger seats of one of my housemates car, I picked up a Forbes magazine from the dashboard published in May 2014. The large block lettering on the cover read "WILL THIS MAN CURE CANCER?" below a picture of a professional looking man in a full suit. After spending ten weeks studying many different topics regarding cancer research, I wondered what this business/financial news based magazine was to say about curing cancer. The man on the cover is Joseph Jimenez, the CEO of Novartis, a Swiss pharmaceutical company.<br />
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<a href="http://2.bp.blogspot.com/-W8mhBHHMmQE/U5E9L12jZKI/AAAAAAAAADA/p8ifWiqszxk/s1600/imgres.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://2.bp.blogspot.com/-W8mhBHHMmQE/U5E9L12jZKI/AAAAAAAAADA/p8ifWiqszxk/s1600/imgres.jpg" height="48" width="200" /></a></div>
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Jimenez plans to "double down" on cancer related drugs by spending the majority of Novartis' budget on cancer therapies. According to Forbes, Jimenez is a man that should be listened to when it comes to making money. He transformed Gleevec(tyrosine-kinase inhibitor) from a 400 million dollar annual profit to a 4.5 billion dollar annual profit. The six page article begins by discussing the case of a five year old girl diagnosed with acute lymphoblastic leukemia(ALL). Today 85% of ALL patients are cured with FDA approved chemotherapeutic treatment. This particular young girl is part of the remaining 15% uncured patients. Her cancer returned while she was waiting for a bone marrow transplant. Oncologists decided to try a treatment in which they removed blood from the patient and passed it through a machine which removes white blood cells. They used a modified HIV virus to genetically reprogram those white bloods cells so they would attack cancer cells. I decided to further research this process of immunotherapy described without much detail in Forbes magazine. <br />
<a name='more'></a>The cornerstones of cancer treatment have developed from surgery, radiation and chemotherapy to targeted chemotherapeutic treatment and immunotherapy. Of course a combination of these therapies are still used to treat patients through the developing stages of cancer. The first approach to immunotherapy in early clinical trials has been Adoptive Cell Transfer(ACT). T-Cells are first collected from the patient and then genetically engineered to produce special receptors on their surface called chimeric antigen receptors(CAR's). CAR T-Cells are then infused back into the patients bloodstream to hopefully target and kill cancer cells that harbor the antigen on their surface. CARs allow T-Cells to recognize specific proteins on the surface of mutated B-cells. CAR T-Cells have only been used in clinical trials treating blood cancers so far. <br />
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A brief report published by the <a href="http://www.nejm.org/doi/full/10.1056/nejmoa1215134#t=article" target="_blank">New England Journal of Medicine</a> in April 2013 was one of the first to address the ability of CAR T-Cells to treat leukemia. The purpose of this trial was for CAR T-Cells to target the antigens CD19 and CD20. The two case reports in the article use the CART CTL019 to treat two children with refractory and relapsed ALL. The first patient while experiencing her second reoccurrence of ALL and no longer responding to intensive chemotherapy, had her peripheral blood mononuclear cells(PBMC) collected. The patients was then infused with CTL019 cells with anti-CD3 and anti-CD28 antibodies to express anti-CD19 CARs. No related toxic effects were recorded. Patient 2 was treated with the same process. <br />
<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="http://2.bp.blogspot.com/-IwX2SL-ttyc/U4_w2H_otmI/AAAAAAAAACw/sjlwgDYTYiQ/s1600/Screen+Shot+2014-06-04+at+9.23.14+PM.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" src="http://2.bp.blogspot.com/-IwX2SL-ttyc/U4_w2H_otmI/AAAAAAAAACw/sjlwgDYTYiQ/s1600/Screen+Shot+2014-06-04+at+9.23.14+PM.png" height="292" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table 1:Induction of Molecular Remission in Blood and Bone Marrow. </td></tr>
</tbody></table>
As noted in Table 1 from this case study, remission of leukemia was measured 1 month after infusion in both patients. These results were confirmed by molecular detection of clonal IGH by a deep sequencing process. The diagnosis of leukemia and other B-Cell malignancies can be frequently detected by clonal immunoglobin heavy chain gene arrangements. These IGH's were detected in this experiment through polymerase chain reaction (PCR) amplification. Seen in both patients, is a decrease in IGH total reads and unique reads.<br />
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Immunotherapy cancer treatment protocols like the ones presented in these two case studies absolutely need further research and confirmation before FDA approval. Remissions were sustained in one patient while one patient experienced a relapse due to the emergence of CD-19 blasts. On the brighter side, the induction of complete remission in refractory CD-19+ ALL after infusion CAR T-Cell is very encouraging and leading the way for similar experiments done in 2014 and the future. <br />
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Work Cited<br />
<span style="font-size: x-small;"> <span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;">Gruppe, Stephan. "Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia — NEJM." </span><i style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;">New England Journal of Medicine</i><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;">. N.p., 18 Apr. 2013. Web. 06 June 2014. </span></span><br />
<span style="font-size: x-small;"><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;"><br /></span></span>
<span style="font-size: x-small;"><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;">"CAR T-Cell Immunotherapy for ALL." </span><i style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;">National Cancer Institute</i><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;">. N.p., 6 Dec. 2013. Web. 06 June 2014. </span></span><br />
<span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;"><span style="font-size: x-small;"><br /></span></span>
<span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; line-height: 24px; text-indent: -40px;"><span style="font-size: x-small;">"Novartis Highlights Research on Investigational, Personalized T Cell Therapy CTL019 in Patients with Forms of Acute and Chronic Leukemia." Novartis, 17 Dec. 2013. Web. 06 June 2014. </span></span><br />
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Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-81037346318767159182014-06-05T08:57:00.001-07:002014-06-05T14:09:53.412-07:00AAC-11 Newly Linked to Cervical Cancer<b>Introduction</b> <br />
Researchers have found a new genetic link to the development of metastatic cervical cancer. <a href="http://www.nature.com/labinvest/journal/v80/n4/full/3780063a.html" target="_blank">This article</a> discusses how the overexpression of the gene AAC-11 leads to the production of other proteins that induce anti-apoptosis effects in the cell. The researchers found that levels of expression of AAC-11 were low in normal cervical tissue as well as cervical tissue that is in the early stages of becoming cancerous. The levels of AAC-11 increased by 200 to 400% in cervical cancer that had invaded regional lymph nodes or became metastatic (1). This indicates that AAC-11 is not the primary mutation that leads to the development of cervical cancer; rather, it is a mutation that occurs after the cancer develops but aids the progression by inhibiting apoptosis.<br />
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<a name='more'></a><br />
<b>The Raw Data</b><br />
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<a href="http://1.bp.blogspot.com/-uu3lZbz7lNo/U4-qOD-qM3I/AAAAAAAAACE/uY6gQLZWAyA/s1600/AAC+11+Cell+Survival.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-uu3lZbz7lNo/U4-qOD-qM3I/AAAAAAAAACE/uY6gQLZWAyA/s1600/AAC+11+Cell+Survival.jpg" height="241" width="320" /></a></div>
<b> </b>This graph demonstrates the increased survival in the cells that over-express the AAC-11 gene, denoted in the figure as "AAC-11." The cells over-expressing this gene were able to survive about two times longer than normal cells, "wild type" and cells treated with just the vector used to transfer the AAC-11, denoted as "pCR3-Uni." This indicates that the cells expressing high levels of AAC-11 are able to evade apoptosis either by ignoring the environmental signals to undergo apoptosis, or by constantly producing signals to proliferate, regardless of the environment. Both of these processes are linked to molecules controlled by the transcription of AAC-11.<br />
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<a href="http://3.bp.blogspot.com/-bhv9eRi3XC8/U4-sK_VKjNI/AAAAAAAAACQ/kMH4T9LVtG0/s1600/AAC+11+MMP+Levels.jpg" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img border="0" src="http://3.bp.blogspot.com/-bhv9eRi3XC8/U4-sK_VKjNI/AAAAAAAAACQ/kMH4T9LVtG0/s1600/AAC+11+MMP+Levels.jpg" height="133" width="320" /></a></div>
The figure at the right measures the concentration of each protein. Lane 3 represents the cells that over-express AAC-11 while lanes 1 and 2 are both controls. It is shown that in cells with high levels of AAC-11, MMP-2 and MT1-MMP are both over-expressed while TIMP-2 is down-regulated. MMP's are a class of proteins that are involved in the cleavage of
cell-surface receptors, indicating that they could be involved in
reducing the response to apoptotic signals by eliminating the receptors
that would normally respond to these signals. TIMP is a protein that deactivates MMP's. Therefore, when TIMP is not expressed,
MMP's are able to cleave cell surface receptors without any regulation (2). The research team claimed that the levels of Beta-actin were elevated in cells that expressed high levels of AAC-11 as well. However, I do not see any significant difference in the expression of Beta-actin in the figure, nor in any other test that was performed by the team. It would be logical if Beta-actin were expressed in higher concentrations in these cancerous cells because it is involved in the up-regulation of DNA transcription which is necessary in cancerous cells.<br />
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<b>Conclusion</b><br />
The over-expression of AAC-11 clearly leads to increased MMP levels as well as decreased TIMP levels. Together, these 2 events could lead to resistance to apoptosis because the cell would no longer receive extra-cellular signals which would tell it to either undergo apoptosis or stop proliferation. I find it interesting that AAC-11 was expressed at normal levels in the primary stages of cancer, because I would think that the cell would need to resist apoptosis signals throughout the entire pathway to becoming cancerous. However, I do believe that the protein products of this gene would be viable targets for drugs that would be designed to inhibit that metastasis of already confirmed cervical cancer. <br />
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<b>References</b><br />
1. Kim, Jin Woo, Hyun Suk Cho, Jeong Hyun Kim, Soo Young Hur, Tae Eung Kim,
Joon Mo Lee, In-Kyung Kim, and Sung Eun Namkoong. "AAC-11
Overexpression Induces Invasion and Protects Cervical Cancer Cells from
Apoptosis." <i>Laboratory Investigation</i> (n.d.): n. pag. Web. 3 June 2014.<br />
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2. Nagase, Hideaki, Robert Visse, and Gillian Murphy. "Structure and Function of Matirix Metalloproteinases and TIMPs." <i>Cardiovascular Research</i> (2006): n. pag. Web<b> </b>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-29903008355158092922014-06-03T15:34:00.000-07:002014-06-03T15:34:27.841-07:00Telomerase Peptide Vaccine Tested in Pancreatic Cancer Patients<span style="font-family: Times, Times New Roman, serif;">Telomerase is expressed in 80-95% of cases of pancreatic cancer making it a viable target for cancer therapies. It follows that a Norwegian study explored the creation of a telomerase peptide vaccine for research subjects with non-resectable (inoperable) pancreatic cancer. This study was a combined phase I and phase II trial aimed at discovering the proper dosage of the vaccine and its efficacy by measuring its safety, tolerability, and immunogenicity, as well as patient survival. The peptide chosen for this vaccine, GV1001 is a "promiscuous <a href="http://en.wikipedia.org/wiki/Human_leukocyte_antigen" target="_blank">HLA</a> (human leukocyte antigen) class II epitope", meaning that it is the part of an antigen that the immune system recognizes and binds in a nonspecific manner to HLA molecules.</span><br />
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<a name='more'></a>
<span style="font-family: Times, Times New Roman, serif;">48 patients were randomly assigned to one of three treatment groups: low, intermediate, and high vaccine dosage. While all patients were used for safety analysis, only those who received at least 6 injections over a four week period were considered for the evaluation of immunogenicity and survival. As a measure of safety and toxicity, patients were monitored for adverse reactions during and after receiving their vaccine injection. Immune response was measured by delayed-type hypersensitivity (DTH) skin test—DTH is an injury of one's tissue caused by the body's mounting of a T cell mediated defense. T cell response was also monitored via proliferation assays of Acid Citrate Dextrose-blood samples.</span><br />
<span style="font-family: Times, Times New Roman, serif;"><br /></span>
<span style="font-family: Times, Times New Roman, serif;">None of the 48 patients showed any signs of toxicity or a particularly severe reaction to the injection. However, every one of the patients were found to have signs of inflammation at the injection site. Observed side effects included <span style="background-color: white;">fever in 2</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">% of patients,</span><span style="background-color: white;"> chills in 10</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">%</span><span style="background-color: white;">, pain in 6</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">%</span><span style="background-color: white;">, fatigue in 2</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">%,</span><span style="background-color: white;"> nausea in 12</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">%</span><span style="background-color: white;">, and vomiting in 2</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">%</span><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">. Interestingly, when separated by dose, the low dose group had the highest frequency of such adverse events at 45% of patients, followed by the intermediate group (41%), and then the high dose group with only 10%. Just looking at the number of adverse effects, the intermediate group had approximately four times more than either of the the other groups. This pattern could be partially explained by a sort of culmination effect—the intermediate group received more injections and was followed over a longer period of time.</span></span><br />
<span style="font-family: Times, Times New Roman, serif;"><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;"><br /></span></span>
<span style="font-family: Times, Times New Roman, serif;"><span class="mb" style="background-attachment: initial !important; background-clip: initial !important; background-color: white; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; display: inline !important; padding: 0px !important; visibility: visible !important;">Patients that tested positive for DTH or were found to have </span><span style="background-color: white;">GV1001-specific T cells in their assayed blood samples were </span><span style="background-color: white;">considered immune responders. The intermediate dose group showed the most promising results with the highest proportion of immune responders—75% of evaluable patients in that group (Figure 1A). This group also developed immune responses faster, stronger, and more often than either of the other dose groups.</span></span><br />
<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://www.nature.com/bjc/journal/v95/n11/images/6603437f2.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://www.nature.com/bjc/journal/v95/n11/images/6603437f2.jpg" height="320" width="282" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: Verdana, sans-serif; font-size: xx-small;"><span style="background-color: #f6f6f9; text-align: left;">Figure 1. Type and percentage of immune responders in patients vaccinated with low, intermediate, and high dose GV1001 (</span><b style="background-color: #f6f6f9; text-align: left;">A</b><span style="background-color: #f6f6f9; text-align: left;">) and kinetics of immune responses in the three dose groups, as measured by DTH response (</span><b style="background-color: #f6f6f9; text-align: left;">B</b><span style="background-color: #f6f6f9; text-align: left;">). Bars show accumulated responses in each group</span></span></td></tr>
</tbody></table>
<span style="font-family: Times, Times New Roman, serif;"><span style="background-color: white;">Although patient survival was not the main focus of this study, the r</span>esearch participants were followed after the end of the vaccination testing period to look for a possible survival benefit of the treatment. The intermediate treatment was found to have a significant positive effect on survival time with a <span style="background-color: white;">median survival time of 8.6 months, compared to 4.0 months for the low dose and 5.1 months for the high dose (Figure 2A). When the data is stratified by immune response, immune responders were found to have a median survival 4.3 months longer than non-responders (Figure 2B).</span></span><br />
<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="http://www.nature.com/bjc/journal/v95/n11/images/6603437f7.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://www.nature.com/bjc/journal/v95/n11/images/6603437f7.gif" height="292" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;"><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">Figure 2. (</span><b style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">A</b><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">) Survival (Kaplan–Meier plot) of the evaluable patients treated with different doses of GV1001. Median survival (95% conf. int.): Low-dose group (</span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">n</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=8); 119 days (31–190), intermediate dose group (</span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">n</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=16); 260 days (133–337), and high-dose group (</span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">n</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=14); 153 days (106–249). Intermediate </span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">vs</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;"> low dose; </span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">P</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=0.006, intermediate </span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">vs</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;"> high dose; </span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">P</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=0.05 (log-rank). (</span><b style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">B</b><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">) Survival (Kaplan–Meier plot) of all immune responders (</span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">n</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=24) </span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">vs</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;"> all non-responders (</span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">n</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=14) in the whole evaluable study population. Median survival (95% confidenCe interval) was; 216 days (146–323) for the immune responders and 88 days (53–190) for the non-responders. </span><i style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">P</i><span style="background-color: #f6f6f9; font-family: Verdana, arial, Helvetica, sans-serif; text-align: left;">=0.0001 (log-rank).</span></span></td></tr>
</tbody></table>
<span style="font-family: Times, Times New Roman, serif;">It is encouraging that the vaccine was found to be so safe and without major physiological side effects and the finding of increased survival time is promising. The correlation between increased survival time and mounting of an immune response seems intuitive as patients who were non-responders would be less able to fight off or recover from any sort of infection or other diseased state. I would be curious to know the other treatments that patients received post vaccination (if any), as the research article failed to note these details. Without knowing more about their medical history and ongoing treatment regimen, one cannot tease out if the survival is more likely attributable to the vaccinations or something else. </span><br />
<span style="font-family: Times, Times New Roman, serif;"><br /></span>
<span style="font-family: Times, Times New Roman, serif;">Another thought going forward: given that GV10001 is a promiscuous epitope, it could be used in the creation of a broad spectrum cancer vaccine. The possibility of a cancer vaccine that works on multiple types of cancer is really exciting and seems an efficient focus for researchers of cancer therapies.</span><br />
<br />
<br />
<span style="background-color: white; color: #555555; font-family: myriad-pro, 'Myriad Pro', Verdana, Arial, Helvetica, Tahoma, sans-serif; font-size: 12px; line-height: 12px;">S L Bernhardt, M K Gjertsen, S Trachsel, M Møller, J A Eriksen, M Meo, T Buanes, et al. (2006). Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I&sol;II study. </span><i style="background-color: white; color: #555555; font-family: myriad-pro, 'Myriad Pro', Verdana, Arial, Helvetica, Tahoma, sans-serif; font-size: 12px; line-height: 12px;">British Journal of Cancer</i><span style="background-color: white; color: #555555; font-family: myriad-pro, 'Myriad Pro', Verdana, Arial, Helvetica, Tahoma, sans-serif; font-size: 12px; line-height: 12px;">. doi:10.1038/sj.bjc.6603437</span>Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-78633949362843788162014-06-02T20:26:00.000-07:002014-06-02T20:26:52.796-07:00Further Hindrance in CTC measurement<br />
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<a href="https://www.blogger.com/" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a> <a href="http://islaslab.blogspot.com/2014/05/delving-further-into-circulating-tumor.html" target="_blank">My partner’s previous post</a> illustrated several issues which
might change the number of detected CTCs in the bloodstream. While the study of
CTCs holds many possibilities, my partner made a fair point to discuss that
they have a fair number of limitations. One such limitation that he described
was entrapment, in which CTCs sometimes get clogged within the capillaries,
causing them to be underrepresented in blood samples. In my research I also stumbled
upon similar phenomena in which the rate of CTC flow seemed to fluctuate. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980600/" target="_blank">One particular study</a> looked into the rate of CTC flow in both large and small blood
vessels for both melanoma and breast cancer. The figures below display the
results for these tests.</div>
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<tr><td style="text-align: center;"><img 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" style="margin-left: auto; margin-right: auto;" /></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><div align="left" style="border-image: none;">
<a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><span style="font-size: x-small;"><strong>Figure 1.</strong> CTC Rate in Large Blood Vessels. CTCs were continuously monitored by PAFC in 150-250<span style="font-family: "Calibri","sans-serif";"> μm </span>diameter blood vessels of mice with the primary melanoma tumor in the flank. Graph a represents a 20 minute observation of the CTC rate at week 1 after inoculation. Graph b represents a 20 minute observation at week 2 after inoculation. The yellow squares highlight periods of CTC absence in the detection area.</span></div>
</td></tr>
</tbody></table>
</div>
<div style="border-image: none; clear: both; text-align: left;">
In this test, a set of mice was inoculated with melanoma cells
in the flank in order to quickly develop metastatic skin melanoma. The CTCs
were then periodically monitored by PA flow cytometry (PAFC) for 20 minutes in large
blood vessels in the skin (150-250 <span style="font-family: "Calibri","sans-serif";">μm
</span>in diameter). The figure above displays a rather curious outcome. The
rate of CTCs appears to fluctuate wildly. In the observations after the first
week, the CTC rate rose to their maximum at 6 CTCs per minute within 6 minutes
and then quickly fell to 1 CTC per minute and remained at that level until the
end of the 20 minute mark. Furthermore, there were several gaps in which the
blood flow was CTC free for 1 to 3 minutes at a time. The rate also fluctuated
at week 2 after inoculation. After 8 minutes, the CTC rate rose to its maximum
level at 9 CTCs per minute, but then gradually decreased over the 20 minutes.
Furthermore, while not as pronounced as the first week, there were also 3 CTC
free gaps observed in the second week. Each of them was only 1 minute long.</div>
<div style="border-image: none;">
<br /></div>
</div>
<div style="border-image: none; margin: 0in 0in 0pt;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><img 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+tn9AUGZ6iUqVGujDBReXnn9OnTrdLQO/BKQ3myZocP7DL6xHeIAL0Wehi4kybSTZoJy/WPf/yjzT2jABGe7fes+0FYUNmZykOgO586D2X8kyFDAHWCkQbqCPUCEytFYFX1pad65faO2L03t7EKaOIGmYrSgXxjxIfRd0a7UUy454q7dxpZfoA9HUPW/jhYyM5yAkbs2S3r8fooPHKe8IwoIadRvrzzizv+2GBCOpDXuDEixCgP4VCasEPp8feyhpQ0o8ThRpvC4mt2itGpdf5q9DI3BcgJYRZ17rmSobQyNBjwdwEnlr9rqN45lIhpB5x+8RXE7g636w/S8YGY+WIapukZP3v66qE3t/7EDzweKh0Vpyesyt1BvJ4+jN/HafZ3g9jO/QG37wvisH7v6E88GTIMB6iH8GWaN2PeT/NxDOdz4PWZhpiOEXUUN+qrT68xBUOnCtCQEsbj9qvHt6p3ry56e0/aze8dsX/uMbF8S4epFweI7V0mxvIN9zhM7NZT2YF0uJ5QLw63A7F9T3lwpN17SoP7A9yT59hvOpw/ezi/rxd3DPcfY1VhYuQ0gpVjGEbEGUY7RXtlbYoD97gCNSpg2rhyAGd20s498Hyk7fzZ78k3hnv3k0baT9q/v9+vDvw58Bc/x3C3tB/uic/t/J3A7TwvMTwMbi44gcfn9/6+evYxsANu78/uN+0ew91dcPcXhCOO+N0xjTNkWFMAb3udZQSYDRGsv2O0gmkPRmsBUzMcacE6PkYG2D3M1IrLH+LxesLVUa9+Dib8XV7n43uupA/US1f8DPw59uvpj5/9nmv8rthv7M8RP7tfrrE8jePwq9s5rR2xG3B37GI3v4+v9YBbnBYQ38dARgJ397Cx7OcZeJrdb/yOevGn0+d+estHvXgaSmLTc+CYbYjhxINY9RLeaIgL0Invds50wAskXfBe4O7u4eMCTAM/GAf30I0wngaPlyt2sTvG0+Hu9dy4Jw6uIH4nftw48Efa8ef5Ax6v58uNu8VxgDRt0nA73NPxgd7C+PtWReN6wD/xxPFz3994MmQYDXBeZ0r6q1/9qk1bs1OUjsPHP/5xW4vH9AdHVCDD2UHKYadnnHGGjRRRx+IOQ1pWDBfid3kddrtYTnk63U+95zguB/YO7l0u+bOHc3kWuznidODu/oHT0O3dALf3uNwtfube/XkaYjfsPM1u3L/D7fw+douBPXnBr+fJ0w88HG7pPAP8uVkV8ONpB/HV73uKp/rmEUKcMDLPKBDwXjl2TpRGBelzYmMoUAqbe9zIYz0BwL2H9Xx6HIBnv7pJw/17HNCN93Pv7+LdDtzc3uNzv3EYrm54jncJ4M/DOwNjgL/L/QJ3x46rh4/hbv4+94PxuOshTpO/x8MB3D0uj9vt/H3c9xXul3AeH3b9jSdDhtECryus1WP9HWe9sOiWz9lwZSEvHVcO2OOTDSzUZUMDO4f8O1cO6onX0eGoL7yDd3m9x8T2nh4Hcg4TA3/INZcXbnrKg8ft01jA3+vvIz78YbiP48I9fpe/39vE2B7j94TnHr9c4zj8nX6PcWAHsCPNHpf74ep+PM0Ot08De/fLe/2dPHu6Pe2xAR5//J6+wOPw92DitNdDzy3LMCJOYL3piN4yMNLwQiKNMA8EB9xjvCA8Dz4n7gXj4Zzp0gqMx+fw9wHuPS4Q++Wed3k8/n6eeRfv9Pjdzv2RhjiMI7bDP2F55p5FdICwxOeVrR4Ix/v9HoN/Fl67XQziw9QD9rF/0gL83e4evw/gjpvnuy/wNHCN43ek050hw5oEFBp2JjHVxc4fjq9gcwJnDPE5Dc6K8Z1L3LO7iA0RDhQkFssySkT9cTPU8PrKaBQjVS4jvL6yoJd0skiYRcD4dfnlYZEfhMcf/oHLUAd+Y8N7iMe3q6M8cmWK0OHvwJAe5Ci05MRm3DDYky4GB9jBy+Jk4vW20mWYx4U9dhwwyy5aTmYGpNfj4Dw4rmxg4X2M6nEPDdwvaWFTDJto2GnmacHw/lWBtAD8Uu7Id08j8bP93g+zhaZcvQ3oS/yeZ88/YaANfOZpXRVGfA1QDJiTXgZb8ACZaHQ4+UgrBcgnG9gBxe6oI444wlbgux8KikKByTg3gVOZWbXPpyEQGLgzzMyBVzAeB11xXD07nuJicrpg53FiByNzkjcMwPvZougVOk6nXzmrgXMjGLJ2wUXl/NOf/mSVh/l7tj+ylRJlCqYFxMU7YWB2jFFmvJM4OGCNE8OJm+/HsDuBHQkIQwQIDM4WT4bO2S2AcIAWnGCKG1vjOYOIQzhhaM9bT4jzxfoEaEq+2emAG/bsnuBUc97FM4bt9Ahu6Of5WhU8Po4G4FwOzkViR1yathkyrIng6Ak+ccAnENjtw45OFkIzEsQ5XtQDtk4D6jJyhS3T/p0p6iaNKbuK3vrWt1odpY5Tb/rSWA0EXmd5Dx8G5cqXDqjzyGFkFPIOGYUM/uxnP2s7XJELwNOFPD7rrLNsxxULvJHtfC7C3eO6H4dlpxTb2Pl+lstADnLl6A9oR/ow+KXd4IBD5BjxcaghchKFhraFQw9RXPDPtnkOP+TwYpeTHg/hOSsIhZXROdoUdsxSDqSNre0oCvhFbpMf3oH85h1sn2e3MJ82oj0gXvKBsoviS7i+yDrC4Y+8c0giU6K0d95moZxBG+KmnSIN+OELBYT18D29y925AmjLUQFvf/vb7XNM/p7eMDRcF4FEeGbSJg0S6xWip0z3Bz29Z3UQx8e9p5WKwVHkDAWznZDTMDknwfMDyB/0YHiY+XLc6FFwPD1aOhUS5mQhIQsMOR6dE0BRRoiDsFxhWjRn4GmA6Xk/jIsdlZ2DtfzdfnX/aNx85gSGJz4AA8GQMD4CAsb9f//v/5n2zjNhPTzKD3kkHzAvp8zSu2FRpNOAPLBNnUpEnnyBO/ZUfuwROAybo+zxrSK25aMA8bE/3unpjgHdPC3A/XCsPwLae0buTno4Rp51CRy+iGAgLYSL87Uq+Hvwi0JIOgD26XTG8fUl7gwZGh00VHRMaFyp+ygOnNlFBwgFIs3nPPvncqgryAhOl6eu0NkFyMRVNVIDgaeFd6E8INdcgaHOA9LPh5xp2JGXpAM/KAzcexw8o2yQfxQUPhDKeTd0qojf/fERUjqEscwn7L///W9TWJC3yDuOFiENyHMHCiOymPSRBjpoKJOcy0b8yFkUJOQY7YWfCA08rbyTDidtCCNIpBW5S1iOE2HEDlnNeW/f+ta3TLliNI5OK/lH1qMEMRpEW4KSi2KLksg3wng3p/Z73tJwOoD4/rrrrrMryg/2Xt4oxLQ9LJaHLkynssXfEcdRD54OrhjiZfCEdmRVyk+F9vqSIYO+xIwyRFkbzIrh2d1iaKNe/vWvf508rT7qvWMw4HHGcWsvqLzPPvuUn376aXvWylXeYYcdyspM9kyeAc8777xz+fzzz7dn4lBGLH/1q181t4MOOqisvSRzUyFRft3rXldWJrRnaAd+9KMflZWpa96vzGl+CQOU8ctveMMbylpp7NlpDohfNeTyNttsU95rr73KTz75pNmrolDefvvty//617/sWYVb+d3vfndZhYQ9E97jUKFn4S+//HJ7Bp2dnWVV2MrHHHNMJb9Ae0/l17/+9eUHHnggsQn4zne+U1ZmrbFXAVDWHlJZe0j2TJyk9+KLLy5rj6GsgsLiVgWkYjxNKlwt38D5DKMVq6yVzOwdKswsLP48DhUaZVVIy0888UT50ksvLauiZH65qsApqyJqz8uWLStrT6yswq2sSqPZq0JpdLvsssvKqjBafJ6GDBlGM7x+aQNZPumkk+zecdRRR5W1YS1r422ywvmduqEKT/miiy6yZ7en3iEzXE4OFTzN1FVk5Xvf+16TrSeccILZA+1olY877rjkqVzWDlz5wAMPLKsSY88ehzbg5R133NHkmIP8IldcJgO3i3H99deXX/Oa15S142U08TgJF4dFxkAv7cQlNuXyscceW1ZlpaydQWtbiANAS+2cmnE54/Ei/3jfzJkz7dnxv//7v+Uvf/nLZVV4Epty+ZlnnjG/qrglNgG887DDDrOyikEbg8wGM2bMKH/hC18wuqrCVb7vvvvMnnRgvLx5H+2BKk727PbIXFU8LezixYvL2hk2e4CfOI6bb765rJ3k8q9+9avy+973vrIqiGXt8Fu7pIpiWZVxk8O0DfiBTjzjfuGFF5ZVYTR/0GD58uUWr79jSEeAXEPTF5k2Rs/cte/hQE+a6mAhjp9RBaaqXIPlpGWGeNGmY/g8J0PDgDj4nhWjEwxn0rPgAELAKAlTaP4eH9lgCoaeQvx+dmLwTrR2QI9DC9nmedNA62eIkB4B78AfoIfBiI2fRsrQKKeCErfyob0PQ3ky2sLhigw3AuKgd0HvhWFI5poJAxjZIgz5dnCoFqM1DPNycil+8UMPhBEhpgXpcTFa9vnPf96G2emV0FMhHvgInvI0QVdoQpqAu+GXKTB6YpxWSi+G0SV6prgDj4OpOHpD9Jzo+TD6xrHu9MwwnL4KLRg94mv0jCbRg/mv//ov88u3ycg799DSyytDhtEO6iffd4LnkVXA15dwiCrf8WNrPKMd1GM+icAV+xjICZclwwVGUxgNR864rAPcI6MdyBRGUHx0ytNIPrhnVNuBfEHmsE6GkWzCMBqGrGMknCUAgBF+6IIcY9qM6XmmDr0tJG6Af1UKbITNwVQco+/4Z/qMZQLkBZmLPafzx/kBjKowAsIp0QA5jB/kGvI+XpLhcpk8OFgmgHxkeh8Z6eWFP2Qeo1gu/8gXSy1YesEIG+2Sy1J/B1NtyHpG/4DTlDaImQ3yxrTaO9/5TpPtPjLvdAFMPyKH+SAs9GE0i1E75DpLJjiWgdE80nreeedZm0t4Rve++93vWp45wJEpQOKI240hU4AggBsKmoaCYTc+9+9EGA7wrjgtQwUaWI4ad1CxIDqVA0B0AGMyXKy9IEsPlQahAUPAcLhzxe3cc8+1ikWlgTFowJk7piKgcHHPcDRCCPr66cqAd5N30gWcoYiXOWiYDgWHZ69EKG8oEcSPPcOopI2pMZQRB/dUcj/uHL+ACsxp0whErzzA3f0KEDTkHQUL4IbR3oydIcK3v5imY8cJ+We4mbl73kF6APdOV6b+mF5zAUJc5B+6MF2IQkKF/de//mXTdEwvEtYNwC+L/ZiCQxmiPPnIH0PDCHTyxHA/tMQvgoM8kk7yzVAxCiwVG7plaAw4b2Fi9GSfoRYur1n7w/cEP/WpT4n2xO1Kp4tzgGgwcWN6hk4N0/90GFhnNxL09TSjtLBOD1mHbInTgkLH530uvPBCa/SZcmIhsHfS3e/OO+9sHUM6RuxqQwaw1pL4UCKYYmLqBZmOUsgUGXQgLqb7mfKCdhwhQDqgG8oTaXS5jKJCfMgYB2lHviBrkCkoU9Cdk/R9WgtFCvnlaUWmMtUEsKNTyjt4F365ul9/dwzSQZ58TSh+SYPHwbtoi1BsaKtQ6vi2JHnydgvjNGRaEDmKTAf+bt6B7KcMWFvGdBzTa3R0eU+cTtLEelEUJNpE2i9kL9OwdGhZM4RiThrJL2kkzaSBKVc65ZQta1nRPxz4HxIFyBPOlcSQGTRgtDjXEnHDkAgvCA83VPB32nsG+V3kyUH83vi7PXbkk4adBhhlhgXOjBhQUWB2ZxoqAo09HyBFa6VRhwlQTmhsUQBgQu6xS1ccYIWb0B7ENHeQRmcUgADjQ6jMdzPnSxp4D2kjLgf3MBoKCOBdxB/78feB2N5BerF3xYp0pONgNIsRHSoYW2themiHMIrTDVBoUMiobKTHywABBPMzXw7N+ZwHi/yI0xUo5z/ej7BjdI53Q3d6sBgqO8IcejhtMbyHd0Iv1jGxAJzKir8MjQPnfefJ9DVDz3C6MQpBp4vGl3rJPZ1a7KnPNDTIDEa0WUfI2g7qaKPQOK7rgDUnjNbScUE5Qa7SUCPbAOnGP8oAsoM6jbxm/Q2NNyP2yEY6TKxhId/IIJQf4kYuMJKNfxpiFCFGYZBLjEQAl3fQCRri5uD9uCOX2JBCGlEuUcT4bBAKEP49DoDyw4gLIO24o/hwzzpROtpeHrGMdpAGRkxQugBxY0gfSgudSDaxfPlLX5Yb/n2DpQMFhpEjOvbE6eCdjPAw8uZ8gDtporOOTIZPiAOlEVqxXoi4PN+AK/LXD0hmcAE6+wi7d/YxcfmSDxa2A+xpN+L8Wt6S+0GHZxawM4rP5NOoeEPtCXYCA8/QUIB8O1EtXUna6gMi1TJGDM9XTEwYz0cmcEdhocJAdLejEDBou2ivNKyMbsAAhKdgYTwWqTECQcVk6BLgzjQMIwzsoKDnxT3xwAwIIWdaAKPTwPu3W2BA3k2aPd1x+gFlg/Lzla98xXpNMCWVGsZDKLh/GJ2dHD7USNzkD/oyGoVWzpCuCxJ/bwx4gTyxqwHglziIi9ETBA7Tc/Qk6V0wlcUOAabBGHL1CgUY5UKJ9OkvQFp4L0B4+MgQNGaKz4evgZcnQKB5vISP84DxXpQDO9LioNwJ736ctzMMN0IZWlnyXwpl4uXi9y4TyuWq4Axh3WRwWkFL6iRTMCgCdJboYGBPPUAhYESAEVM6ES4z4vowUvB0OLinMafTR0eTxcIoF+TPRz/gDQyjKjTKTM3TcWJqBeUG+YV8ZRSDUQmmYxgJZveby3RGnF3ZAcgP6OIyw+UD78SNDq2D5QvIXjpl0NllOaBdQdY4nL7IQOQjo968w+UVi6mZqmfk3t9dr0yQj3T06FACpwF+z9O8n3rKqUaPPfbcQy76zUUmk1EyKHNGxmIwTUc6XC4TB3QnPtygu8+QAN4N4nJyYAePATr8xOXP3hEHcZ64jxVK/Puz+xtU6RwnEvASdhIxTUMPngYfLTIGDRsNGESFWHHm6xFiICCvfPJ1ydJuWfhqlyxY3CXzl3bJS0s7ZVGHEoTXYDTpvLIoy/WW9Sq9vz8mNkxKY868JGAulrz5NBGFBjOSR4QHFYieFPO4MBtzpCggDPExncOcNYoO9CRsDLRnV6wADIXCwg4q4gc+xcO6JEDBQ0/snK5x+gHpZ8SJeV3meNG6me8nbfjFeFjSxjQcW/YBbggJlDTmY8mrA7eYEQGCBqGBokd+Af4Y1UIB46wRpslQgBg+ZiqKIVKGqtlKGwNFjHw5rQFxIWhQdOih+E4ElFTKhkoez4cD4oj5Fzd350oeiNefMa6IpfPn8PAZhhLQWMujcgcoD4yWV1EVHb0s6yzKnCVd8vJylQFa/19e1CkvqyxYsoyKr41JWQWpBe5OZIDWu2qEaxTq8WVvvArf496TwZ26w73XIe4BdcTrDXD/wwFPA+9DHscNIGsQUQroqCJj6XShxCBLeWa6BDdGqZHVdDhRapAlKDWsowQ0wOQZRYDGHv+8F3mCPzq8yBxkG+tVkI10LJFFTN3QESMsHzNFEaMN4aPPTKehoDGqTFysMUSB4f1M3aFkufxxgwJK3lirw9oZFA2OOkGuo2TRcXVAC5QoLy+eec+H/vM4ue+BB+S000/TDu0MeWHWS3Lh+RfJD7//A3ntPntJc1NBvvClL8pf//k3ece73yHHH/9RU9Bow4GXLTIceBsEiN/LghFDOsukkbyyVZ61qyh65MXjgb7esfRnysefcSPtGOwxhEXX8LxxjZdxOAZNAfLE8GJeRkaZJ6RBZHqA4VDcvEcNeKZAKWwaUhbW+vCdx+cZWD3k5NWFXXLOWTfIe9/zdznmqFvl2PfdLocfdqX8/Gfa+K5UF9GQIU3fKymVgfldzoYgr0z3sbCLhpa5WyoaFYAKREExlYMixJwuig80QtlgSJCRHK4oGfSkGCqEDrij2MDIDMFSuXiG8d71rneZH4ZjeRe9FeyY7mHemnehUDhTARiCkSIYBjB1AzMy6sRIEMO2CAMUEMqDdHPFUDGZ9yafDF0yPMsCPRYJU+YoafgHMCjl6s8O4ke5YhiaNUkoXUwLMgqDwGGoFR6iUqMUMSKGoPBF4vAYaaGXhV+moECcTvJPvlhITS8F+kAHlCIP7zRBECGUPJ1UIB/Vwy/35AM6O92ojAhJD4Mbz2k+zjCUoPwwWub2DLhXhSZXCq65gvz7umfl2PdfLke/5zY5VmXAMUfdIse89yq5+I9PqR8UdnqSWo5JmSln8LNGIpYDjnp2MagD9eDh4qvz/ariHGp4WqifyAefRsGOz3nQOKOgII9plFnM6yPxLKBFniFvkRcoHYwSMe2HHEG+e/tFRw4g91gLxDpK5MNJJ51kI0RsTScMU0LIMjqXjPCw2YJ1nrwTv8hf5CJTZZzdw2gSnWVkFx0/3AiPUuTn5SFznM7IQeJEBjFyzmJhpiqRmchlZgrwD1CeSAedUUAcpVJZ9nrNHnLOOWfLjTdfLyf+1wmqEH1Qfvqzn8qxxx6jbctJMmXKVHnXO4+QS//yD3nbOw6Tkz///6w9IK0A2mKQ3awH9bWpLpcBcpz00H7RftA+oTwydejl5aDNZGTNR654ZgbByxb5TrnyzDofH5Ukb9wDnlEwfd2r2w3aQYhOVAeNBQ0xWiiNOZWHRpIGjkKBqTwDgHtGL1CCmHohPm+g3H11MPclkaPfe7dcf1OXNMuW2rej0Z+nhVuSiy4MDaq+TMr6Ghd89Br7AiOkpg9Fh3lZKgWjXSg1aLMsJmZUhEWBVELyyfAfIygUEhWDhpoRGLRgCt+VEugAc7HQCy2ZNVRMQUEbKixXKgPxQGvCEz9TZNAa5mZIlAqJIgHdSS/hsKdSMZTtDMQ8MdOVjJzssssuVuFhYBp678l5mZA2zthhyop00bsgLpgeN38P+ae3RY+FdOJGPBgUBRYYMwqEwsEoDocv4g+QDmgHbUg7eUBpIg4M8TP0SoWADtAOu5hvGGH8/e9/b6NH+EPBY6cEftwfV2hB/hEshIMXUd4QdIBnBAjvZ1E2U2nEh/CD3qwfwD9li+JLLy9OR4ahRVmU5/Sa086LCjatyypwVaHJF1W5yRfkovMWyEc/PkNtNtUuTpO6aa9SZstXvrCxnPvtDTQC7Q2rAMiXC1JUWZuzey03ii4rvn4Bvo953p+p43RYWBcSj0YMJZAJvJsOKDLD34ucQFFgFAYgE2hcSSvpZFo9blyRlzTqNLJ0QAmP8oLSQmfSl3fwPjpxrPdktAcZx2Jg5DXhCE86sGdzBtPzyGnkK3HRLtBQ0/lE1iN7iYd2BRnGVCPtC26k1WnrVwwdNGQmU0zITeIife4fQx6hCXmknQp08qk5kZfmzpSHHnlcli5ZobJtK9lJZRp1q6hNU6FZ5PHHn5XHZ0yXqWtNVJm4l6WHOIibvEAr5CXtB/nFztPIFfpBYwxKnucJv/gB3NNhJa3QjTiYJoSWtJnEA83wTz7ZxEIZ8l5oi3ym/GhPccMeZcrpNCgKUDoKImYYD62agiABTI+QUQjNolS0W4hFhhwwEw0qDRBxYpwQfh0oZs8RVbxmyPX/alYFaAvp1p5hqfyqKkAvqwIUVqgL6wBUaEpZS5cs9XF8jHR6AaeRzmP62UF4GKIn9BTOQcPrFTAGBe+jbs6c0JL3xaNxuIF676ACEgY3L2tPT71y8bjcLZ0v3u3oKc+9pYe8xuF8us15BuPuPZULecIP7qQT42HS7+Y5do/LyukJsMfE6SGsP2cYWrgClC+jAOuzFgtKkHKt2jbJhb9aLid+Yq50FDeUJi3bYlH5WuZrj3qqnPN1bUxQiDRsXut/ScPmclq2JhMo3yq/jUXEfD4QePjhVoB4r5u4PgPqaiwDAW74pX57HUfeUIf9GXic5KknuhC/Iw6bli/4Iy6QllXul3fEcQBPA/A0uKxOy5zYL+De3+VumLz2+svK/DmtN7k86a+2KZ1MEatVUzJami+s/A7y4mkhvdh5HkhT/K50nmJ7vxJfXG7Ye97IK27+Pg8D8Iubxwn8XXE8tRQdIPylDiJnKI49+XwygBEgFuvSQ2Yqgp4zfjxBzihOsDTS8Q8ErAHqLnSZkCsW9KFAnPr+fLpx4v1q+vlK0g5hvbCdyJ4nnikw4AyPwc7zH9vH9xhogDLDPVePj+c4Xuy5YpxB8IN9zCwxM+IPe9LqI0/Yexy4YbAD2Mdl5/ZcERb+Dgf2bvAfu/PsJn52P9x7/H7v+eCK8TAA+zh+dyf/IO2XfODHyw83j8OfcfNnjN+n04U9ccVuTqcMwwHKlXJO+NHYgG/iJeWUVwWnwLSYlmOuQ6u+KsDqv6RlxEgRob0HrEWp0HA5FpqG8Gsi4FPn1VWhr/4aDXF9xlBHeY7rvF8B7p5X7L3BxT2WtX6NZSbu2Lk7wJ54cMNw7+lxv54ef/YwIE4/9u4OCOPhAGkHHo+Hcbh/zyPp4YrBXt+mhrBqr3ddWneoPt3qzohoIa+0U2+5vLoXl0i5W+tUKdCVOEgn4Op5BTFNPf1u8IMd/tPwvHmnF+PxEqeH9by6AV4upMXf426ezkGVzv4iDEOADO2xOJipFK7Mc2K30jxckhhPZAwn1uqCsg3vceJzrya8WqEMlIOJ9F3a8+uvAkTcFI7TgMLxfAHu3S68PxgPExuAfRqutBCPG56xZ/QnHUecBq713gfwBzxurgB34na/lIXbux+u8TM9Kp6BvwvgnvbrV+zcnjCed64ext/NM2l0P3HYGLF/j9PtgMcNuOKGncfnYXBzwzNwd4f7i+FpqueWYQhgNMZoGedU8OWVb8xGyyrpqTKqUxQWQmrZlJql2I1fVZA1rNZONUwRUK4qzC0uUC3nNQ0xX66KR71eDBSrE3Z14O/lSl30+sg17RbD5SBubjwcV5etPCPznH4er8fn9351Wc09xuOK/WKH4RnjiP25u783dvN7j9v9ETdyjnu/unz3MNSYMiM/aqe9BSnoNa9NMrWjCeVHX4cTqcrlW9WPhldX4gbEhXFgH6cH8E7s0mE8LSDtBo3RDbiPw3J1P37veebKOzGeBq4eHvsQSx3g6MqIR+L39a68EBCxJw4QB36Y42TRE0OfMTzxDk8odh5X7L5aKKMRdmkhqvbKkJBCWcKuoefIfXhXcO0bPH2elzi9fu/54OoF4AakwwG383B+7SlM2p+7+3Psx5H2kw4X+yHdXPHj93F5xaYn+9ik3xcDe+DxuF+3j8N4XH7vz+4O3M7t/T5+5poOw/tjf/XylX7GL/Cr+8kwVNDaimS2oXmmNBDXPIdaXKF/TjsJMk5vGNanHLXnrSZvHR91Vv857nPaq9R7E49l9Tu0B+YPObyxc1ntiHkWk3YfTAxl3KtCnEd/BtRP6rO7xfXc4c+xu8PtHe7H7dL3cViAm78/dovt3Hg8XGP/bg/cDXg4h9vXc4/drNZQl0zOqR/7VbeSto+MCpVpJ7VNt3qi7yuoq/4Tlvi4ukGhie38HrhdbB+bGG5XT/am48cAv3c34OFBJUzyvBJwTL/Q76lQXL1S9cbcJAL/jAixSJVFwK7J1UM6rp789ReUab47CEfEo3YQA2wkCCA8Mao1miIUhGJ/US+9q8pD2r0/eR4svwN16yuIw+Px+3S8q3ruDXF86fs06tnFWJV7PcRhBhI+w+oCmmMQaUF4h2cqeqWyq3xRN+q8yhkVjyYHComCY6Vm8sDDJohuRxuQp94oOF+yKYEFoRjWavLsux3XdPSn7qf9+nO9OHqLtze3njCQMI566YzteotbXfW32TYDhBkRFB01BW3z82oKZWEhiXciKs3nECCdzlWlvR5WFSbUjAiugLAbxk9v5nRPrmyNZisgEbq/3iLHD+6u0fLsdqC3sIMNG7orsd1Pe4Eq8IKuq1fv3VGSJe4RnsOXrgwZMqwuqK+JTLFfBfXdDDZBVjGyU7at7iqDkEP2V7BF0yGkXk0OMKyPhCACerxJ+FEKXwvhZ2JxPAa7KdmxyT27UNkxNJzyOEPjomiLoPN6ZR0Qf0wXNWvNaZFOadJrk3RqHVnWlZOugY0TNAxWUoCoBGwb5qwBvneCIuQfdOPAOU74TSswPVUc7FF4fMTI7XryP5Rg/r+c53DDTk0EAiGZ3vOkmLRM7is9yAwZMjQ+UFBcSUHB0XqeY/F+UqUj/SUoRKoI5bu1b8tEl/Zn8yx0RpITLigLhEEJYh3EaJYFyF7vgHKeGIelcjwJB65yEB2bU5D1fAfQO7UZxi7gANsfxFRXuUnb/0458/QH5HOfnCsnf3qhfP7TL8sXPztbPvOJR+Qv//eChRnNsJqdZnxXes4//3w7E4azbTjbhHNQOIjJp7A8XG8VxxWeWAkC8f2wQF9XtIN9SnpFIQpCzXp5pgypSZKELpQhQ4bRgmSo3kAlDvXc7ZJqHZQfq/dq9MoYUCkf+rjBF+7u25F+Hl1w+YuM5rwUDivl4FGOIeF8Kz5rwT1ntWQKUAa4nU3S1BKOipg9t0P1gOnyw5/Nkx//eKH87McL5Gc/ell+8cun5ebrZ9lQwWhG0AJS4CAhdm5xKFEavrAIhQZ4BesJXqliP735H0qUrbjYSYUh6yr6TNshPZEQzamyZkIxQ4YMowNJ3aWOl9mdwno/F29B3tiIjkHtE3cb3je5gBvhXKRT/9cMGYAMRubymQHW+3BAXXd32JLN9mKmyLgfKbmcobEAF4R2uyT55oLkWzjJeSOtLpto9dpM20zOb9pcdYGJoT8xipF3BYWr33OiItvOOEqbUSBO4mUEiG8x+amZjjhcPVCp3Iw0CiYkEX4ocaS5qNou6aIU45IMvcMMGTKMBlBXo74ojypvqOEmdpKqXI6ltX38lLVACMG4rut9EqZnqTY6gFxG7voiaEbu+WwDXyXnMzt8vofv8XFiPacPZwpQBnjABgVshJQ1stiGzUG0ixwSWiizlrZNSrnmUV9H6ipAHDPNvDHfmELx4TBDzC9+8Qv7rhQVKg43KqDJZMsrv0G+ke447QiJIABGSY4yZMhgSDQWRW3d5clHhhTmyE/whQyo7AatQZgUW9PApwNY98P3llCC+LwO3/njW1Wczeaj+hnGMIzxlQ9cF9bnymCAdhrYPBDqjHsY3cgp05fpGaDUxD0FPgwJUHB4RiHiysgQW9rdr2Mweg98w4oPybFTYbDBpzCO/eCjcv01HO60jZUzn8I47rhX5de/3pwnNeShOvm1ZhRxhgxrOkKNRVBz55IpqDFq9J9dLedfsFxOOGGuFLs2VQtGf7rU71w55ZR15KxzwwchkXesFepWKU/9txHiUSoIyAuGDq0fwNcTkO3xaNFgw+iq8Y/Et8Ay9B2UE20hm4byUpDbb18s7zvqfpn1/G5qMd7WBxVUEeqUmfLx40vy819tW6lvoxGWdmd6PrTGF8Y5E4LdAnykEoWEre8sgOajjyyOdv/O1BkyZMiQobGAbOYjxXxJnA8W86FkRnsw+++/v40A8VkiFkHz1XPkemgAM4xF9F72uDXGUpbBhGkyDH3C/Gx1Z4qLr9TyhW3W/lxyySX2Je2LL75Yfve73600Vzz6KowvhcwqeoYMYwG1Qru23jPAU7MEaA0CspkT+FF0+JL2lltuKUcffbQcc8wxZvye69prr73STt0MYw/ensMFmF5byTWAVXLd/qVABbsB2BXAJ+P5vD/3EIRK4fPDDKVOmDChZhTI71cXwzMF1iRNua2FE0BK5UXZFFiGDKMeocYyacWdSyOfAvNVf2EK7CUpdml9T6bAcrm58pVT1pFzzlkzp8DqKTQvvfSSTYsBd19nnXVsacNQKUCelmwKrHFBGYVy0quyAVNgt96+WI62KbBd1WKiLYfOl4phCuxjJfmfX247WquHQXWXsPYHQ29h0qRJpuQ88cQT9hV3Pwn6nHPOkS9/+cty7bXXVj6RkSFDhgwZGhOuzLC+B3Da88EHHywHHHCAHHXUUfKe97xHDjvsMOtwPvbYY4Om/NCIOuJ7QNvi60lB2j1D46D3kqFbUR0sGK2wXWAwfsz8HJj12c9+1ra8c0AWOwQmTpxo1/TZQINVaTJkyJBh6FE7Wm07ftfgNthH7pHz7ORl5OeHP/yh/PjHP5bvf//78pOf/MQ+Us0OsaGAtw+k45VXXrE1pK+++mqlE429pzFDhuFGvp4CwzdjmA7jDCBGf84++2zbPvnd737XTg7t7uarsEFqEH50afFhYFxTbr8ZMmRYs7Eq+bSmSwKX8Yzw80Fqzv557WtfawuhMdxPmzZtSBURZhiYVWCJA2tNXQEibfXaoAwZhgMVBQgh4YKC78JQMVjwHMP9pKfAMgbOkCFDhsYD8tqVDA48ZFfYz372M1vKcN1119kOX3aI8f3HwZLjcZvi4H7PPfe075DxlYFY2crajwwjhcpBiDFYELfVVlvJJz/5STstlHlivhrM6M+vfvUrY1g0eq4wcr04GhfMXILRlOYMGTIMFGO5gUVOu3xmY8vdd98tp5xyinzuc5+Tz3zmM/LpT3/a1nkyKjPYdIrjIx2s/2EJBVdXgLgO5chThgy9oTIhDrM6wz777LO25Z2h0YMOOqhyaij32267rflxxScOlyFDhgwZGgexfEamsx3+1ltvtTPeOBeIKakLLrhAdtxxR/MzGOitQ+xthoPZhKz9yDBSsCmwNMPOnz/fGPN73/uenHzyydZT4MqBWuwgcI2dcL0xe4YMGTKMLtAYrzkyLZbPnPXD9BPKDiP8dGa32WYb2Xrrre1ok8GS5fUUmjhu2g/3wzVTgBoY7Ie3cRI3a1ZZ2QhQmgE5MGv33Xe3eWJOheZgRD6Nwb2fH+EgbKYEZciQYc0AsmzNEvIun/fYYw+5+uqr5Utf+pIdbsvHrdkZ9uc//9l2/maKSIYqnBfW7La9MgWWxlNPPSUf//jH5dBDD7XzIg4//HA7Q4IK4+t/uILRVXGyXWAZMowljPUOmstntqEjs1n4/POf/9wWQ//0pz+VX/7ylzJ79mzzkyHDWMJKChDCgkVqH/zgB+0gxP/8z/+UI444wg7O4th0TvD09T+Y0TsCNLaFYoYMGcYGkM/IbDazcArz9ddfL3/961/t24588ojRoO23376ytCFDhrGCuiNAnAbNqM/xxx9vo0CYj33sY/KpT33KPp4XKz5+P3rgu8AyZMgwFlArn2o7Pixx4MvXYwHjx4+XqVOnylprrWXrgTjklqt/BmN0dmQzZBg46m6DTwM/PuoDfOproMgqWoYMGUYGY0/2uLxG7sayHMMnKTDcj66ObIYMqw+rGXGl8Ge/B1SMWOnx0R+vMLHfGHF8fu3Jb4YMvWGs801WbzKsDmL5zT2yG+Pb0OGv1e3YZsgw2lBRgIBXiljY8kV4Fs9xxQ1FqT9zxcTl8XH1d2TI0B9kPJNhcFDbyPMdsPwarFsic5HdfNrI5S+nQf/jH/+wc4CeeeYZU3ww/oHSDBnGCmwKzA07v2644Qb71hcV5bbbbpNPfOITcuyxx9qVI9OpKF6RANeeGqfYD0oTV8KOLDSvds0a1AyjBz3VsQyrxsjLnJEDR5d885vftJ1fyO5HHnlE3ve+99lW+G984xvy3ve+Vy6++GJzy3gsw1iDdYdgfoZCUX5+8IMfmAOnQXNkOsKDHWEslDvzzDNNKcKvCxWuaQET23GlYsUVzN3dz/DCF0GPXaGYYWSxKt4fmXqx5mIsNuzOQ4z83HTTTfL444/bCA9fgudzFH/605/kkksukXe/+90m8/lQKTI6Q4axBDsJ2qe0/NrS0mIfymNnAJWDj+jRi+DTGL/5zW+sclFZ6gny+Jn48MdBinPnzq1Mo8V+0uH7A39/2sRuGYYPcRn0xdQH9qxHw7A4k2F5v6/aVZ8xfY175BGnLZ1mN+6WobGRLrdVmZEC8pzdXshiDjzkOBNOg950001tZy9y/q677kp8Z8gwdmAqv/eQuC5fvtwUF7bCc0Q6WyddMdp4441tPVAa6R6WV3gq3I033ignnHCCnSdEZXvwwQd7VJ5AOi5QV3ioFfP3JSmq6VY/RX3WsGpHo4hbrsQ7SHtZ/WQYLChV9VcpqjQ35cT+uFeT61L7bjwlPtWO8rPyZhqUIHrVMhPpxJN5rZRPCQVZjbKmqjj62Km/6i8X3mWgbM3wzNqGLi3rnNl5eQeTpMlMsBl69PQWT5MDeigNoJfekxf4NezJDnUA6oW0V6iTYSSQyB/nLIfJG/hfeZRr4ElGvAN/57R8A09ShiqjKryoMVmclHAc48BRV0YqONONUSDk8P333y/rr7++LFy4sOJ/1qxZdro/SlCGDFU4PwVZVIuqXXr9HGxVteIOOR/kb60Yw83NyKFGAZo4caLMmDHDzvz5+9//Lvfcc4/NGeN+880321zxvvvua89egeJ74HFxZVj1jDPOsErH98SYOjvnnHNkzpw55u5h47gcbo/yFdsD821hsM9JURvHnDUkjApouCCJzI3GlGtaeGUYGKAhtETt0RbbygGhj32RZxjeGgC9aBnQGJjyosb+tJG38kSpjpTTcEcg/bcy02e8WcOhDUmJMsZPXu2Ube1B7XCz91oIs0aHQJcIVuE9pLDyjiEDsff0BuzJg6cV/mf0Sp8tscFo0pMoSHFItVHX7DIMPSiBNLFVfqgVJWflA/BCsSjvw9cqhdSD8j7FiWdT2BH+GkKZEp40Dkz4EfAbasrqIy0jHShAyOxbbrnFznPjUxh8+gKl6L777pMTTzzRzgXiG48ZMhhTV0w9wGdu/GIVIVz0Gb4OofmlHugVS/yaAz+xGTmYAuTKBp+6+NGPfiSbb755cMzn5YUXXrAeA0enb7fddvLRj37U/AKvdP5cDx/4wAdMCXrLW95iYZ9//vmKAuRTZA7i8dEm4OnqEepULhf00kxipFt7Yt15RoQYYcKDpi9pTPPhkmFQADG13MoY7qFzQU2zNhQt9lwqd5myU5aClouqMOqllC9oQ0DZEE7LrNyahKfhV0WGBsMUJi08lFp9zmv4XJneqcZdUuUHvtHCRNlC8S3l9H05dZNOfWfS4BC/XUlTU3LlPSOJ8P6gkAMaRU23pr/ImjqlTZmRUSOpKn3WgCZ5GfG0jyUgOOrQ2zpU8BfGhIvqMSqvlJ+L0qL8rWWn5SgFLa9ck/pgZIgds8iwUDdy8KJHrWWaqLtDApfNbW1t8uUvf9k2sLCM4Ytf/KKdCE1nFLnOsgZO/EcJypBhYEBuM0oPR4ex+1BPaMuV5zGwoxv7QUa7GTlU3o6iMXnyZHnHO94hp512mlx44YW2c+DAAw+04dHvfOc7toCOUSIflXEFJVZiHPhhCu0jH/mIuXPk+ve//3056KCD7CvErvzECg+VEgOw7yluQJtA75nQGkp/26Qp1y7N2qjYMmcaE+lQewpD/YaLgkYZWElkGDCgXzCwPeVgjbsK+VJJG3P4QxkfBaZJG4icKjBNKDPqpRvtNK8h9EJZeIkEdiQcoMDoH+fN4KdEOEV4q8aWH6cuzfpe3qdu1kihYAU/AXqXNAYjjyRtVnfIdz75I5VhRNToqMll1CtQB95WHzZyxHOG/qLXTlQfEXiOeLQckE3KnoxUFlTxgcMR8jm9d3YrouDbg16srEGIJRj/HXqwjIFR+De96U3yyU9+Uj73uc8Zr73xjW+Ub3/72xV5PBh0yjDGYCyDjKIOwNNBCQp1RTnclP/gLRgL0DDIKdOD5FEt6jQWrqwAdhJwTxhXYAjj4Twuv+KHHWWMIPENGj6uSo+ESkkYtt4zvcYCaV9/9NnPftbe4/F63DGIH9u77lssl/9zjuS6tAC0t1zOd0rbpMVyxLu2km23ZOSA9DXL7JcKcuyHHpXrr2lSRWlrtaVBXSTHHfeq/PrXjHjRwBBjKDqw8lszVDlF6W9lrDRXxYPxGrPVhiGf65ZcviDXXPO83HrLAvWpvUt9LhaXyTprl+X9799M1tOrlFussQ+UVzUntPzW3pekSw1jefpX0h51rkteXSTyu9/PlpfmqieNjzUzBXlV9t13LTn40PW1MYInm011IjU2P43R9CgTaGwaJnEbGvgLQ12pInQUYONiUVPBiI/m9Y9/nin33d8l7a2tGqJbursWyg47TJTDjtxSxrWy9olRA4QLYVGIEmUoQwrQ3Khkd06hIGyxDaV+/gXL5YQT5kqxa1N9hH+71O9cOeWUdeSsc9tCGMpJy6ZbmYdQBXhSUVL/8KOq91JmvZneLX61Wy657Bl57KmSNDerss8oT6lbJk1eJEccsbVstpnyd1FTk2tShUjj0jipG2FUjxE/Uje0JUp+MC7DAx8qnZKry3AM02VDBX8fMp7vkfFNyc022yxxzdAICLxCe6lXZXt4/LbblsjR731AZj2/qzLqRFNz8qWidMpMOeFjRfn5L7exemKM7NDwoQMLgwfuDtUIGRbibRioolFW5q8xDty6u7vNjnv3G4fxe0ds7+jo6CivWLGirMpOWRWg8s9+9jOzJ+6lS5eW58yZU543b155+vTp5fPOO68m3nT8VXSrKZXPP39mub3l+nKbPFweL8+qWLmnvP4Gfytffe0c81UqLdPfFeXZs8vlAw95REvm8XJTrlhWQaT3C8rHHfeM+dPcqgnv4bfeGzM4bfhT+pe6jGxaSvrUXe4sFcudWqZdxU7ze/ppt2uT8BdVc54oN+eeV3rfVd55h1vLj82gTCwg/1aSxi08JGxDjF36CxuV8KCOLzy/orzHjndrPA+VmwsztRyf1Pj/Vv7CyXdYUIPeEAWhS+UOfdY0clUb7Cv+hgRRBmpAnSAd5McyYzjqPXcYTVoLM8ptuYdUVFxaPurw28svv4or6Vc6WqL5IQ/14s4Q6A5P1lIo8KkR0J7P+/WycqH5GaW5as4qA3KyQuXAc+VTT11u7sBkjQaB+ir5PKjFQgmaVXd4y4I53eV3vPkmje/mclP+UeXxp7QM7yxvuelfyrfftsA8l0od/Ja7NF7qiJUjDG1Rk7o4xYMH8uEGORvLY55drrvpWc72jjiO3sK727Jly8qXXXZZWTvF9pyhcUAZIZ+QVUWrAeXyLbcuLm+y8c3K44tUey8rn5dVntN2PlU+4WMzEu6tylgLZEWd3FSeaRMWq0H21wMxpc3QQzsA1fN5uGJYIMfWdSWI9RC8p6D+zZ8j/RwD/4zuXHnlldbj5eyJLbfc0rR+zqQAxDtu3Liaj/Lh198XX9OorKXITZRScXPpkk1Vv9xM9c6NValbVx0YgsYdDZT1JuExw+ohUB1iYrxc6GuX9LGsvVx6l8G2VJyitltouWysVWYjtdlcvWygRULZ0MuoVyjYJWM43kU2aJvFQq7y+nq/qXQVN9E4N9H4tcyL04KPxG9IFeNKNk9hTxZefz3Fw4/w5piXS6Up+ruVpn8LTfs2muLNpbs0OThq2m08w9IPD9NrGrnUrzmoMFTfUcNX+mjTtyW9UkIT1WZTKZa2VH7cQstwU3XaXFUsRpQCj7NTlRoSIorLEJ4cQHoGAPiOTS2MtnOPQb4jwzE89ybPcYv9O+Jw3KeRjtP9ExdIu2cYfWChQlFlFEVpaxe5lijnoi1bqJR3SWVYKch+oJqR+UHWUUswuIW64u5VnhsKXqn5GKrfo7iceuqppgTFTO3KiftDOUkj9s/UF+uJ2FG2aNEiuf32220b/J577mnuHpfH5xWsL7D5diV8rtyqYcbpfVOyC0ntmpokVwjpyAmLctWvPa5cQTMMDKqa6m9M17CaBftcjqkarNuVlccFxjZWYYoyrA8iDH8BlHkQiKHB5z4MxeLVWcrC5SlPjb+gfgpUnDbJ5yj/xB/B1eQq89JYJmkdFiSJTSHUC09LArMrSFFpUjKFvVl5lylFczS3anyE8/sMA8fq0xC+hE9NEbLiZIq2OeFrykyVH6sDSY0oF+wueFZjsouUuN3gA35z4+sq+fTF3/72N5PbGOz93v32BJfLsbx+6KGHbFOLh+3o6JBrr71WfvnLX5qsR55j78oOICx23nb0Vd5naGQEWYs6X+xeoUpPl7F4WX/ow9JxZWmC5LVesEa0iEIUlB7bCctVY1BtwO7L8EvCFmn2gF/6oyesCnVrH3PB7NRimyRztowIYTgvgrU6MG+xqNpdwtjpiuOJ3G+//eyodXYZsBia49ff+ta3ylFHHVXJRDps/wHZaECU2JYdnrXhS+Yek9bELxkGBdA20DqAe9bk6DN8mTBnKd+p5dKRlAvAXiuLlY2ahIfD0l9f9BvcsAv2jlC+XlVCHJS18lGeXgRhuTqolCgV8AKKkKdhKJGkrc8IeUVwsJvIw4ZfTXsJWtmDXzKsNmrLB12mL98Cg9PCiCLCGX6ibIgLHuPq8XZLubBcH8N6B9+BaHq9lTd8mfg1u9r0DDZiOcumFBST8847z9bhXHPNNWY4I2jevHlJiPogvMtq5D9fDUCOEx57lJ+vfe1rdtzJpZdeajt+zz//fHu3twd+j3GsvvzPMJKgKK009adUZsZIa0CxSRYtEVnckVeTk4Ur9H55XpYtE1nRgT94SflIfwjr/BA20aidynbuGeRw/uDq/lxhHwzYSdCAq98zHcU3ZPgEBt+NOe644+wgQ5SZ//u//zM/JIIEcXXmjsEzJ5B+4QtfsK31Rx55pO04+OpXv2q7ymL//t50HH0CQTQ4Fxt+4zygXIfGmTSeNXQyX/abcsjQDxjlXDdJaI+Ap/ggu6sabOe2ww6txxzubWu7l7N6TqpAYvyWRgKjsDJ1BQdBrrVJOPOJBCjf0eBo3KE0Qxz2uspTAnuosRl2OOc5wpPSIN+leWDHInlRW3NI+JNLcpthYBiQXEkhKOSUTVQgKrcCj1N28CN8qgo/h3eaxhP8Gz8mSQhJiSyGGHFDgdzlRH6OJTn55JPl85//vJx00km2KYXR+thvGtAQg7xn1Ae5zlIGngEK0eWXX267hdnx+1//9V82EjR9+vTKzIEbnr1MPN4MoxOsSihY55Upe0Z62uWG61+Vz5z0sJx0/FPyXx9/Vj554jPyyROelBM/Ol3O/+VM6eyED1RvSJQdZgxKygJ0cDE5eEr5xLgi4UnnPfhnMHnG26oawKAoOzD5m9/8ZnnNa14je+21l7z+9a+306AdnhBPWAxPKNhjjz3scxocyOXM78Ovq5sRy4DGwdsDySiILpUvHi9X7YGoh2BDMYHVe+/YhtKuUtwI/kD/PNqPKTUJbJSGHnB4NH/WILgPGgyAP0wlpHolnNpZQxEOuQRhVEgN5avGQtl7QHKtNC5c8T/yMD73ZFWQpM/2VCf5ij0ZPZMDPvV3peAZ+oS0bOo/QrkEyYEJJWEKrZUP8kbljskclYXlpqpfs8OfXmqgZToMShB5x9BJPeSQQ2yKis9eMB3GgYh+MCKfxsBPT8ANec0sAN+IZAZg++23r9CWkaWtttrK3oEdn9sArDuK4TLf37X6ZZNhJBFKj/PailLI02nNy5NPrJA//GaB/P53Jb02ye8vystvfluW3/5fh9x4wwrpTsS+jfSofzsnS9uJwKt5GxmCLYjbjP4Engn1JfgLb15d1KwBAjyzMJnRnw9/+MOmtBx99NH2OYtPf/rTdo6PMy9KTL1K4wmE2QFxusE/bv682vBRH2sg9X0qfPIsQKw0isDTOPQCZ80HtITmTkuuaqyx1p5wNPpWLjI90KpGGwUWwMk4vY7XKGBeDYMiZNFQVmqI00Z7usOtuScjQVa2ylccnshaGVekWGthUxL4xU8IH9LJVXljGBqavoF8V1ElIdNd5KtV6UMDiiX09NEF8pRhRGCFoWVh8gRe03+1w5ZflWhmz9besL1XyxEeL3KvsHrBNxCRUV7ggDIl7NADmYvx74H99re/ld/97nfS3Nxsp/UzfcWxJD0BOe0dV74gz9cBfvKTn8iGG25Ykf+zZ8+WDTbYoLKVngMYaUcYcXKwjOLVV1+1K/FlWFOAPOb8N3haOwrKV/nWScr362vV2CBccwycrG/2NtuPLNQrOg2hurRN6OzO2RTZCq0qHWpWdIp0qikW0ReCUjQoOkOEyhSYwxWXW2+91eZxjz32WOsh3HHHHXaAFh/Ti7V4rxgxXAFyxM+uFLld7K8/8HdyDZ9i0LhoEJWqnNahEZu73qgJjYr6CFYZVgOUX6CjkVvBGgroa+uwVCFxbkCTd79u2a0KTuj5qn2y7sXLLwA7NZWg3vgE92ISp3JpYkcDkzQkPLIzB76y1OAnWaNh/3gYGQReTx4SlGzxiaZSlbwwiqV0YGGt+dMftecsIGhDX2nkUj+WAJWdgxWmZAdj9OcWYay3VnymfIfTz0M41qQxJZvEQX1QmYfOny9Tts7rKE1Dz5GuoKCYsLmFtZgshGYE6Omnn5a//vWvdu4ap0L3JItdTv/hD38wc+6559qovn/cGjAiFAM5j5vbc3/nnXfK//zP/9ji6XQ7kKFRQFm4qQdj+sT4RXk8aDUKeJrncMo/ci2cZRY2r9hMTBI1cp9ZgyZ9fvCBJXLy5x6UT3x8hvzXic/KiZ+Yqddn5PjjH5Xv/veTsmQJAydad2g/aPujJISbpA3oJzzVNXj55ZftK/C77babHH744VY5dtllF1sYzdfgYVgYGOMVrC8YKkavxIoypH/JbH0EbMM1w2Ag3RxDbZ5prDGBrVBFA2M6j9A4MCKTPJq/wNhYhV81Vpk0TlOW9FYrDvYoThxIVwtKuyp8bUjV4k2MKRbYa7h00GGGpaEOyFIgSbfeKK3sQX8QHPZpkYQeGUYIoXQMXjb2S5nAmyhBamfWRVVsO/Q28CQNg3XIrAxjBJ4earisptFA6WFU5he/+IVssskmNurDOiDkOspJb/KZkRw2szz33HM2gsQnjlgD9NOf/tQWQnOUybJlyyod0+7ublOQfGSJdmLnnXe2pRXbbLONuQMUJA+ToZHgvFCvbKp2NpivMBvb+ahQmcvGJGzDB6u5mkMwSXA6BKwhIopnn+2QCy94RS76TVEu+HVBLjw/JxdckFNeWy7/vGKxlLqr6bG/Gp4J7xgI0rXSQE/hpZdesgVynNsD83JGD+uB+KKwg0RQaYZKsekLyLY3ryOXigz1QekMjDF7wuDGNtIYfPpkWF1QHsMnSYaj9JHTmGeeecZOYGbqCiC3N910U5k2bZopQT2BsEyXsRHmU5/6lH0rcr311rNNLlOmTLFPKGH35JNPWucZ8FFt1gux8wyghOEP5YfrSLYZGUYSzvGutAQVpJBrktbmqfq0jt6vp/yxrnalOfNtkjQpn4UqGVaA2gh/Hf4ZSF2qqwCxWwDm5hwgprh8XnfmzJkyadIkuycBroX5dXTA++FZBRxqVLgCUveV3Kv0l5Vehv5hdMmnoQEKCMrHvffeazuzkN+sxWHHFssa+B4Y6IlWKC2sAWWXF1Ng3/3ud00JYpfwPvvsY98ZI052lzFL8JWvfMXixA34VBjrjeJRn7gdyTBGYFqHlrkK8ercDFPCHB7KiHezWrSpD+75nqSvi8Q3gdMzPANHXQWI1fw77bSTnH766ba6n54DXxKmshxxxBHmh1EhKtXog5M8q3SDjZUpCqXVDCKps9LL0F/U6y3GWNN5CVmNec973mNTUigpTHlx5Ww2PoDNTl/QG62Iw5UVlJj9999fNtqIE95FtthiC/n6179ux6fwIW0+vkr7wQhRuq3gHf4e4hud7UiGntGXGkW7gCIT/DKyw6EmwRADdyBvp0onG8AUg8srFhtM6AZmpZJ88YtfNOZmzpdew0033WRa/Vve8hZj/piBVyVgMowNwKN9Yf2hRqOkI0MjwifMA1hjFtaZrblwuc50F2t2TjzxRDunhw9T07FFUWGUHz/14PKda9xGsE6U9oBn7Pm6POuM6CijBPnW+rh98Dgw/pxhTUEfpa55gw+iss+h8LBTkjPRWCdaVO0krBNjTaizCQoTt4PFNaYAwYRuAAvUUH4Y6vze975nlYRTPTnLBzgDOzM3BjTtpCd5yjByGCzmHAhG8t2rgo9eZcgwnGCExbed+zcZke8oKKwJYn2Py/R6BvgoTdxOgFjBcQWKLfAOwuGeHuWJ48uw5iEu1lq55/fwkfJG8hw+LxPGgez4D1WASihBbCZQRaniL7kOFmq5UgFD0hvgfAjmfDm5+cc//rHdsx0eJo+ZmXuvJCMLTYOmY3DJk6E/cNqPJDfwbtLRiHygzUlyl2HksDJnrOkyA/mMXGdjy8c+9jHb3MLnKjip+bDDDpOf//zn5ietlKTlOvaxwuLxOrjHzk1fEIfPMNpRvyx7lHsrecdCedC2zeu97eBNlKRe2an+e/uCugoQh1UxN8zaH84CYriUk6DZBsmHTakoGF/MNrqY2ItjNKV5dACK1lIVSqsZRFJnpZehv6htjGs5xzqesfMahlg2My3FDl9G8zkLiDOA6NjybTB297oC41Na3rl148BfX0yGsQot+x7nlXuobHbkB2e2tehVTalF8vYcNmBVq2298DgOjN9WUoAA2xn53gvzxZwDxAdMWRNEb4FvgXklcUb3Ff4ZMmTIkKFxgKxm+gsZ/cILL9jCZXZmMRXGAuUPfehDtmCZzi5wpQe5ztWfgV8zZBgaoI6oTsGUFwqUK1HWQxka3qurAHHmD1sYZ82aldgEcLAV88ZUDioG8Ao2eqDEtWtWmYceiWY+iKTOSi9DfzGWRyOQzy6jWfT8wAMP2Cg+02F0cn/961+bXGdLO2cBLViwoNKx9fAu6zNkGDyoBPcT/A1I9GTND2t/1ITDRDG4eR1OJH9lzdDqoYazXcNfa621rAIw/cXIz/e//337uB1Dp0yPcQYEp4lyfgT+fPFbhgwxapqdhG9Xib76y5AhQ5/gI/SLFy+2Y00Y9eE4E0b3+QzGww8/LKeddppth//hD39oCk+9nb7+3F+4EpZh6OG0js2ogCk07PrCuAKULIrWRsE/HKycaFcbHVKjLpXnykCR5Tlt0gj2NQoQDA7BONKc4VF2CjA3fP3111uPgU9j8P2Yf/3rX/atMA5KBCNJZMgRMqF3pN/uM4wkXExmZVELH72qgue0XYaRBeUxfJw71KXvSgsKDWe7sd6H73HxcWuUHz5r8aMf/UiOP/54W+vJVvbBbjwHqjiNJTituTKgQHnFdn7Fzddo+TPAfzwQ4e7xvccZm6GAqSxRkdfKPb8P10qKTaFhJikxel+yTyLlpKjKUNE+vBeUIVOM9LHE+UCqLJVQhPgmB844FZU+pU59cIVK82q/wQSPQdFaaWwTokydOtXOeLj22mvlqquussVy1113nS2cYyfYP/7xD9tBwMminCY60kOkIVOhQGNSZxgZhPKosnqGgFANM2QYXjD9ReNIB5aTmzF81oLvefFtrqOOOso+en3cccfJQQcdFOSoKi3eIc4w9HBac6U9pcxccYzLATcMdu4X+DIUytntY39xOQ53mcZyjxwlgzkp4EIeyE9iTItqllyJYxUSWqjyEkaGGKHs1rtO9dYpuXyYKiNrbK8nfLnEFd7nhW4Iy21QsvBhBHGiQCyI6YR1YqYLgEV0uPlnMkYKni0QSLQqeHH0zXeGgSNQWg2k7iu5V+FvzSq9hD4ZhhT9E/j4HT7uGurSR0bTKCKzGQHwUQDs4nvAtTv5SKk3mt4OZBgaQGM30Bzcdddd8rOf/Uy+8Y1vyP/+7//K/PnzzW327Nly0UUX2eakX/3qV3bPlWfWdTEYQdu9fPlyG7DwM/wYsGCdF26NVaZ9kX8tklcFKG9fXVWFjq3xNlpUVFWmy9Qh5WopqRLEwYnoNXw31cZ2VBEq21Z6VQL1NVXlCTs1Gid3dQGhgFcKr0RcvVJhMmTIkCFD48IbVuANLbLcG0KurvjEdvjzdiDD0MBpjEEhRWnhC/2PPPKILFy4UC644AL7ZAkfmV20aJEtPbntttvkj3/8o63bYobm5ptvNv/EgZ8vf/nLctZZZ9myFRa2c6Dx2WefbUtbKFd/X8wXjQnS1y0F6RCbAcMGDafESFFB8rk2aZV2aVaTVyO5Zvu6fJP+wMadpWVSKnepnT6Y0gRvY1RvIWq95cmQriQOCMYojw+x4eaKD/ajr5L4jGRWsQcbULSWqlAaxgtPg4Gs9DL0F6sS9GsyL3ljB1yW00jyYWsWRTNq4G7Qqad2IMPQIC6byy67TP70pz/JqaeeaqM63/rWt2zNFpuNOKxy++23t81Hv/vd7+yr/Jzijf0f/vAHO7ePE7gZOWJRO+G//e1v2wYmNi1dfvnlcuWVV9q7eKcrQkMD4h2MuImjWyV+URWfKD5rVvLy5JPL5Vv//bicde4MOecbT8k3vvGMnPPNJ+TMb94tV183Xz21Kz8zFYbC44M1qDwJj+vFFKA00ztxrrnmGtMeb7zxRjsb6O67764MoxEGRcjvM2QYqurUH8CJg1X9MqyJqB21to7hGBBfyGhkNWs43/Wud9ki6EcffdQa2UsuucRkviNuHAmXyffBg9PVwbPTmzW2BxxwgLz5zW+2Z8xmm21mi9QPOeSQmrCUSVqJYcSI77CxlosF794+v/71r7epMhQongmL2+CX6+BJ3WpMSge+E5Yk1a55rcP5nDz9zDI585QZcsZXF8hppyyVU07pktO+skLO+MpM+ccl86VczIfRHxvxYWeZx0ok3JeCAgRRnJBeERh6Q/nh4EOG3Tgzgo+h8hVhlCAfBYorzshCM6UFOnhFkGGgGOxqtabAR68yZBgueEOJYaqEUYGdd97ZjjPp7u62tZyMEHBCNH69UYzvMwwe0jT19pOpKkZ6dt99d3v29ph2lrP39t13X5sic+DO6J23w8Q7Y8YMs2OxuwN3DIdf+hl+mHS77TqAv3cwsXpyD+VFFaDkyZQhgQ4laWppkba2zTX2raWQ20oKspUqNNup23bqNpEXE0JyBQ1tPR1VGM0GEMeK+lNgzz77rA3FMazGt2M6OjpseyRa5e9//3vzgxIEESFuulBHBmRSM5s8ZRh+OO2dWUcCvJt0NCIfqHhJ7jKMHGoFvy2OXIOLhQYN+YycZjEsDeEpp5xix5wgwz/xiU+YEnTfffclITIMJ1zh8AXprpjUU0a8vXUwnRkrMix0jtti/Kbj4HDjG264wWZ3ON6GaVAHfivhB1Qn6kvdgci9akwFVVWakhEgYiL/bLxSnmZ6q9Cqdq163yrFXEFdW9StTZ0LSVVXRcdeH2KskoNn7RjYbUqBQRuld8BwHERxJQcFiIVVjsZRfvoDL47Rlu7GBxStpSqUVjOIpM5KL0N/kW4E0hgrvMQi2IkTJ0qL9pyhia/hpBFdFY0yDA28/Vx33XXtNG7/JAn2XjYsP2GXFwqOw9vlGNttt5192f+5556zZ/z4QAXLV1jK8vjjj9uUGgdecpSNK0D49bT4deAg/GDUKuJQ5SdReIINgxxJ/Jr9MOShtp5mprpsdCfiZ5Qh7eWU1ARFSmHb4FtT3aEEa6+9tl3vvfdeGTdunBk0VA5A3Hzzzc0NeCFllSdDhgwZGg/IZ2Q3jeB//Md/WK+fNT80pjSsrAFi7YhPvWQYGaC4vO51r7M2luUmlJcrIkxR8iFbgL0jVoK48gmrXXbZRS6++GIrX+IkDqY7Wb5C3KwH+vGPf2yHYX7nO98xxSseyKi05a4oNASqY0hhG3y4z6s2ky+hHGk+bYeXOthp0pwRpO6WB/1JtsKbxuQgDsJzDwE841xRcjgs62tf+5qdFMrQ6ZFHHmnnETAlBnw+Ev9OvNEBn5F0kmYYOkBpGDA8DQay0svQX4wu+TS4iOUzi5859JDG75577rFG8eqrr7Yt0n6obaUBzDBs8PaXNnfjjTe2NpbdXOz24rMlnAvEri92eTlof5mlcQXIy43TvDkviIMuUZr4fBWHXaI4EReDGRtuuKG9B8MooIeFTzAe58iDdIVdYA5b5ZuwKEt72B5Pm5Aro8R1qFsY/bGpbfMVbhgpCiYJbh6ik6DTRKCifPrTn5a99tpLNthgA9lzzz3lv//7v210CMKDrLJk6Bu8AapXsdDoYcOEFZ2llAfLahc0e8LDvlyJI6n0lXgzDARx/R3MuuxxZfKhMeCjBnzG6E1vepP85S9/kSuuuMIO2WOt54QJE2T69Ok2XeLKUobhAzSnrtC2cnAhZXTLLbfYtnjWajFVxXKUeKBiiy22kIMPPtjWb2HvigsLnZni2mqrreyMILa+M7LELrCtt97awrtxRcfLnWePqyKHRxx8E4xt8NyHdiAW+0GtCdfQLvAU+N3OTqx4Du1I8Kv+LEJaGCySzLtiw0IpCuK1r32tHczEoUunn366VZIzzjjDCIaJiZlG7ObuvCNt78ZhxO8HqtnVOw27ckoyDDfSJRjKFOZUbT7HwVZeSnrlVg0+Ep404Dt834VyxYbhTi1r45Vu9YYPVvWH0h8NCNUvhuU63A4zvN65EIyvbhzuL+3GNV1/gT/H1zicL/h0xP7cxM+O2N6vaT+rD8pjMOPrHcNR+pwLQ2PK4XicMYMixMYWpkn4OCqjC6wRiadXBgteNi7Xefb2BjgPjVXEeeeedUD/7//9P/tKPzuxUWZe85rXGJ2gGwZ/e+yxh3zhC1+wD5d7HE5X1gKdc845doYQp0XTZm+66abmz+PApMub54rdIDLmynLPgf2qXqTpKROD57H65YmiBlWqqAs0obPcqoZF0CoTKjvHCB/eomqetRbhjfw2aZuSMCAZZ/HzZz7zGRs+Y+iMb8W85z3vsSG0d7/73XbypC+csyiSaz24mxcOcOLGzB/HwX3svy/AdwihvxSw3WcYSdSWoDKjcNgaQ5MwIwsw4QN8qZ2dzwA/qOFigWFedjR0mRGM2uS0IpSNwZukzLdf8p1J2NEBKFELntN2QwOvV1zjOu91kiuKiddJtwf+7HY8+xQ49xiHh/f4/V3A/dF5ArjF/oHHh30Md0/be5yDB94zfFIk5GrwEdOT7dGs9WHnD9MpdGa/+tWv2m4wOrpMf+29996VMIMF4vM4/eqfUBrsd41WOP+m+Rg6jR8/vkJD3GM//ozxuunPTlvCM+XlwG0ksLLcc2C/Kj7QNKvcd1iI5JFriEHzbHUW+ZQ40pu2/0SOBY/mM4Z2qAOBMZMnT7aP4bFYjkOTWDD11re+Vfbff38blkOTRDvFb3d3txHdid0TvGDwj/ECI5yPIjlWFVdP6F8oL44qUTMMFaC0lw70prybTc8J0DsUGFNwUGZiv7A0I5LuW8vNiozGE20/2FXjz9ATqFcu/Lz+YRgBmDdvnixdutTsMSgY1NMVK1ZURgn8njUifvYIdZc4lixZYnHgz+H12K/+Tq6vvPKKLcp0xcdlgYP7dHr96vZ+31f0x++aBGhM3jlYj/UgHGvyyU9+0k4OxrBYlsP3fvOb39iowVDQycuPuBcsWGCfbGAtqSvBwP2MVThPO1/HJqYN5en1xuHhHH5PWEd8n6EWph45odvb222hHCM9DMGh8Hz0ox+1IVIqDl8MZtU4wD+FgQDjmoYTHWFHL4ORJMJT8RCiwP3EBZgV1poGLdtyUzAoQKq5BEWGn8TeLLTc0Wq4tY/UsU2xWe8ZMdIrPgibj0aTSk02KpShZ3jdjoGCQ+P34Q9/2BZNfvCDH7R1BvjFsDuEEV/qK6PBLJ6k/rIukAPzaLzYPstx+8cff7yceOKJFgdbdWMBzL0rOIwYIVPe//732+iyK0QgvrpxeJpA7Ob27pZhZUArZDNynVEeOq/IcRRaFFaUVz6cef/999shfGAw6BmXC2ngnvJmCQUKF0ss0mU81uFtqPO4G7cDXmd6oldM8zQyGteH0jR8H8aZlCvnRKCksEuAKbHPfe5zdkUIspjKC6cngmPv7uwkY/sdu8g4hAvhivDlXQB/Xvge39BC027XjCEGG1C0lqpQWnmBkRw7n0F7pLmSFG34RnszKC8lhCVPjA7Bf0G94Qu/rPUJU1xJiaEAmcLj8eJW+8YMvYO6xveB2GWy3377mfLCKC/PdHioj9ij0DBywIcX2V6L4sJU+LRp00z5YTSBY/cPO+wwU6J22GEH+wgju0ZjecD7qOs0sKxnYHT57W9/+0oyIw2XHy5L3M5BnDyvKh5Q66eWX2CnNVGHdto4nSgHtr2jzFLeb3vb2+SII46whbSsJZk7d27F72DA3+/3lCNrWdjhxEJdl/lgeOR+Y8B5Oo2Y7rhDn9gf7um1c2k4nTF+7/Zx/EMP3ttzOvuC1Qvdd+SdMD4kyTND2l/84hfl2muvlZtuuskUmIceesiOUmcxlYMKQ0GlieuER1Ayl8l8MwKVr9yymp25aC+kuCKk4fFkGB2oX1rYasU1hUYrJ8+mAOmTFb26qZLDV1mKefVV0Pt8ty1zLrLOByWoovQktzUKUC2CSzAZAuJ6xGJXNjVQv1FcmNqmUaKO8oFMvjqNknLMMcfYCBEjBzSYPGNYpPnXv/7VFtaiSGHn0+M0rnxfiumyWCZwAB+f1GHqg2l2drtwxhg7XRhFQsnC/xNPPGGK2De+8Q07rZZ0e9qJl/NL6ECxcNfhcqTvWJkz1mRegTZuKHcOyTvppJNMLh9++OFy4IEHyvrrr287hIYCXn68n3dOnTrVtnPH9pgMtfXU6fLYY4/ZYmhfpI4Bsd8YMS25j/31dD94GIo4hxa2BsjhxONTGPQIEFof//jHrUeI0KMXyKFZYFXaKIoNQ68suCM86O7utoXW9Cj9XcThhepHe2PnJq0J9wqNcvQVwRoMK2J+fApMK2Rl0bKWs952l1TxKbVIMyvy1RZfWs31uVV9tyufqa2Vv5q88oIpUh5H4KEYWflXUa/eoHRw/gdr/WJ3RnLY8ckIj4O6znQJ0yQO6iOdInaIbrvttpU6CpheYZrFF7piT31GIWL0AUXogQceMPnygx/8wJQwBDwdJRQiRppxR0agULFuhY4Z78Mv60deeOEFm6JnKj0W9qQjK/uV4eXDFeWHJQ6f/exnbY0nO4koc0b7H3zwwSTE6iMul1jOA9oNjMv8sQboEdMnDeNjNfhhqvDkk0+2gyupEx7O43CaxvCw7uZhgMfdrzZ1ENBzbvuI1Y6gZ1RGgJw4fs/5A5z/w3kDFMSkSZOswnB+BAREMBEWRo6JHAM/rEJHsQH03pgHZigd8B6EIVv10HIReKwZchCvmz5Bkz+EtMqwCkD7lenvtgg8LcvkTqRL8gVVfpVHLr/kWXnjG/8ubzvoEXnrm56Qtx78oBykz/970SOSa2qWnI0EcciVFrDtIGN9EEpVc/Jci/rpGHuIhZwrKYzCMIqDkoI79jRI1FFGZpj+5hl4ZyRurFg7wkLmTTbZxJ5x93io636KPPBwbNVldIizSVCQOHWYDhYHrjKqwyjEL37xC5tGY/QHg3+UnDvuuMNkA9PnX//61217L9Pp2PlaEt7f9/Ku5RdbdlYl0xoHyhIaURaUDQokHVFGYhjFgw9Qchl9yzCyqPCyXik3OitMHXN8AdPR1D06EYzSorTijyufp2KBucfhV+KgnuEfxPXY/Q0u6sc5kOpVE9MQ1s+VWw8FgolvxvzkJz8xQQfRmdvnGHUqDISMCd0T3I1CQnhx8BbnUPiWSwqI3ug73/lOG47lyqFcHs6ZYXDhPcXBjjfDShTV8guIXbDDMHXKCIHIzGe65cYbx8lV128iV163hVxz7cb6PEmenE7jqz7L7AbjQCxioiHnDtbFZOXYE6g7cV0CTD9QnwFu3hvk3nd8OajndGI8LMCOOHxUCDc3gMYVJYtvDbFOiK3WTJ8z9cU7OJ6fOBkd5gvX2CG8aYz5ICf+2XTBCcWkk4aZTtOdd95po0AczsrUPKNTle8SVpNXF3H662FN5iBo7covo3xsg0exZCkCIwsomix54BMKGUYOcT3lnhFTBgT4LAYnQjMlTBvKMhJGWtmMwJQ167coQ5aYsD7X6yWKE9PabGJg5obBh0WLFlncGHjC+WLwQV5GR62qTIHFBcBOL4QQR2pzz2K5b3/72/ahto985CPmJyZeTwIGYYlAZTj78ssvt/l+4gKEoXLS46Q3Qi+Rq48WgfR7BgdhFEJjt98MQ4dAae3VmAHhLm9HdNKwmqU0tbLLay0p5NrVe4vy4iR9Xl+aW5MzLGyUp9nCha3xYT1R9QyhDD3B66b3/hhlYSrEh9Spg9Q5eoooLEwzYQfq1T3qK1NfTJmg7Hh4rqxTYCE0PU7eSweHK++hE0R8bu/KFWCKjLje8IY32OcAGCFGznDyPKNGhHnjG99oghx3puX9tFtL4ypkrcu2sQzoxCgaU4+M6r/jHe+wHXyM2tEpZVTOeSXD8APaY6gXXFkmwkABszCM/lDvOK6As31Yw4U/RobojPApEzYzsLkIpZb6RHtNx4K2l44D6+z4BApxUx+yOhEQpGIECIMAo6dGb4w1ASeccIJceuml1nPgWG0qkxPRCZqG2yGoOI6bYW0qIHEz5+8FjkEgAheYwK8ZRjsoW7au05gmZVqGNwrKfElZh6/WSbGg/ppWSLmJM2VywvIfENQn/Ks/U3ho9FQRyneEa4Ye4fXUwYJlprcRmig91GUEJb1LRlniKSzgSgvwK+tI6AzRoaFXSb3lmThRrhg1Zp0JH3Gk3u+8886m4GCAyw+ugEW4LLZGKWO94KGHHmodIhY748aING6sW6IxYBQaNxSoerInQy2gE2X385//3EYUONeNEX5G0xhdYHcv7pnMbQxQLxgMYNccCpDXB+rC0UcfbXWEesaIKec3cZwBMye4c8wAo3zUD+odI0IoSyi9tOHUeYAdZqyjLgWYW0dwuYBBGWKXAIXhSAvFNAhHZUNpYt6Zs4DYTULPA82V4W0KAH9eENx7fF5AfSmkTAQ2OihTjDbGjOZYEaPMhJILF7Wk7HmwhlEbS1+ckWOkwEeRvLR5xsafM9SDN2wYBCuClB4/CgtD54ymMKrCFBSnBW+22WaVOsiVOpk+5HDXXXe1xZl//vOf7bR4dpFxpZdKPaeXmoYrOz76w4iQg3DEx7A/U+Gki8YZwY7y84lPfMKEOlM4nE3EsD8jyzXT5faboScgy1F0r7vuOuuAOpx+fZGzGYYWXu+8LKh32PkIKfzuH0Rl2hLl5sYbb7Rvu/3pT38yN0ZRKWfaVzo0jAqx+4+1tXQgvI31+jjWYYugnfBeGViXwxAcc4h8CR4iY6g8CCkKiDDxiE0aEJh5fnqFvl2WQxUZquPsCYbNV1UInp7egA/3lQnBxoIN9FjpNOmFSs19PvlIHepLUnIJD+WLzZLvapF8ic9dsDE+4Q+bAmP1DwpU2CdG5GX8lcM0yugE+U9oMASg/sR1yO8ZieU7QYzsMvXBOgGG1+lZep2kXqPIMITOifAuNN3dFyKjPBEHi5uJc8sttzT3GISlA8WIEAuwiYPR5be85S2VePnYMgckctgi9+eee65Np5FmtuVziCJu7D5jaoz3+cgGsLza3eqCWIZPkgxd6QdAF5fTTBkiw1EkkcUYlE3OeHv88cdHRAmyckv4cqzD6RDTw0dN0/WPQQk6M5zVx9ERjO5Rp5g+pu2mbnDMBaO0bDBg0IHOA2EcHtfIgXwOTtkPNJYeOZ5eAsoPW05ZG4Aw4spaHgqIyuLXeqDAWPjIwmbm7lmkRS8RYevD2ISnEOIC7y8QVV6Mg0PKDCMHrxD1S3LlZmm0lzg5GvrGlvrlBiBUGc3ltGfW+lEvN9poI2soAXWS+ksHhl4jw+c8exyExy9KDUKV0RriYmqtp04RU+l0fNhNShwsgGbaC/88805Gnzh7iOkzdoYh5Bkpwg+NN4016UVRQ8ATplgcbCFO2oePr4a+9KtA+USJhJaMuiGDGTWAlhkaA3HdgfcZ6Qx8XrQRIR+NpX4wTUYHhQXSnMLO2iCmwJg6oxPB4ANtOOf4ccQEx9rE7bXLg5EDeR2cGjDQWOpqLwgpFkyxDQ/CQjgMQ20oMsCFYT1hhz2ExrhAxFCQbnDDjivPHm7oESZOhlPIjVnU4Y0MIwOvW17nXImJ62VcJ/GPHX64Yh/Xa4yHw80N9vXg7oAG19+f3vTgfvwed0+7p9evoFAgzXbbI9zvWATlA6AhC8k594eROkYMGDngEyjYDdW3wDL0DZSPGy8HZmJYr4UdnQtGYn0Ehw4FU9ZcmXamLPfaay8bcEC5PfPMM2WnnXayESB2gLEuj45OrOwS71iH7QKLCcEzPS92f9ErxNAz4wRoDASnUnkYrl7JHNi5QSASJ4Z7D0cYF5Ze4Ol4hgaaLrtmlX3IkZT14MPLLivD/sLrpF/jugy8TjrcL8brsft3ewzxuJu7O2K72A/G4+wJsT+EN/duD7DPJ4voe4L7HYsg79ANpTGWtzHN/X4s02mk4WVCGfg90718Sor2mFFYprG4egcABYdNRii0nKWH0kN7TecC5QnF5/e//71NH7MrjN2bHjZdzwcX8NPokM0rUYECwLhAi40jLiT33xNidxe2blzh8cJwfxlGJyjN0cH2YxNeh+NrXB/dflX10Outg3CuKHkcaWAfG/fvbp4Gh9/7u2J5BBDkHsbt+oZav2V9TViTtmbCaeb0jssupmeGxgDl4bzOFCULnwFLUtjB5Z+Z8bLDoPT4R8qZNqOsqR8sfGahNNPdbjewOjP8GK7UmebhhIwrhxPJCYZxOPHcLu3mJnaPBSRXtxtU6Ouy6txAGIHCgON4bcYHAV5XAXWO3V6cBcP2deqfu8d1FGAf18/YPV1vsYtNTyCch439+ciOywaufg+44of1EAz1c6ZJHI/76xvGDmekaeiI7dzgN5b/GYYXXg7A6xmgXOB9dkGyNo4dXs77Xr6uMKHgMGWMO2FYwsLBiewYc3jc+B981I+zynkDxGpH0DPyMfEc3DOM5vecuuqfqOAZ/07AdKXxgvQCjFHPvie/A4ImaQhplaG/GIHCgCt5bcYH9cHJypzI7luhEZRxfXakFYy4jsZ2sX1vSIf366rsSYenjQWgrEPk+2Gevv6j+r6xAKclMvz++++v0JJntk5z8KXDaZ5h5EAZuJISY+nSpXYWlpefl6vfg7Ryw2gRJ0J7205ddwy8/vSG+vxTK1kGgNWOoGfkIQpEgyAYDlfinA0+Tghw53RJDstiNTnPrvTEhZAhA1Uq44bGBnWcNQVeb9OKTyODtLLA0wX5wGRPbRiOmsqPHhIMCBxdwu4v1oi47IaWl112me3eY+fQ0DSIGQYLXm8d3vamjbuBdJjRhIHU7IHAFkFjIBYHIHKuAAcYcpYAdmiP7B7gCH22xNNjYJjNBacTe/RA82vX0ZbuUYiERwYfXnZZGfYX1GkUCK5gNNTjWLCT7v6m1fM41gCdGAXgHDbkOOe60SCiBLGrCHsOp2U3ETK/kXkgw2gCfDQ6eKmiAAHO+KGHxRZJDjTzoTPOjaCysFWSj6K6IPKwo0vAqKZs17EpFIcVmUBtOKTrqytCowHInYHIm7HcsLNwlqkvDo7kfBhf2gDo5HI+DPThq/sZMow1mPRzIcjXldl6x1Z3FzKu6NBr5DtgTz/9tD27MMqQIcPow2iuu5nc6TvYBYSs9m+8+Qiay3xGgjhbxr8inmHNAmWNyVAf9ikMgFBhyx1KEIgrifthQRUVxp/T7iMB3hzerr+ajkw0jjwq3DBohRFKuRLvKMXKOQj5Gkqk6ybPsZ13ZkYTXO6AwVeGoMXwSZGhpjzbo1Fw2EUEXAFysKQBmV/vEyYA+jqN0xteQJr+sV8Pm/bD+90u7ZahPurRcfABXzhv+LvSHOp+0vY9o2fJ3cd4BsdLXVQUIK58c4dtshyf7Xbufs8998g111wjBxxwgD17gcTMPFIIKUzSY/cZRhIVbhi0wiBGLd/wMGrRKDkY6fo6mHD5lKE+6LCy0JmT/dn9h7LDjl62RvN9R74ftf3229v0WE+Axr77tx5Qdlw5issjVpjWJJ4bG+itvPpX51Zb7g0h61S6UjA43+ehsvB9Eb7vQ6XhFEm+A8aH1TiWG3dfG9QIwgfaeDXLRGGG0QW4dwhrd4YBgPIYPkkylKXvSgefL+IbjJwk/I53vMO+38au3uOPP1523HFHOyWYtZ89KSnYI+tZBoHixE5hdpah4GCPOyNLHK3w4IMPylNPPWXPvmMY957iboQ2JMNIAZ4YnBow0FhsEbQzKeBjg3yJGTu2vTMaxBkEp556qlUgTqeMw2BGFxO7PppVvCFHwlMZMowkXLaNNSCXfeSGA/H+/Oc/yyc/+Un7kCZKEBtafvjDH8qGG27Y4wiPy3YUmiuvvNIUqRNPPNHC87HNJUuWmKLD1+Q//vGPmzsfv+aL/X4qMcBPPYzVshleOI259kbvsVcWNd8CQ6t/4IEH5NBDD7VvjFx44YXym9/8xk6OPeywwyrKjzM1GH0M7DOSY6+whx1Dphh72WVlmGHVGMujDJz4ffrpp9sShp133tm+to8yhLLCiD8jPz6SU49O3j4899xzdo4Q36JCceJU4t/97nfy17/+1XaW0WletmyZtRmf+cxn5Pzzz7fOs8frswaZwjOS6AvtmU9Z3TIi/OgoZ1sDhOFsn0svvVR+8YtfBAdVclgUPX78+Ir27pUhrjCYjKkzgMGoOhkyDC2q61LAmv4tMD4fcvvtt1c2t9QDsh453huQ8RymyJohPqrJKM+uu+5qp3I/88wztpia0aXddtvNRofYMcyxKum2gXOIeF9sn7UfwwloXVsHGhHDxRE2lOPMD2PGoztp4A93FCJXfFZVcYYPmg7SlDxlGDlUOGLQCoMYVdkOD70CP7y2EfmgbznIkGHwgLxG6WCqiqUMr7zyirz88ssVw5oe7PjMSD24nN90003l5JNPlvXXX9/s2SzDjAFfJGd3cHt7u/lxcHbc/PnzK9vwMZxJxBohrt5uZMrP0MFpm74GcF99TpfDwMqlfpjVlntDKDZrDkKEiZkC++lPf2oLoLny8UE3zBffdNNNlUrhcGYeWWh6NE1ZEzPyqHDGoBUGMfZtLwF+eG0j8kHfcpBhaDG2JASdVZQb1usceeSRZo4++mh573vfK+973/vs+pGPfMRGcHqT4y7viY+z4E444QTZeuut5YgjjrBdZbgzi+AYN26cTXv5wYsoYjNnzrSdxChMPqvQGG3HWESQqcH0gorzKvwZ6pflasu91QzeG2qGe2BSmPP666+Xa6+9Vq677jpbCM09BuZlhX8asTLU+MiaoaECzFRTBUYVX2RYU1Ern2qF9Jr+LTCWK6BssIP3mGOOMeWHHWAoPkxpcX/44YfbeUE9yfG4w8s3Ij/wgQ/YwYosdG5ra6soM7zLwWiTzxYA3Pbee287eZppMleMiDdTgoYH0Do2lEmpVLRrjVvifyQxXBxRWQMEWMT2pje9Sf7whz/UGM6P4MouAuZ3Y2JBvNHJwFmlG73wssvKMEOG3uDymZGaD33oQ7b4mdEbNyeddJLt3Npkk03Mb09AkWEtEQucWTxNW7D55pub2wYbbFD58riD0Z6pU6eaggS8jeAdjAzFbQbtSIahR7qd5jnYQf9QBmZnd6sDYlj9WIYDNgLkDMh8LQzKnDHDmewQYOcXhnuY2T+mB6G8wowuBvYCzirdkCNV4TJkGAmkBf9YAnn3nV5puNzmivHRmnpg3Q4LoFlUzQdU7777bpsVmDFjhmyzzTay8cYb2zKJhx56yL4yf8stt8hb3vKWuqND8VTZ6Go7RjsYbYMnuPq9KgF5v68OhowVVLbBc+U0UE6DBjzXOxvCtXcMzM0w55CBV8dmTCMjQn30beH7YPRrBh+kKaQ/5EGf9Wal/LBVKfLnpicwiM1ffV+1dLBYVxVhw4PE08CqLLNnheXHn9KZ8+dA15VBPFFcPfjLWbn4u8P7Gw2TJk2SL33pS5WTnpHfKCPeiQUu/+spSY4nnnhC5syZY+t92EbPuqHjjjvOZgYmTpxoX5pfsGCBbbPnnrVGTK15vHE7wfSXv8vTkGFwkG6vDeVA63IZZRSDAoqpPuNWKmlZFRM+ToplTS8d40qvEIcccogNk/qOAQCDMpzpa39gZCpRjN6Y2AuEq5seoVppOeeVEH9q6ng3l6iAQtXSOyqy3a9pgCbdFZJEN5WL3UDbyGmkUOGGQUsHMdZXYaypykVKeOwJJkmnYQRpk85BrkS61VSsVSiVVRjZPXVBnfQnp37IJ1xAzeOaiCl86a9e9cJdcNNGTroqbnZJbnMq6EKc7hbHNlpB+ruNQkbKmuxA44TAEfm155fcNUnJGoYYgdruPahD1ShZN+TXnNGvS023lpf76DuiJA06kLWM2vP5Is4D+vvf/26yGxnOzi9OgPbPHq0KbHn/29/+Zlvbmf7i/J+rr77aDkXkPXvttZcpQ5wfx9lxX/va12zmgLbBTQwfGSItvbUfGfqHmJaM8iAx8kmb+uxTy+V7339Ovnb2Ajnr3Dly9rkvypnnzNXnF+Saa+eaPLJ6kShMFlMlunBDjMFV7/tYbGm5VwX2fYhkcLzUhfJfaDy4wpQwNdo92xWdSVkMzaK53//+90ZghjC7VYt3Yveq1Chwxy9KVu9+42xwr6YPOQsxBuWqD95HIcgVZeG540qu06YxUEnJoBVGyF/9HFIdqwq5UUZrZhm7nDZMg5aG1Uc6B67SVG1DU4tgKVujmuQr8UBW3ASVCEMc9Ob9GTdtVKzhJyB0UD+VjkVyrUivSEEYtSAPKI5QpQpTUMKd/VYBDViEq4piTunjq6ArgfHPQxwb94SjTCJ7o6MbpyWmMYDc5UOoyG/WciLTkcPI8Oeff94+cXTeeeetUhFhlIddX5wBtN1225nhG2LrrbdeRaazMPoNb3iD7L777vYet0/H29t7MvQVMW9WUdu+ch8WOoNnn14i3/nW/XLW6U/J2V97Qc5Rc9bpz8lZZzwm1177knQjKgqhDtWUUK9t9qrRk+TuM1YzeG+oTIFhHn30URu+3GijjezrwLhhOAWalf/f/e535eabbza/VBh37w3uztUrmQ9/roSyuquxW4yWQkmlGD2r0CgAemaa5kSAmz+7SxVaj/Di6JvvxgA5VnpDA0s29MPQwHMlR+rQaFlaBW8MBgJlQgU3OvBvAha6hF55oJY60NjRKjYKrOxIY3i0xjVPx4J8FdWouykviWKjSS+oMeWHXpoZdYjug66jKlCpScM4HaBPoFFZ4w/1KbwU6vG2YEYr8prLQkIxCEQ5q7UayFPhw+TCTSmPzy6lQ6feQxtoglKEp6BKViSFXoIN/giT0NJ+wxQCJmcnKvZPoawkaQiArGVjC8eXcILz97///UqndvLkyfbMouYf//jHtpYH/73B5X1a5rtM9w6u32cYSvSNc8xXMshRVF4tlTbUu230YScpF3eVpvKuKiK2ULt1Jd+s/rUsg0wYDpC6wakBA43FcurMetVVV5lW/61vfcsOvPL1PtOmTbPti2j3F198sTF5bxp+DK8w8dqh2D4GLq4AUVwlbRwYyg9GBbf12hTaYjRSOzbUIKuIa6Y2ytJhJjRoSivoZTSDcSENDVwQ0GMC5WbVa1qTh8Bb4ZdGqcWeAqvQnHkD1xgIak0hSW8CeNuqI9KIciXNYYolOGj6qTfUI6tL+KFRS0YIPTKuGr6s8ZRtdAR6EL1ykilBSSOu/oxv7Gm0gzx1al7oGHAPvaBbyKuNixlNlbZmlD/KLeoL2kEBaI3fQI0KTYimSD1Lwph/fVSNtJznAMGilUIgvRdAY4DFy5zU/IlPfMJkuisnyGNkOCc6s1uL7e2rgsvvWN4jw3n2zm3aPcNIQ+VfLtT9XF5V+BI83K4GmdkqxVyL+lD5kGuWTmX9EvKnwXh4KEG9rSgzzAvvsMMONV8GjrV5hjZnz55t97g706cVGYdXDsIz5MoCOr4pg31PYaqKDeKKgXwaCIwXjBrzUz/8quHFO9DwI4OQWlIOLWBi1oskjZ65jnx+VkrBkAnC+E3Km0FjMGvYCpUHnjFa2TOg3BEEQ5WmgcCVFwfPNLTck9akWa1UCtKOwU/iVx9Dry2CTelAE65xWIUNN7k70PptcSSPoxrQBHpSN2ycTO89v4BrklHLMEbrkq3F8mdHTDuFOUXhFebDygZauuKkHT3km941ArzjyWeNAHIXWewjQch6DsB1Gd9fxMqOtwVc3WRoLOQS2cDMSlE7y7ZW0IQko3d4oBxXl3sJv7pxDA+o+RWmXWeddWyxs1caV4xQdMD06dNtzjdmbipOT4zu/qhwbJ887bTT7HTpOHwMxjh8ETTDyflSQWV5YvSeBZwmuPCz2oU0ekDzZr3XZGqDhbKi9DBaGNPy44tAEWxBuA03hp/t9W2s88kzQqKApYwW2hhRm5PEUOfzRivosjLfjRhMiSE9JBSj6aNcDaRf3SjvEiMVKET6TDZw1Z8iRp+oMQi0YHDXP0Y91ASeCFcQ6lJTqEtAhWDOeIcGfJRC6ZDX7FkdUeUnZ3VEZUxqSgqalEy+QEGjmt5q3eJR/dCxsPqj4cIUewhnF5M5PhpHWGKhwadceAdysHYEqRGAvMb885//tGdXfBy33XabvPDCC9bxHSjqdWbT8r2enwzDAed1/bUi4J72PSkjqw/sDOySvLIGk8lBogwEg1fGw8UtQbNJcNBBB5kCxKI4/4YLFaa7u9tW/f/73/+2sx0ADO1M3RtzEwdbKNmKedFFF9n3YVyhAnE8JmhY5EABcM8tbpSH3atRYW3TYYmiVIWV6LARbnihwrXcqdnT3PFvWU9ySltvw/NBCEMuSDeSqLx/0AqDGGmg6qFZK7bzExUb4igfcIUYlTTQcDFdkeYbvA1aQnvFSjmwtLJbK3Q4SKyVsXlLGtpkeCakkF/qC2kOzoxeWO6NKWiAuTLqSucFRUCvalVWAQdQBPNMG7oCpLRjDZUrSI2OdMNqIxdGHDoJSj/NbG15Qr/AHyWzh0Zqm9ih/BHOgB2jQTwmCpDd6k/JRonwqb1nKp0BP8lorCpOIZaRoWOah12uMvLD+k12bvE5DD51xKcs+IjpBRdcIKeeeqrt/mWX10ARl0m6fDIML2L6wxLIHB/RyZsb9V4NMsVki/Kv8n1B22SaZdtMoSbmp9Ut054kd5+xmsF7Q5ACCfiwHbsC2MbIdvgvf/nL8pWvfMXuv/Od79j1bW97mwkdr2CxMlMPKE9/+ctfKhWRIdc0nNjlclG6kxXr5bIKKnqxfqWx0Cs+czkf3o6hLhrPENJqxBDIo/RG+JJHSA5N6PZGHbqyCn/yn5Bz2OG0r7x+0AqDGMl/GrygWfPrPMUzxIEogV+SoAGMFtVpoIZLaK+cg0rCkitpZiSBexYs6o3+o8yVWPtV1vRrHaHRZjSC3hosYFWDUQs15aLWkWJJCsYk9OYS5SqXMAp+LdLwmLORxKAojQbEgrkCI4DSROlTUpNjXQ52SgIjZaLsYMH6p6AEISuU1vnlaq3GoHFrMF5R1AYiTAtpqVmZQEtqIEpRiK+iqxqc71hPsdoiv9+ox8Muo9/1rnfJWWedZWs8keEf/OAHTRYzGs+nMdiyjhwf6DRYhgaGsUXCGxV+1RvlC+Nk6zgl7aZaB6zMS31D/XD1JHe/sJrBe4NLBpv2orLwfZhf/vKXsueee8rixYvtTKA99tjDdgp8+tOfrig/gErDfW8NCO4cjnXuuefaaaHxV4c9LAqNPSN9LLcIKu1nsViTbXl5LSqe1Z3e/srndvQHXhwDLeThBykNQ/LamCkdEMg8og4W80o12jBt4DAMc+LTy2g4YekMtwFDlobqW6o8A+DHMJZhVRq+hLXUQBsaKNwB9BkJGtWCtFji9Ja0oPxr2Vo7VNCyVvuCppMpPnYraX5MxdXyz9tOJ+xR8vRZQ9iKOa0v+UKIr6j+wi5KfbapGrW2KZAqzUJTjV2og6MBcbkF5Q4uKEs32UQmkSWlDcpQLHwZ9TEyk3+7wUBDFCLiVVoW1K1APVNaa9xFpW9J6xj1jLFn6B9Gg5RiGpz1PsBiM0ULOpOAkUWQqyo3k/RxMCHn+CDHv/CFL8g3v/lNufTSS62DO378+Ez5WVMBjybT6oHl4U0skZDUg0QWqD2dqYo8Wi1YBQy3A8Rw1SD7FpjDKwsjQVQMegheYVCIcPeKFaOnhgR71v+w+wCwDsjDxvF4dBPGTdSeaxDUeWlRsdyqhGDRL7P7TerWrEJJBRztRKVXNwYAgQLPara7pYvpMOhhf2HVDyRk/QNcXGKqR2nfU7msGSDHVGLlqTy74gJY0NdtCgF8pJRJeAseEmlTd+WfSNiPKI1M0JAu5+WQFk8SzsVSl6a9WXOidUOveVXkcjlGvLRu5JvU7zK91/LWRjtE48oMHAKPhPNxGEwCxbI249wnz/ZOhKAJwsYG8mLlEWcyUlC6tGhOkRms4wk7XOCFLts1icBQQNcSbsobRnvopzxhO7s0Jo27qLQs5TulSd/VqrSGhoGK1LUWLY+qUgGcjGZjD0mD0iBwGUsHl928nPTPCc1Me/H9L+/4rtmyIoPBeD6RDwwk6H1Yw+abatxPuo6tubBzgIALl3iEJ4bbY7xSYef39YAb/qlkjngRHu4cxnXJJZfIX/78Z7n4j/8nHSuWWTncdkennHH2/fLVs+6V07/+sJx5zkPyrW/fLgteXq7p1LRaQQ0Eoc/bSEJqlUDZU0a1Hqbmu1Rulkv+/qScecadcuaZj8q5SpuzTrtPfnPeTFm0KOQr7vmOGHrhjUEDPRk0wwTku1sfzzvvETnz1Ifl62c/Kmed86icdtaj8p3/vk/5R5UlTRd/sHk9Xh8+8G5/Pw1nqCeWLp5VscsXmmT6Y4vlm+feJWec9ZCccc7Dcsbpj8h/n/u4TH9U3ZvYykquCzLr+U759jdul3POfEjOVr4454xH5Otfv0Meeiic6g6KTStMifa3hmpkY4k88dCwoKw4rt/LzEctbrn1JTnl1Lu0Ljwj5571tJx92l3y85/eJbNfQvVjjVjwb+ufLI8qy/LQjNEi5YNEIsA3HIayfFmL/OI8lTun3y3nfu0J+caZT8mZp98uV135guqJqoTauUGMwmkAIyCNCLekJ0yvNQJi2Yxsd2UHurlxhRK/KyuXGdYEODcaqzJibPyvRvk18KzyhboFWTC2UOF4V1a80nDvxisKbu7u91Qqt6uHOAwgPgfxsjbIThjdbjvZaqvNxUbv1e3OW4oqdOaqAFoqZ5+6WM44bZ4Jopfndmpa1EPU6I0JaKZ9iqug9Lz0TzPljDNfkDPOWCZfO03NOXPl/F+8LCtWqNeei2ONgy1mLVYzbHdKpF/9dLac8fUl8tXTlyt9Vsg5X1uu/POSLHyFxeSByVCke+PdIYfxcEU8VX5D8migO/SalyenL9L0ayP8tQVy5mldcubZy7Q+LJCHH6KxZaom9OpmvdCh7k/KaWcsktPP6JbTzlyuSuBMefD+rgpPlFhTF8Eb//i3kREWaSap1QvmjltfkW98fb7WhZJ89WsdcrrWhe99a7rMfZFDNFicHDpdCH2EfzAJ3TU8lK7clwvS1VFQ/nlSzj57nnztrG6j5Rlnz5IrL19oFGpiu4w2Gtp86NVKLDHcE3djIVZy/OoG4I6JZXNjoR5d3U6vfUp2f/IWxT3CCCWk0JugpPQzTfj3MImyE/KF0Xub/lV7VYyqChA3lYc1GjYFtioTV6BYEcKkt1XGSFeo7u5u6eioTleAKVOm2A6EXXbZRXbb/TXS0tpm9k3NeWlp3khy+V2l0LyLivftpLVtPX1fKBjrISt4SlJHAhuAZYcAysAlFm9C71yT5bepaR393VKft9dC3F3vdxJpW1+p4BQZOQauvHnQCoMYQ86qIHLKW/NqCkAAe5rs7Ki2DfRpR+2b7yJNhR31fgdpG7eV5JM1MGFFGSMf8JGboeWelXMQ8oVyEnZlaWOt2Wkyb+RjHDeavVbNz6bqc1tpzu2o162lMH4DyTVRV0IjTxAU46b24C+X205tt9N6tLXmmankgHy3xsmwt1sYGMEIoxiNDhb6e923slcUmifpL/ndXGm5ld5vK01tm0khz3SYUpmRGgW0hcbkleMADCW9L4b7nCqH3EGafAsn5mqcGl+ThDjzrVMSLiE+FCv1aY2Lj6jxgv7RsaYYhgDIaL+mZXc903iAsmHUwu55NOP2SYNu/9TrijpbRcWvxlFx5D55JmxyDe68i7Wq3lkgTnPoB4jDzaoRXu3vwYSwtn6Pu1zeRnpZkxbQj7Kq8cqDygutDKwrtZ1gyrNhsANnnuHjULeA2TtMoSJtsWXvUM5K7tLAvie3CIPjpS6quRwC+OiRK0LMOW+11VYJsYNdfL+ik2WGISuUg51gW27TONQIhzP68f6JBwUhk5iIbMCEaGRQKUyQYzTfbGfMc245J3mWm7Vqs66hXcoF1ohAgZGlQigPxaAlI5RyJd4a8JJaNjbesbVkSh/WbdgJvtBJ7UIrOCKon4OQt5APLWHSjrWicnqzWpZsnp51LWqoC1r+gdtDowasbuSwZ62T5lv9UW9i5KhD1tWL0mIvDXGMKiRJzpkCzFoelBJoFugT+m2aTxXaRmWyaYE8r1hEz3phhAmFlBO0ibOYbwp8Y3FqhPix2MJkWoDFribEZQ0L1n1AX/2NSRhZ+YkaXLPjhsKlXKxAwkXrNtOcYWG6huFq+gceCKYKkt4y3WunwltjjrN6SqaDwgnphMejvsPeRc0KcfQffQtnybC0897EaHpzdhyG5pZZGE1mOMkcWML6B0sKP8TBlVyF+CpOFSQPldcM4H0JepLcIc4+xDs4XurCqTkk8F6FKzlsuTzppJNMKcLEfuzeTJKkSo6UKe0Ep9osxgzZv8x7cdSUdoOjloWMTpb8QJfgFlRHp2VDwATRMKDee2wrlQszDM/ur0qjhqKXomeKJXmo5LUHnyY4tZk3f6zRq/UXchvq3miHl1y1LtS7IiliadEzguyJfWrdogNn9Ao0C+8aUrGZoQYQPCqT5NF0BCsZDAoN5R2bpO4nQbFxGRD8ahmaMsE99oz2JNNBFoiOQzJKGAIPAEli+4ToJZVbT5umRDPcXCpIk+9myDAoGPKaHCtATHexE8FHfFZqfNJlG7hc/ZFMdr+gLCVOfWasNQH0KKGh3lYqR0/ogbZrKKDJSiTBoib/3Ac+TBzVOOuvFLphUMlBSL6mNDTFdqd58Xo05pAQxunjVAjXhFgDQL1Q0DzEnLjq7cBizzBwoIgk9VWJH9bBcMTBCjV8JzJMadt6FhvVSUqIK7e5pHNoUz+q5tpMQjJ6ZCa0L8GEXZNm784DQhJHBaSZ2lvPoMCRfr2vvFP9E4TpagWL75km7/vYYoa+wFuBIQOLpNkKDxDYvqDa56N7h7onZwQFrMp/X+C9wdHESKh79XqxqTxYg4iv4HO4lSCrr+E2YMje729RuqjAS7+loue4Sx1FIdBTedD9NDI0/SEHXhfCk5dvnINapUhzp35iPrCzheohNVLU0EiSWklxtcAV9fPXn9wFEoZ4wrlRUWPWn4gyDAKgu5uknG0dGAjTwjk7zbhJVQmmQJmaRE3gHt/a5pS7rV6UOb8p6BthZC/Hh3NV+bCpLvVvhrB2Qo6CX18HtDpI0t0DLI36Z2NWZA9j+VBlLFnfSNI5F69kR36Qrp7jG3n0nt++YLhy5xJ1SIDgRdGB+bjGdrFQ7hmEIXx4shGhBI1c/EMDzXsfaNYnsg4RRqRMNMO+yDVGUBlCfymoSGoDI9XQh4cRJFgfEQ4y9DySXq0TtnI62DgqXvqNAQdsCIR8uyKcECXKUuAFblJ+Ugi+4BO7iVD1j9NKzhn6hb7J/jRcGUFN0DgYGVHFx76PqO0C+jtKA75QJuJSovxRclD+rT+tQZEZoSzVQpNTtEIPYfwuxMManGA/cPQc3nnN0qjX8H0/N9Uv9HGoaTjYdCC0Gy6sLp2GH0OqAAEf7QEwfq/Mb/QLRDRNHO5AaFmYoAz1DPWj/kZfEfQFgWbp3n2gR2TXIJWjkopBKwxiVN4JD7VQmtTSJSD2He6UVnSjEiU6CJzh5Zb6OaibqxS8DiR1IlhV4Qsj1UvFvSba2HMUhyKwTF/S0DhwNvdUu3wIuVo5/9DdHqP6USGB2nm52K/aV735CCGeq37cf4a+AX5Ly33nQa4xP6ZBdY1dbRIY/6ophBkj4uZoiy5Tghi7ydkOro7gDx1Gy3FFV0EWLhZZpNavLMfo8/IWeXVpThYvU28+/aRKFtNqVViktYlYDdTmlXobMgj3FtQNm1pjGVA6aL7Y+FIen7jU0nPIUHnNwN+32vVlCLMKJUcBSCaMGJgBrKzq6LMy0DCxxQig8XNGCjGVkhm0JBNjP9WVyrs9VenE+HPsnvYzuKifg1XnymanVvK2cprtLnns94xWNLo6+rGqBqIuQRWE8XDuHkkaaGTOvcWdIQ2UH2/4/VDcWBFIK0cBWlvsjJrEv63N4bt/TAtp+VoRc5SFKjt6NSWo2Cn5UlGNNrmlltDh0ag5Ff7mG1+V4z50ixx95MNyzHuflKPfM1M+dORMOebwe+QH33pMli8uJI2hxmEKFG0Nakkb2pG5DBZC3jlDj3dAG1W0Nb22PknbuLzmO295UmUs+Ygx3wgv0NGx0zoBaarScMhQeUVf3lWfTgPpaNbENITZDGXeUOhrbgdKFS+OwWXq4UZVfjROEa5E0UjIDS78Tb2VYX/KF7/98T+aMVRlMtLoqfz6U7aJP0hko2r9CZshhis4fnUlp7m5uXIiNYgVoZXhk0EhLN1bVAYWQVM8JWYW8hz3ENb/5Jp4ZtcwipPLxTD6NOv5glz+txVyxT8ny5WXT5Wr9fqPK6bJlf8qyF23rbBvbgM23DBiEd5IHB7PYAGFh3yzFAQlqCylor7P8oKzf5uOCTC1yof1s3wLkJGtQr97NiMBUh4o2OgY7NJdTcSFy70/D0WhjwZGWhViRtMrUsF68qOD+QYdqyzSiN2NvUYhnXpJsk0BYJLnDKuLPlByTRAjQ4B4VAclB6WHD2EvXLhQurq6Kssi4nPi0uAbeGbMmYXPnBNXlk5VGFZ05WXZipwsVrOi2CzLuttkaUeT2jebYlTOdWh1D1NjKBMFVSTa26fo/US1V1OYoEoHB4lOkZb2ickgTzJyVG7ROxQhoC+3Dw+HkajVB4pPQfOtSpy+lMNLWeO3VHWeRcW8LOlu0ftWWdbVIss1P51dYRF0WfNRLC/V62ClIwNoMAWoJ9SrIAOVPK7dj1aQes3DaMjEiCYy0ClDGmsiTYa6rKP4a8TOUL93dCJWaPwehef++x+Qn/7sZ/LAAw9UviDgV/zVGqWr7drSqykxy5X0TAsV5PqrX5Fjj/iHHHv4PfKhI6bL+97xoLz/8HvlyMNulh//ZIYs7mxXRSmsCeO7iTRzLJQu2JZy4mMVNDu+UCbK+hp9X6Ul1FCmcVWXW5jdIALlh1aImTw2ef3738/K0e+9Ro561/3y3nc9Ku877Ak1D8u73n6l/OgH94d8MBLECFfNrugMq4uGpWbcOfdRv5glY7ET36+ZWLmYglypraQlJdTgVtWxAqgWm5HDwHi5TpotouraCwcnhWOVtm801EsfdrFOPfhZSCKsvIPnxqZToyPe8bvTTjvKR477qOyy8y7S1cU6GyU1gt4WILOIGVoj00oVmR+2qYc1OarGmCR87tlO+dvlHfL3q6bIZVdMkX9cOU0u/8dUuerqFrn/Ho1Ko+TTEdUlxXQYiYkF0gVbI2TlWuBdOVWSiDsgtDtxJ1nv7LMpLEdGYUIZ03C9sYa7VdxDGoJFGJGK9ZgXnu+Wyy/Ny9X/WEuu+OdE+ccVk+XyK6fKNdeiNK4InnKMSrUm64bMIjEBQWkMJgYjWZXGVJ08Z8EbNArx1IYaO4iKYeThbAKKCGo1VjxagFwpRzoFAcGnudtdcF9TC9LyZYvAQw7DUGiowMFKf9Q9HBLmFBnLgA6BVnVhjON+0mbkUElSXbgDidd792xXhVrT2Lgv3LwOVVAKawv8hOiiDcX3PA0xEoiFOcmqJo2boMABOyBe4Wm3fNZktr8gniTSiDcCRbWuOZ3dD9eK3cCwWsltUMTTXzHGjx8vG26wkUyaNFEVgGTRjYkx7oOSk7PFv9CaJ6Uta3ogs4xXcjdbG5FvbpF8YWO120j98k3EtVWt2USvG0tbyyRpVv/NKDrloDCBIuttCspP/BGf1gPqAmiqTLOpFSND7JNPQlpOtGEJ5wPxp+kkAvy7MWCXso9M4CKNDUVP80S8TqVCfoq0NpH+9SVXmKIJmqz5Wk+fN9F88p07TQ2jV11N0sRq6AQJ24fX+kME7LRqVzxaCqxs9KrZIz3hkOE4NYOPnmMevPcONBbnj8YDZVYp056zhxfKGMDEg0PO0YAaAiVIP2foHY3HLdY5HYxk0WlQ4VZtjAJvmDrEf9IFNee0kjTCIM2eboS4ZwE7E/TJc7KMpOJuGIIqMJS1aqzV2I7OZckiZZQPzT0NsS30bU5aI1cUsGd0hmNU1I2FwsE6QaKo2EGBBW0DuBJPX3lZ/Zb5hiJrfuJmMF0iKGPdGidHK/oJ0orKS/DPqdRq6JS6PVem1vSKCeA9bGUn08EGcMpzONRR88T0nKUn5AcljuA2glVm9ChEFj4lFSKBLr6mKkahQFqhXxLGFCFoT1hMUgYVA+L7wUHPsQ3euwYay8pUa1AMXpGgxYMKV45SDB5FhgxJzyPD8AOhiLLAd/RMVib8DvczDRaEYUCpSF9b/xqovEhLGO73K0JfG6FCvpLO2vQGPxkaG4WmvHR1d2tZ0sDnpKjtcbFY0Ga5VfmwSTrLzWqabLc3I3zFIuUdyhwONo6wYufHjSO+7xnEEz46Shp4cN7hHcl9EpWN1dhouysLqqi4xm0RcTIz01S4oSZx0d/KFn6tf/brSBQcG3JK3mX3GNIU3MN0YIc0NYUpMEZpm5rUrtJxCVfo4t/WXLlehA5DSAG019yZ8gltmYbDn6fOw4wtjBoFaPDgPYTRXuBJJWxkuKAYdHjZjc1K2xdAGRaMcvpta2vSa1XwWRp6i60t4SvxBXUvNLMgNNCyKjxHGqqoadpIK0oPaGtr1TxpfpK0o8hlGD0InJWM7jHSoXj88Vfk5M9cLce85zr5wPtvVnODmpvkA0dfLb+58D5tn5HX8HHepmsNBA8XGJbfBDj0jX+DLxr/Tinlu6JBIFs1Y/EQNQoQYz9BSUKhwVWNJQDlgu94AfITFCr7qrz9JaNZCUhaULwwGl+OaT/1oQpWOPMIvxqHJiZvC79fkaaWpXpVtStZLN7UxEiR+qxGa6DeQld22/noaag7hUr9aSpo3S/gxlQj+SMNaQXIr6uDOL7GRqXYM2RYXXhVyjD4qA6j9w14t56fCsZnnn5ZHp3+tDz37JN6/4wsXbpUHn74YXny6SflwYcekfnz5qv/fr5giIEQp5e7aNFiefDBh7WhnKHXh2Tx4iUy87nn5PEnZsgjjz4mL774ogr9JFBdjB5hPDaAUhvOvwGLFnfKpRe/Kn/+S4v84eKJcvEfJ8if1fzxT91y/92LtPFWtQM2VuUHDl2ZS9Nlq899YOXgJcRoi6UtGk0bmpDdq0JiCg5yLTmEUZUTZBzqTTCEH6e/49XwoVULEu7Vf7jSyEZqEAqdKUA0vShNvF//fE2n8X1ZlZVlMq5tgTz42FXyne/9Si75yyXy/POz5cc/+Yl8//vfl2984+taJ6YHJcZSZYmWK664Qt2+Kd/73g/kz3++VGbNekF++tOfyQ9/dJ78/vfX2ggQHaOgxJEOCxahktIRxUrJGiJkCtCagMbg2QxDBORlv4sYQawCrrm5Vf70p+vkkEPeKQcdeJCceeYZMn36dPnwhz9sz0ceeaQ89thjkoumlmKM1IgQr0U+P/vss/LBD35Q03+IvOc9R8rdd98tP/rRj+TQQw6VQw89VH75y19qg5oI9AwNDXiY5r5U7JIC0zmKkpZdS+sWWnp7SqvsJoXcnpLP7abqw47S0rKuTYMVGLWoWwGIY3X5UyOOo7Ao0bh4QI0J4zp0EPiDy1iVg0pj03RFDW+f2NGHMjvWkl1rFocqNpzkbB9j5Yof4uVW46gOOymSDKLoqb9cvihNLR1y+y2XyRc//19y/vkXyDNPPifnnHOOnHzyyfLd735HOwcLE94HKE45q8unnPIV+fznPycXXXShPKEdhbPO/Lp89jOfll+ed6F0dHAGUzjnKG85CzkanPqTZG4UYTBynWGkMfr4LkM/QK/SihiNwOBSNFxi2FA4V/5UCLe0NMsOO24jCxcukKeenSVzXp4rS5Yt0Z7h8zLruVkyefJk2XLLLUNgjz6CD6cPJ2Kla9NNN5MNNthA0/ucpXnZ0uUyb858eW7mTHnxhedll112lnHtTInVIUaGxoMyc7xgl4XOLIJmI3qnutkHP7X82bXFjqzKrJfyIcHgxhAahzDVFKPKOvhU0xtbULFs1EUv7s+C6U+uSR58YLF85uQb5D8/dIMc/5F75PiP3i3Hffg2+chHr5a/XTbLglj1IJGloPwwpVaWDimWOvSZ74rxSVXyxIgSU12qCGkeCce4DeBqi6tJj7oTb7nI4uxxqgRNUrsmmwLsJqnJ2p8DDzxQeX8Xu/fpL/DWt75VNtqIHWVKJw1jZw5Znlpl/fU2lNbWNrUjrUp323GRKEGVkS/zzM0AMNBwI4dAzQwZBgEw0+irAqMDJqtNQPUDKtS6i52y997byGv3fZ1ZFfSP4/UTeSlve9vbZKONNwoPDQYasylTJlkaAULe5H+S9h132lUOOOAAmyLpmTh4zriyUWBHmihf2tfcE9hUrRq75juUSVlYjPIQl2r8FEZj7Ik1LFo5GCWtoBqoLoIzE1isu8GoQmB2QO8sspzMebEgvz1/hfzmt01y/gWtcv6v2+XCiybJBb/ukvvuLig/qsKTZ5FyUHTERmOaJZ8bJ4VCs/Kq1rZ8ixRyzdKUb9cou6WUXyzlwjLNY1VpMclp7yQO8sMU4Xi13UTaW7ZRtwlqwm4wV3YOPvhQaW+fkDxTp0NTvsMOO8jrXrev3RMfo2fUo3Ft42T/1x8o48dNtGfyx3s8r42G4UrRGFSAvM/QeIXeP1SrbMMi1LQhgJfdaC/DoUMQriVZvnyF9ginyIEHvcHsWaBJuVA0k9eaIvvtt3+wVwtrVipCeeRAGhDoPhK0335vkI033iQ863/SCdZG4GCZNm1tU/IyjBYof6nykysmhRg3wHbBXcuereGMSiiMC3yNzEoIPFJBjSbUG/y9KC0+jRRQHVUaJ23tW6vrDqrWbKfX7bTB3Eqac9tKS+tU9YVyob6VV9lswJqfBQtyctedRbn5lia55Za83HxzLlxv6ZbHHm9SXh2vuWBVkL49SWuoe9zwG95eVD9dHRNlXOuO0tK2sTqpH9u1VZatttxKXvva1xLCQH2xdKhhkwMdBhY/W31JsMkmm8ob3/g6teMpjEBVoZbp59UCkdVE2LAYgwoQjApWt5BHGqOAwRqgMR2rcNmXV21BZaIceOA+su60qdJtiyaD45577iH77LO33ZvIarDy8vNLdtppZ9l775BOUk4Wxo0fLwe88Y3BLuzzzzAKYAq4NsAufXO2fibhOxQe+4p7q6oSYYFwEHP4rvKtoaI4qZ3F2V9oWBuFQtFSBagStSoHdkijphG9qKmgykhJSvlmfSWjPk327F9yJ7y1KOzn18uTTy2ST3z8Rjn2fffLsUc/Jccc9bR84D1PyjFH3iAXnPeUdHSFs4dQcyp1lHfaXaKM5e2NsqyzJFtt/TrZdNPtNX2sIwqr/ffd57Wy8847232s/Dj2228/2WKLLcwunBck8oY37CNbbz1JOjroLIRRoUA7bjDqzxJRjWcsYJQoQENZKKOtwHtLb6hGw4uReCcYyHvHUuUmr9ozVQG5YkW37LrrbrLHnrubSxENQsn3RlUgpkxOhsQbTPkJQj3ct7Y224LnIOxxZPprJ9ln333MPRb+GRodqljkOlTJYJu3gnUxNg2VLkMabtQEoFdrqGPE/Dqw8ldu0t8wBVYrTni3Kjl51iSRTk1zvlPTgPLASeqki71jGkjrki1wbgoRrOjOy3OzWuW5F9pk5vMTZNZL02SmmllzWmX+/ILpeDnpUsNC6ZBuS4fdogCiBHFGTzhccautN5U999rF/MLn7S0tVhcY6SF4iILDDqsjpptvvpnsv38y4msdHqa6D5UJE/n4K+nEhPg8r8GAEMdoQE2R9QvVPDaWAoRW770BGN6ZnuE/T7SnPfFXzYo+E9x+estWNYShUrG4ptwaBOTUtmdq+qqCAFsM5z5gp/0Qp12FmYcGMZVsC6lB36nvRzCYQKmB2lXS1htC6LTX2jwH8ImHlRBbJcKgCos53BriZwLGZmjgY4+1UPqR4SQpltU4maDfSfJy6FYBTi+wWyaOn6Q9Q0ZMQnmts/Y0OfCAA+zevA4ty/QbPhrlxchany222Dw8KF7/+tfKRhuub/fBLycDR9CASQyJgbbuA5eYqO4zSJlgkjD2Bygnu1kF0nH3jr77XFPA4mZtvJOMV2ib8KVTm+8acos6YDYm/4IfKkmJtTJ226yefT2RlmASbwhVeagPq2zEWfXHKE/ZRobyptP46GKJbfvmhu+cfcWdUHxl3k+jBpy509Q8We+mqhKzjrpxP0n9riX5AtvlQ3h7tf1Q9ZTvbHoLK/WhSlCQqzlpG98lBx/8Bmlp1Y6K2my48cay/xvDtLXnl+U/rvww4tPc3KL15UBpUWUJ66233kpe99o9zG8YuWIKLMiIEA4TeJ8rN0nS7DEg5Bd7d6v4AbYWK8h9YgoHSgYPFtJG6VLyXW/81t6uypq9I1glUD8ET54M0fttPZla8PkUe06FrniugOeqXcJRjQoSWiVkDaBKuFFDNvATZz9NiDScEO6vzjsaDIFFPZ1edPpsVuSD/Md+hgr6Ln1FhcJaFvb2hLMrCsuAk+Hx2EUR8lR5rAAban9vbBzC9gziSJuhgTeqVaz8vton99/fNEEr/UPIlYrSnWyleetb366KD98YCtNfu+22q903NkLa6dW+/vWhVzt5rUny5je/xe4BZ8T0DGiRuKuwD5TkuRrG+cwaIpcrxlPcuwF6tVt/9nh6478MMcJGchrmRGlR8rF2xmkYdiYlRgsm6AW4BaUEIF5s0THPrCfSaygRPNMQ20Md4G4R2jXcccaPvr8SRnkk+fgpgyeh48l5Pvp+vUcxsVjULag8GlCVoKKlT2+VFzkcEbhyUfkjKkseSluzKS6gnGeaze4sbzb3Zp/HYDF0p7zxP14v2269rfk4+OBDZJNNwy4v7yQA7hkFcrsDDzxItt02hHnTQW+SDbSzwAdoWasE2GmXSO3IAJMcyb3CyUX6Q3Zi1wg4ugLED+Wj0DIk78EdE6PmTVa6PNfGr+Fr5HttGMAbKnV8JVe172WKNI55dCCdvwhWQBnWUNSrQL2gFz5pLFBBMeGpIv8HCQhEj451A3vvtZfdc47O5Elr2QRAI4M63d1dkra2Nhv6B9tus6285jUhH4ZV0ss99FfcwW89C8/BQD84euxBi63aCeobqvTkru/UHa5yCPqJ/thK/sCPvrW9imqmOzrLsvHGzarQ7GfPhx56iDQlp0LXg3V6tNJssskmss8++9hi6AMPOkBfl5fOzm7hszeV+IO2Fe5XG8TZU/2q5qcGdRQTUrOSrQbvKx/0Nzf9lQgjhp4zFpOsL9kP+uhox+hQ9khkbwlNuzmXDzBzNcE8Lq5uGg0kuLcGNklzvwubcPTYGOpmbUCIp7W9VQ4+5GCZNHmy7Ld/EKjE3IiUATQWcS933333kU2198vapXXXXrtS3PU/ieF2fcmdx8Q1ufdRzLrozS3DYIBR5KGjclTO9VCXZTxMOtzKdqHL0RvfJe5JvbaJn7o8rNA63NYSdkLuvedestvuYdS2J5GA8uPTYQcddJDsrv59A0Ge4TR7jabQXp9Ktz3yU2s/INRoLNwTZyqPqdf0/a0r+8Smv8oyGDUK0OBh5SG00Yie6ktjgUR6QuOG3tg13NYgzhT++14lVkb87rEG6FbNe8wre++9j3zkox+V7XfYQZ+CkrQ6VB4ONDUFMcXOlg984Bg54EDt0WqmOOQNDN4msEanxFhAXAarKg9nbPe3uuVH+P7Ggf+0nFmV3Kl1z8HH9trEvtKSs36vaOcs7rHHHvL5z58sm3AcRK+dJo0lqfD777+/nHjiCTYaBFC0CnZWUXjfSi1h6nH1QYRDoGIMYjrHoAI0OkGdGIiGO/Kwmj0EIF43az6s7Ptc/lWP1suzx0CnHXfcXj772c/KhHHjpWhba6s9xkaEp40rizs//vETZN999pVubRj4kKshyt/QoK/KOH4al5aNiqSEg7FpkXoNfL0ySMIMO/ryzj5U1lV6Cbu7urpEttxyczn83e+WllbWT/X8fndjMfRGG20k73//MfY5HEeJxUtO357e3+PoJ/b1yqYeiDx6Qf8EWC1WQW5zHqAMaywFSOnj2quRS+/TJEtnk3x7Dxf/NnBKJaoUYjWEx1VloDBfWkVP9yMH0hfSCC3IgeUwoVOaOtj7tdatNp+18HekTX9BCML5u8MWTLXVx0p6tFzCvS/Cc+hT8rjSm82BsrIHfojcbrms5B+Y5+BScY9fp+D9A81rf+DvsBKM0uBvtffbQyqBCZAd7tJTudcixBymv7S/aPnTMNqVnDp1imymPUJ/Nz3CRvyqeqBZyK+RRw294c0221zWnra2PfsHNUN+/R7E9yGu5C5x6p2G9t5wZ38BXON7UC8Od8tQH4FmLg+CDHDaBtkQylyf3Vrh/gG7XsOjx1H1GPsz5+hxIKh5b3IFWAfeCLa1rwlp8XoV8qhXFvgl+bGr33MTp7sC8hneUig0SWt7m3VaeoOfCO10HD9+vNIyhCkUnJ+DH2hczV8lMSEzSfsZaM29GtJi1njQ+8SPIboNcSZheNa/8N7IE9DHYB9iJBxP1dDJk/4HX8B9hIv788XdAeG+GqZnNOwIUE+Jj2kO4mxXoZ7qRFARhJVA1dBeEKBC+AaAMzKcF1KUpMuSu3ImPYtpVBl9Zfg70qYn4OLO4WI2tqvBD68jbX5Xk07LR20iQ5p7SHgFpCm5BfG9o8aO+EKc9fJS5YXe8zoYCPQM93H59PWt8LxRUwNXG/PeEAROWAMU9t0AgprRexZH5jlCHwcSMrQk6DecZm7gq6DQMWXHEf+F4GAgR3HPlOeY/3pD8OuwMPoTZEDVvj+oJMuQxDSwqDLUQSBlTND4PuIDI3y4rT7EcjQOl2Alq2ABz4WSTMPdA+r5qIuVXs9DYhE1ciYteTT/ZSlQZ9XU8lgtQt0Ju8IYCXKZwSXI3vCMnxi9RBmhGt4Q3XoMvC9Yu1/3VOM5hdhfLWLbkJVgUy1p3qd/1uHuHxpWAYpRQ5Z0KdlzYunEqQlQ8xCAl4Qpqu4QsOoXYsI8w21Ig1+rUDvt7YaevD0G5k3XArXXoIra+Ny43eoaDtJj/YV2yO07TAyrWnrt/UkagSUv2NdHcPBcePb6Bg2Ffxsy7ymgCgJzc5MIE4XlxdPtz6tpqrQOeQmmlq/w58mt2q4Kmo+a+c9Vhwy+w6/7DmlMHkgXfMIVElKeUV5G2qxMR0u08T08Vix2SyGRXu4W4FdH/KwZ7ZFfoEewr1Yrmp/wZ0jXtwp6jtfK3hJY751jEbV04KlKVadTMHEDbfxg9vCx2di9eeFnpaKp+g+I7/uDkJYArnQqwlNAVYYY9LbCj5G1JbASDgc16d58PWhkvI+jHhYvWiyvvLJAFix8Wa8LE/NKXbNgwQK7Llq0qNpu1EDjJQnJU21aQS9p82lK9VKNOvbPvRWSgnt3i/3UgSUmXY/Cs78njs2Q1LuYP4D598eah1o0rAJUKRhFfF8fIYM1Q3IJYqJUYBHyU3VdsmSpPDZ9ujz00KPy6KOPymOPPTYixt/NNZhHNE2P2P2Cl1/WVGuKNek0EuE25AOQfz5+t2jRgpp44utgmOlKJzdV+0flkYfDlYoXoOy10hZPR5VhvQzCHY1OGlElsDJWY612Ai/35FKFCicLF8JzUBcjCctXLJLHH39cHn74YaPvI488EuVj4CaUF4Z7N8GOdzz00EN2/9JLc0NyLKMkmofkOiggHqdiuO/q6pJnZz6r6dA0xWnW8pqu6cTEeRlpU0vLwGfcU2aPPPKwPPvss7KiM5wmHFjMyzhNx+g+oneV9vpb40X/IgasKD8JQmgPEJ7SWDk+7Y33WA/GJmKlIVC4+lylbxoR5bnRgEFJ4sGNl1ege/UxPPMX7OIwmN6Qdtdni8Yjr7rbK5M0hc9+gIQ3FeZk4XlOwlXuw7P5SaKGToysd3d3y6xZs6z+PvJwaA8wPdUbZDMyhzDFYjifp2dQH5CT3OqPKltR8SRpSWgXIfZCyYTOpkK9VWSuw/KYgtkFGnFXHcFxe6617+QxZbNaaKxaGdEoulVEWa44JDeRU2CuviH4ZUQgBOru7pJ58+bK/Pnz1MzX+/l2TZt58+bVNfX8Yur57c14GL/OnRvuFy58RTpZDadpJsVOhphOxqKasWXLl1fCxXH3ZPDXH1MTFjo5rV7Gbb50dPA1Z2irqaupSatCGKEJwnHlCheAm8cZ/AUDEnt7jP1VgQLU1d0pL6syGfLzck1+0ibOd2zq+e3NhHDzrGe2bNkyS2Mtv9ZPb5+wUrBqxPB3aAhKykMLZd7cuTK3kq65URpXziOm6t43Uy8OTD2/mHp+MbX+QjordVMNdCxqo5DkUo0LTL9WG8vw7Ijva1GhWsULIt0fcE2FrSm/GFV/hOcpTs1YRrV+rwK9+DF25kf9WFw1BVc/HP4qDax56Tn+WhB5/YJeZQyWB07qtwd+IkTPlofkuaIMBaA3h/yKfcerU5V+Rq67u4umFNGx4YpB0eGZKx3kzs4Oe47XxyTNnSEoagn0latWBkK6wqR6FDYBI8qOims9xacGSZyalnoxVt3tUgc4BBnHX7qeVZ/rRzCiClBgyjD0DijYsEqdB80O7ppwzvkMv+nsKVzekUEr3SSjdsE/jrynYqm/XoAae3BQcLx5XpoK4TRNWyOhqnfa8A2WeqaeX0w9v72ZOCxpCPacCkpNCOkMv6Q7FHqwC/dmG6W/GkdTzX1s4nf2xRAPR75j8k1KzYIa3Cx+Tk0NNA2LAJ2+ASG99VHJRRLESzuuqPFUEOWYnCCfIPFf80OMCZtr2JKafJ70B1qEvNSnCyaddzf1/HpcaYN/rpQj764IpIq8COmkjKv5S9Et4e1AP2ik14rfKqB9yDF8TBnQu1N7/bF0N2s6kvQU8s161Tw2qW9MkrfY1Mtnb6ZeHJh6fjH1/GJIV6BfuGLHGiAPZwLPs1+hjRI0qc8VN+OiYGeNpcqX4JT8alj+8Bd+Q7G4YHRetvgr9E7i80fAQ5IOJJU72nQeW5ltatjjcsQRjBXUo0N4dh5359A+hHsX9PhArjjlzN3aivAMwi1T9EUp28F/9lgpv+CevMtNEj4s+K2G8TLFhJLFb9W/cZfe1+hWhiSc+vW0YROABQHSaUuHUS4ss45HbRH/aulr4eDvYAhTvXr9ge9M1qi98b3Cfu0+cHWwBXC7c7r+ElWS6PBrFvqAv+DXXfw3V/lav9roO4xO/JKX4CX58fq3Mip+uTeTPFmUfl+tzwGBJ0LZJOXDM2HsrneQmxGBKz8umEGhWYVdS8hAmwrqFs10izTb93ZbpFuaZJkUkjNBAon4WC9uHGYe4mpR+zb1G7bIQhIKJsdHffU3nIFQgJGMoEVpyYfhwaZ8u7QU2qS5OSetLTRWeb1vrghcjD+T3tg+NnEY7kPDt7K/tL0/E4ZvuNSGbbX02Xdnkny3FEpKl6I0a2XgIPW85rlZhax618asoOFr00Jc/hzHHb83bdyeq5vgn4ZUadpSFn2N3pf0Xo3RTCtdcyijFqUzGzCbVUtpynVqyldIi6Yxb4s3+B5QONE0MG2X2pS0/Dgon4pU1DyHvOJXuUPjL0ibcnWT5rUlX5KCliEH2Te7IEFKKGCRVjvjmDiVBzQM72jRcmvRtHGSahNKkJWj8pnSO53H2EADv8b0cPc4LAYaVA1hWtQf7yAelNOQr8DKVGDlV+qBcm5zUf0bWcJHFwEKS6vWFVTL5hzl3iVtKvQ1RnXVuFz4Qf/8CrXtkmYN2qJhmsodFl4rluSUuE1NXco70EDf06TvU5NrUaGpbnE+6+XLjee7ft5raeQmrjNOb38X9+l3Nms5VQ3+kribNKymvQnFLSlvDaW/aqf0ajU6qo2SRL0o9D05OhDqQwnQovTjwwUFbbGgk32b274lRSgkjZaI0r+p3GWyo0V/KR/KqbkcyqbSVPCF8HCncWk6lR+RQy1FfQ5JU17XcoT/1C2X69awlCvgl8YA+RNiGY1wOe6NrCO2s2vi3N7aKuPaWqW9PdT91rZmLTPlUSsLLTetysgLFPc24xXzltAuhKH8oXNTLtRv5RitOdSjZUZ3fYVCy1PD55KCGKf1nDqkXRD1rWWv8SM/+LAFPDOhHV+hZKzAFK0q4zR15sc4rKRx6BPtUmuOEieE1m14O5FVfLg3X+qy9LFgOaRP6xyGemxpg4m61BiDSlthor3HOFeZr0njD9lWXlLebdeHgua5bXxOxrW3S3vzBI2ntWI4JT2+p35xxbS3j9N8hG3wLW1KKc2b8S9fvEdOWz6oU+3qTz0hk9XO60yutU39ankk8ogTpQvW61yiIkXzaOQl5VA2fL6jpZW2W9sjzSf1h1qFzCZ8u8rA8SE59h77LIiiRds4KIDsN5ml9NJuj5k2ldVtbYG+DFLwNtCiCS7IUo1B278S5arlou/Ia9h2LXtYjBisPLVMpKR5to4IUP7UKAtnKBKbYYNXDBSWFStW2ND88uXLZO6cufLY49Nly622k1tuni1X/ut2zdo8zc7zen1MAz4ohx+1mUyaWJBlS5bLMg179x0vyGVX3qlke0GKZfzN0EJ+Qg558zRZd90uWdGxTDpWFOWFF5bJXy69U154/nH197L6n6UpeEi22fIVOejQDeTlua/K7OfnyKLFC2VZx2JZvmyZLFum77Br1ZDezs5OWbJkScVu+fLlZpYuXWrPXPHHVFDsLzb4X7x4scWFX+w8fK0/fefyTlm6eJmMG6+NQGtJXlnUKZdder88+IjmReZbXsryuKw39VU5+C1TZXnHPHnx+Zfs3cRNvJ4mvw9xL7c0cl/v3W5w6+7ujvxAF+71ulTN8sV61XctK5pdq1bSQr5Vrr7iUbn5rgeU5zSNWjaiZTOxbb686a1TZNy4ZbJ42RLp6ijKzTc/LtddT1kvVzNLzdPq937ZY8+87LX3OupvqZbhMpn94mL5v9/cLXMWPqtl+Jzme6b6fVx23r4k++4/Wf0s1zyvkAULVshFv75R5szDz1ylDfE9o2l6Ro44ch29XyjPP/+i0nWFLSwkX3H5eZ69DN3er/j1Z7+nHLn38o7j8mfiwzRp69zc3C5/+tMD8sQTT2j6Zkt3+Vm9Piibbbxc9n/jNK0j86VjuVKko1PuvXeW/PWS27UeLDAeL8kTku96Tg44eIJsukVJlq6AX1fI40/Ol99deK10lpepuJmttHlKisVHZf8D1pMNN+mWl2bPlIUL5suKpZS58txS+E7zp+UHny1dEtLKsDnpJC/pfLjBHp4gz/AxdjEN/RrTBzuP0+1jf7g5Py5ZEuKs8JnZaThN1zINgwxpVz7r6uqW6//9tNxwwwOaX+j4tNLxCW0oXpBDD91EJk7UuFcslcVLOuXWW5+Tf1yFrKD+P63mGaXTk7L7zk2y+74tsqxriSzSuBcs7JQ//u4mmT0XebJQzZPKMw/Izju0yl57jdN3aNqUd16cs0jL5V55biZlMlf9PaPvfkSF73Ny4KHTZO31tGyWLZZyURsCbYTySWfLNCyT5y6MeQgCfrQBGe7GEct37u2qDc+cl2bLow8/Ko89+oSs6FyusrlD7r7vCbnmn7fLwmUvKf2eVvOIyopHrC5sstk82WKzgsyf97zMm/+shp8js2cvkltve1au+/eN6u9FqwtFeVjL8SENc49ssulC2XTLnLz88hyZN2+2+n9O5s5dIHfd9YRce80N0lGeo2FUbug7Sio7yhpu3XXnyXbbsnZynsybM0vboedl9pyX5e57X5KrrrpF+ecx9asyR/3znqKmbfvtOmS9jZbInLmz9D2vyEtz5stLc1+U+x54Rv55+e3ahszU9D1p6Stpnopyr2yy0TLZfEuRBa/MkhfnPqPpmitzX3pFbr91hlx93R2aFuTVo2aKMl0peL9stNGrss1OBXnhpRny5JOPy4szNV+an3kvh+Ua1an8+XYfTx1jR51ZuvRVvV8o990/U678xx1K+xe0kJTGpelaPmr0XVts8bJsuFmXvDxvlsyfO1tmvfiszJ23QB546Hm5/O83aP18Uf3N0jzNkK7yA5q2O2SjTZfKFtu2yAL1P3/+XM3Ti0aHG298TG6+4V7plBc1HzOUZuSJ/DymtJ4j22+TUxk9R+Xzi/Kiymim3++442m57pq7ZWk3dJ6h75mu1yf1nY/ItKkvyE67lLV8XpIFc17QdkDfo/m79wGtz/+4VVZ0Ka3VL+HQE+CDTTdbIhtvlte4Z6tyWpbxqggaUIas4xROyM8pg3otHDbEFeT5559XAX+vDdktXbRc7rn3djng0DfL00+Pk0ceXqEZGy/FbrS6Dhk//lXZe982GdfSIS+psrLJ5hvLi7Mnyv0PdEin9u5KRdUNy0WZ2L5cdtu1XTbcsEtmznxKCdAuU6ftIHfey9oCrZBNk/R92nvrWiSbb9Ele+81Xp554ml5fuZcmbr2Wvqm+apxK5GKQUP3yk0vFsZC0x43bpz1WMmLG9y90tOIvPrqqzJp0iTTyD3PDo8TfyiAU6ZMMX8+HejAXw6tvFRUxaKgQr9VNlh/G3noIW3Wn1VaNmtetMhz2hittxZfyW6XJ5+5WV584SVltnWtkSIO0sbccIgvGH83Z0Vg/N2eVvdHOPJNXsaPn2A7v/SVFeS0B6dSXt8xQStbh4ybOE6223EnmfFIhzz1REmKhUkap9Kqs0smTy7L6/Ybr43tI9aQbb7FtvLUk93ywH3LJde8tvKm6vPFTsmVFst2O7XINtvktayf0p5iqyq+W8vtt6xQBVDpoV3xbk1nk/Y0ttoipxVEm58nZsi6a68vreOnyJ13LtcK3K5xateOhkd5aHxbUQ54Y7s22NPlwQcfkbXXXtvKMKY5+fUrSgD0mTZtmo1KAC9rpw0GGrPbgrgoR+KLaci988ZLL72kfLm+bLvtbiqQ8vLsc1rmjBIoQfPlFbLRemV5zWu0v9j5ksyd/aqsvcG6snDxZLn3HlWeiu3Ky9pPKmpPVnuQe+zZLtPWmSfPPPOEbKGdhkWLJ2iHYIkKq4n6Ps23vre5eaHstOt4WW/9ZXLnbdfKhLYJ2gOfoG8r8kblHc0XizUZwmZURPOJICW9lDeI8xLDlZ8NNtjAaEC+oQFI53/OnDlGR+qO8ySGMLwTO0Z4XlThNnHiROWz9qhcQo8vDsO7p06dJjvssKM8+lhJ7n9Yc6M9Wr4OzrEnkyctlL32nCLtrQvk2ZlPy3bb7yEztc9z371FKUKbXLfSW/13r5Dtthsn2++sTdUTd8t6622gPcsN5a7bX5EF88errjJBu4ldUuxaKNtsPkl2361VZs26V/lxgkycupHcc4/Kohcn2fQvceZKy2VCe6fsvtcE7SHPkZdemC2Hv/Mo2WbbTY2+ISMhP16Faqk6ekC5Om/3xCPYu92dd9wpN990i/LrLPs45zobrCOvLlohc15UGd81VUp5pXO+Q8qmKBZl6uQuWXct7fTlVsismU8qP06TiZM3kgWLm7SxXSa5wjiNmxHSsnR3dmh5lmXKVJG1pzVpZ3+pzJn9tKyzzlrKS9PklVebtNHs1l7/ROksjrNpe8oqr7JtwviSyo28FHLayZr9rKy9zmSVIRPk1cXtWhfy2sAib1QuMbKj2WzWclxrYlHWXa9L37tUZe3LMnmtaTJhaossXlqQeS+1a+NPnrWcu1uUPlruKmsnTyrI2uuqnMyp4jRntj5PUF5ZS15donw/X+VsWeu21UWlWUnbjGK3+tG06XuK3XPlsYcel9b8eGnTxryo3SFrzOvA6e0d9R2221bWWmsDravj9L0l6SwVVCZ3aArVH+9UeTJtynKVhyq3iou0PGbKOuuuJ4XWKaroj5PnX9QyyU1Rfm1VFtY6ntfcaSdg4kRN27rIGe0MvPCC0qxZ1lpX87NgoipSLZofzT9+Nf+0zZipKv83WkcraK5TlUytkE2qSG64nry6cLzMmz1BFR9NT7O2n8UuzYeGV1q3t3XIBut2SpumeY527NdSud3c3iRLOyfIc881a3vOeJnyjHY0ypb1ZdpWdKq8adLyWiFrT1lL3vn2t8mkKVqXbapOy1PTBsuOmAIUFxK9QJ4XzH1FrrnmKnnfse/TTI2TZm307OOQyhOMMCI2OrW3OvfFOXLrzbfJgQf/h0yZtp76axOlLW1cwqAiHdpjLKtAuuqf/5SJKsj3/48DlIe1wqi8ZymxxacRlrRR7li+RG6/+XZ5+MGnVXDtLV25V1TIdmqFUs8QKUkrCsqtt96qjfhk2X777U0xwLjQB+QNgU6eUOx22GEHa2gR8DEQGhgaznvuuUf23XdfG7KsCv0A3s3iPRSypUuXaHpLcvCb36x5mSC5FlUCSJoahvw1ySr8l8mVV1wmM1Sh4xswpA8QL+/ze9JIb/vuu++WzTffXDbddFNTiEDMErwf///+97+197uXVqSpop3upPIEumipqD+NP9esCu18k+/vPPytNhLkp5CSK0ZO2TpfKi6X+++5XV58bpYc8vZ3SIuWdeu4NisX/FGvKR/KZpn2oK+/7l+y3jrryB6v2UcbJxolfbW+g3Tgr6tDb7T3fumfL7Ej47fYajNpUyWI8VmUNfzQ9lBKXR3LZMaM6fK3v/1N9txzT2uQya/zpJc19Jk9W3usjz5q355ymnB1Ojqwwx/2u+22m/G0+/f4AO+68cYbZZdddpGDDnqTPo+3YXrybbOBmsZyF8J8sbyiPdh/X3+TvG7/fWSjjbeQHPnWqKwDo17h8+6OFdobmin/+tc18q7Dj5T28ZOU5sEfQJaC7k5GehbKj37wY9l9l9fI1LWmKF1WKGvzpy9Wj5p742OUkLvuusvud911V+OfenmBPjNnzrQRrDcrP6KQuHvsj3t4//rrr5fXvva1MmGCKl8an/vxuHkf9euKK65QpXcb40nnxxiEw98DDzygvLiWHHHEEZJniril1WQAI9zMMNqxER1LVYl8Qa664mr54Ic/pDzTqoKzzWjNaxkRZ4akq6NTFc7lcvHFv9UOxH6yySZbKZ+pAtNMo6R+9b3GQyu0vivd/nHpX7UhW1f2fcPrJN+ijWkyzWLtkTGwymKl+WNPPC733PGAfPAD79eybg7TBWRbPeI1PPjv6ISXJVe/92fg5YwMYeEuDfK/r79RdtxpZ9lii02kWxuutlbtqKgfQoRQ4dqlwqLcVTQ+v/Ha62WbrbeVLbbdSiMtKN2pMKFOAzoQ/HZpI1DWgl3y6lK59rortDz3UQViQ3XNBx7RAuKeovCwnV0lrQJFWfjqYrnlpptUzuwiG26wkfETI3fwE9IbSerhupU3c9rp61zeIVdd9S/ZfscdZOtttpBubexbtNMVUhPeQ94w3crO3UUUD5F//vMq2X6HrezzLnltwFu0PnneYSLCGg26UUo6ZdGri+SPf7hU1p22jmyw0fqqICy3SJ3ODqc3sohRU3aGveud75LNtD5pT0ta2jRFwYsBuYi8LqncYYE1HdkrL/+77Kf1YBIHjmpum9uU3pppEyf6Ol5BFN3aFhW1TItKu2v+dYNstMlGstPO2yiBmFKDD4I/DGGhBc1Rt8pH1jPdfMuNKm/y2va9Tuum1mvopvFT1wBhoDmnviPsS8oH11xxpey1976yrtKgpHzQ0hKmoYkbQxgMYUr6nm7lh6v/ebW+Yy/ZdLONcVEDKEWfTBtmeAWhUiDMEGT0nCdMGq+Cp1Xv15LJE1plXFNJxhc6ZUJzt7Q3aUVRfWSS9g6nqrY9ThvMqdoYT5zQpszTafN9E9R9QrM2NKoQTpoyThWVSar8TNRewWSZMFEb2TbmGjVONfhvUQWpvTUX3jdlvLRrBJNVSxw/fi2Nd5opOhh6wm4YKWH0x+1JN1cEO1e355kGj96sx+MGd7fHH4pPPX8VA23UfVw7fjRdUybLuPEFade8jtc86620aa9pfJvSasI47eG3V9Lo8Rp99V1+727kx+1Jl+fBjeeP6Qb8Q/9J2nOZNJl4CYdR+mnvbIqma+LEJllr6kRZe+oUmdjeomXWZeU2Tk2bluM41eYnaO9+yiSNV+NCoRo/sU0rTFk1fMq7bOXeVihqfpu1NzdV49b0qpk4cbyWbYe6dUm7NtoTNf/EPUWJsBZ50rJba/J4TcdUfZfyi3I39KGsx+lzqxroQ76gD3knf04PTEwDHxlzO/fnz7G9x+d2Hl/sH/pR1uG9k5WmrEnqFu04yTjt/UKr8e05DUOca5ufaVPXkgnj2jUPZRlPfsiL0qa1aYXG02anIlN+KDVTtP60NyvtmqCh5lvrQas+U0emTZtk6wfaNK6Jmt5Jk9VM0XQq30+mrkwaV0k3ZU1+eO6JNtiTF+ez2HhejV+Se+cfD+v37t9pR3yBH6vvTRvC4xd/dh3XanwwXvlnQsI741s6lb+Uz5RPx5MXwk5EppSVd6C3yooW1pksF2UrpZ+mY8Ik4yPCjGsrSavSvN3khV6h+/icppuyU363/KmsaC2q2wo12kPl3cSpPTDKZir1Qv2M0wLOsebCNVID97WN12gFchx5TqPrDXAa2NNYUb6sP2nXRrVVBfU4VX6UtNYQ2boevfq6Plv7oX7owLa0NasJYVijycoRDOEYx/SGtkV7gq32HpQK1hsxAt+udqwwIozWHW0Ebd2IXjFt2gijoFJmLe1N2k6ENTXjNAwdS+LlXdp82Noc0tmqHYWWFuV/7XS0qbxlZL5V8zJeG3HiZl0qYULeQvo0iOabdTqqiKtyPY563aYd/SZW93leUM8YEe7Qa6fWcxREfY92bNigM25Ci7SPU7qoIh/W+PDuYHgm3W7PPR2VNm0rWS/TAuPbCAhKQOC9MBipdEBuKJ+2TWiXJu1stYyfoEZprQIH5Qf/ljZVXIKyqeXUonQbp7TWRrdZ69u4cTlb46UktLWKttZO/fEKypXwrKFrp13Q8iwoPdraxmv+xqncCnwAvQMdQhjW9LQqX42nLdV2p6DvbCOv0ETLGT9OZ2hI2RSU3u2a6PFaLhPHK321ja8ekUMIfEODzpFfAxSjSJdMseGGm6hbeKZShRXghNGr3lPh6MWtu/Z6WsC4qzApByYKu7rQmumNKAuppo4SNG3qNCJUf0paFLAkPsKijS56daEsXrpQlbBxGgYGVLdiGNaPDaMmCF4YzHuoPsriSp0b7BHY9G65d3v88ezh6CEzSpQOX2PU38QJE2WdddeRtddZG6ljw5G2I4DcqOYOjXK5Jnl14WJZrtry+Anj1U+YjoPWvM/fHb+LxoiKEqcRE6cP/wj+XB7KaXgtm5KaYrnT3lFmiLPUpc9LZaoqnBtttLmWHUmCjlAaWhNfKAN66DDyOtPWs7gp73IpKRt9pmZqjOpP6aRknqxKzQRWKlLO6kaRW6w2eoEw0/x1dapCME3LZoKlyfwRFUVtVUqh8TNtw5QeDannNaaHG+hG2eEPOB1wcxr6M6M+CHf4IqZj2h9x8o0eDPwahjjV2EOgQVH5lN0rOe2xrbPeeipcWB6Io/5afvCv8SkNi0p3dpWtv/66mjXsNRw8rn6q7W3YEjvr+edkoipX5Klb4w+HIJJO8kX+QlpJI0IU5YI8x/mI750+dGCcNu4nbQgzdepUq89xXFx5djvigd6MRGGXjgO434033lhlxYYhr0oL5ESZMjchDZ+RP7VTOm64wYYUvfFrjiFE6K7u8BlxQdjOzm5Zd531NO/BzuoW0cA7+NE0sAiUEbXJyuPUB82FlR1TbyZbeJ8+8zJ4l80C6zI3zSYAFVrEGQDfkk6C8zt6Aa1c+YEnkJF0bHkOdKSeIn+UWvrc1b3CZMSE8ROVRkpT/iAaBp4NBLQmynbPaW++u4spminSroqyyb2kPtsIBmXZzbsIhYXyrMarrKSycn1baG3yQt3LlJG9RA2yBF4ARNEdtpRPm6bv0cYT/5YW2I4kUWJJfUWm4MzgBPVmLc0P8laTpn6QRvAYHjAaxuJSk0zvUR+nTl3bFCDyaKMeln9uSBNNOXyneVWe6epaIXPmvKTKiCoRqswQBtrG9QPEz8gklM5ttttKlaZWpb3yIIkwHtQ08j5LGn+dmtQu6dJwK8jPOmvZQAL2yG2SHqbJ9aJ8HOQvSyo0nBKhs3up0mCCtlFMlWl7YyGSeoZfKpKWi0Wg79bUafq086Ft2tS1tO0zOqkXnDF6b+26ESbQ297T0aV8sKGWKapo4p+wXPnR9/mOMejTrW0So27TtH2F1gB+499mLtSTBR1sOOP7laFPpnto6Kkc2PurqTyhAHlOMpxQgrDGGPZsVvaD6DBBjwVzrEYFjPqlIbUKgjA0mqitspO9T+0rVAvrP9BqX3n5FZnx5HTpZOorp7o+AY359KqIyRSUspB+z6PbA54t3ujZ4XmN46UR4Ypgd3sHzyYqlYG23mpr2WDdDSxd+qP/ypA+Xqi0sIqnz7NfnCNPPfNEzTs8zbEdSL/P7dPAn6UFJVV72EHYQ98OJac20CXmr7WiFJbKlltsIeuvt6XGRXwhicRKvSuSd8oIYx5YnxTczZpLJUlmq/ni3Txp+o0XzNqcq5o9/JDcU+CQHn8Y96LgdsGCl2XGjBmVvNbLM3nF3ukG0v7cT0xDt4vt/f7/t3cuYFtVVR7fqGk5T09ZoswzM2qmkopFqTiFD5a3DLXoMRAotVLRCq0MuXlp8oLiNc3U8I43QBDCC2haKabo9ISPM00iiKRZVFOMqSAXadZvrfN/v83hfT9BLn0Hzv/79nv2/ey19t5rr73PPvvIn68z7/BvOwQtAPrhnRNEWzCFDuHcILRA7jS7xycWdsvXvZ0f5gEPyM5aD8/gF73xWnr2udmm5C+yODY4eZ0Z731GiKGVtSEve468/aqNiz4gP8xyG0zwVxwZ3M2gMPJoBsLpKwyyKJt77LGHK5z0A789j6yBtyfKTTs1PqKcm5NJE/zwt8fgDX6kg2fOt1DO2KzMeyvmaSb8A5IxNsBQd5vFW2OeFFOAfCMAs8zcTECoTwa2yCuix6/ebqoaVJ+AevvpT3+a7rzzTn/8z5fIjzvuOK8n6lO8brQr+4v2zdXqKbwN8MIcxl+asMdkMmNR/O1RH0i5Z9FGvA/BU9K4h4d77lbPiEof7yMwLo2B2OoYOaYK9PHE4DMH+oS5UZA8nLZEHFN0uWVRNm+qngy5Zg7iWz6NduUF4AqvKGO0UXobcUytN94FL1DGkHXkSRfhrsEzU7KsXf52/m/TK6+86ryOMhKjNeh/TMB32HEHm0SxpsabWNzf+BJRggyDywkvo5WB7AtfaMIedSWYLCvc2NBUO5li5nUC/Y3xOHjhcOXJ0lAnfnM4QL/AQd+gLnQP/MiUSRUTcx7Pm5O8zJAz90Ch41uGPu5Z2mhHhNLfrW8a4+AvShz33Qy5xx/Ze7w3oDmKs66hbCnEI488kn74wx/6CcEI/9NOOy1169bNOwbh3iksuvOHtOyKgCCXWBlTvNDedOzKS2/hHRS9YYZGy0yMRTGvGkseVyLyunjRWgsgbOOey5YtTa++ttAYt8wZFR1xVTQ6sNGHPWcf7uWZ0EdYY0eo4o+f0mEIl7BvrxpWGH3LrFzvebfNMrZ8p8WlIXuLsFBWoaxMbP60mS5YbDOwN9543e3t5QsoB1ideBHH+G9C3V9fpKNvRl3ZwLGcwcDidHrdHze+653vTcuW2oBGMS0VKf38G8tnBQOW/fFKo/hPtbwJ7y0m37qJzkOAIYoY8DIoRzPqYEDxiANd3l6sExWdHnaRitkXq0Cqh7eiXfVGPbJSpjpT+1U412ZhMahGGH5arqb+ReMKV4AiLS22k3X8UPCBymdXSx+APvwxeZsG5GP+CDMPj5nQK6/9nwlS2qfVFQqQ9y0rt8dC0BGXW8Q9xJecLsJkF924nRaDaBQ/FK4VRqD8QW4HSqt7l0E4fYn8WCmiHfnmY3ixIvo9/yE2uB8xrBwU2f1EJw4ZLvAf5dOs5uWsJZ4PlvBXvKQ9kQNcs5ztRp6LZ+mJLA8ysP+GcgkfikHR64a0bXUbOVQPqifqmb2EgwcPdsVnl112Sbfeems68sgj03e+852GnLNoDil8BbcKPqmC4C39gr6Jn93D5JpzSGwq+rV4GbLarlSepUPm0x7IH+7GLzIHEDfuTEsgU2rDUdRbLFmTNw9TyJ/aMjfhRRq3Wp7RZ61uPR5xKIfd3y4MvnHfyCNWI00WWdp4rBRg5QUafWSztOz39OwN7Gv1gd0acDx+MkXG4oiXZeR1Eu6g0v3hCas35hO8ga6i/WLc02iwpNQI5VYYiCv0kpI8SGu+6Cps8CQD6Ofq/YYUcJc08KYYI8wFPD+UHPelvOZDoPM+DtNd8WYxceDJA5uyLJ6fBuPcWmrltKvxlJft4+gbU3bI5E32BtkkzMbKzbeIuqddoWg5ncU91vsK0AsvvJBOOOEE33D6mc98Jt1yyy2+RHr11Vf7kngeNwrCLwM8RY6OEDB/KzSsd0YVJLUtYaIIQBTcoZKD6dGAi7hFtUYHLPK17FiW9QOmPA35Z61zLbDcBDWbQ3nEBBgANFBgZxDW45W3gq8PwAKEPbS4koe7EB42YCJknWIjrW2pfX0APil/+IVpdj8eaSw13loDzXu8w+rSyus04bTkyzjHw60ooGbjNoa/+wxJiDoMIBhQxMxNB/QEXLkgaGgtdAiES6EwFwM0Zl1B7XdNwTfVvCzuonXSWqN+XcGnbTcGhxykgFPR5nk7wzu14J0b3hhTvV8VfPb+EwO6CwKPXF3Ad0zIeiOwIQv4iQHSB9OsPxcPVtwWhsS0E/yIZ254ZbawxAQDJZpWSExYTa11Mv6HQLXYnoC6IpQ8izrw/GijZvVbFgPDSmWtPs4880z/7ALyHYwbNy7deOONbnhU6Y8zjCcul1ihd1541IKjAP5SZ9Y+zcvHM+dj1IkD1rkFPmInEoMsUl1Mxj/quBj+7TcUEU0qiBkrTFFbMSjyIwNs8uJXS2leHt0HbFKErKWOQ1HI2pjFpUkEJcSJ8YhHOJuhBFjy3/xmdnph3gtppw/skLp+aDeLYhME3jKzsDlz56bnn5+Xtu38/vTR7h9L7zDZyUs5tN1OnbayzJGnQUeOXA5pIuJOFDpIcoflZZegMH4pvYsM3LR3D4/8na7GGGyIiAXwN+OstnsQRlt3Pgb1bE9QXbA4Qa4+zhb14N5RjOw2xIfPWzbEOhNE0vD23pKli9KixYt8K8o7Nt8qLWNBwCZ1SMRFr79qk3G2vZhuQdF4RkmfM3usfpkS5PeDVpu4ra89QKqIqVOn+vd7fvSjH6XddtvNFaGbbrrJ3/RgpiAofiDECwSH4A4/VWA02eCadyisLlAgUIyFiSGywvDHrnw6gecexn7i9Gkqxf6LWqAxrSnyBsiq16hRo9Idd9zh9EMvy5GE8wbLOeec42FPPfWUL+UT1uqelNYfA3mJjUJodmM+3pCgPcL8gCujJbKy8KI8ednK0H1bhTcDy5LOd2uYPLKhoyxduiL97OePpOnTp6UFC36f/uVft0tsEGRf0l8XLkzTpj+YfjbjUesSS1OXf+5sjRvNHRh9lhf3RynibTKH548/9SPYbKnRBuBI5BADi6uJ4VR48egByjAhVM1u90JIyN4M8KVcJxIsKLC8LcVKDgY/lN0ZM2b4m0wMBrz2zeZegVnyvffem+bNm+d7gNiU7K3U6xaKKC8xg/AoF3bRH4IeRIoYBKJjZyjo4bGa8wGJZ1lAuy+DmwSQwGYQl4CKPFdGTn/M4jfzz1DwhiPHLFBG+fGm16xZs/wbRLwV17lz5wb9M2fOtHYx3fkC7WzQzPPO6wD/3J1D/Icv/qjQK9RolEAVivYQNEVbgHpkQdjxwwR/8QmDfCgc/NDPPI7XjtmCTxE30ilOUEMMbMok65ueKHgd9y6sFQd7TW644YbUvXv31LNnT/djm8OUKVNSjx49XAECvqLf4AWqhXgB4ho8pf6LesCfIOSM845wDPyjHlQ/1hY8v7BHHUSdxZ/ic7H0GA8PRHPzGxqIG/XTVscYyry4cDCB4I+j+iwfu7VHMUPBo6WQn3yJgBL0d1MSb0zf/e7I9LSNA3dNmJxeX7Qk7bP33mmrLbZI997/4zRsyLA065e/SpMm3pWWLF6a9tt3P7uD9XHLBtnYqm+APAw7Xcz7urdR0VRQSH6UkzHPi2pX4tlY6jLTK4Byk4Iw+GtXFFhPg394uXFYmMePOF6P/hdXbhQLEZTA3I101HnwGp5HvJBRLg9ME0LOPPbYzHTxRRekO26fkP5z5tNp5112TJ3fb8qOKYgTJ49Pl1xyWZo0aXL6wx8WpG577Zm23IqFAVN04Bs0kbUjykgp1ivmmjZLB/Dd/wZet2ZgYBDI4URGLZgjioX2SGOiEkO8uCVMQUDDmiHqBeZp8DPmUxnkq0ormMyM2M9p8KVB0lhcq8D2GlkrKA0Kz/Dhw311Z+DAge4+++yzfUWIw6mGDBniA+jnP/95HxCIm79GXAY08iomhsdDPKdtBtpuNBoa75qXf7VhPGQCgolBcfO0eMnidMHoUemss4anR2f8LP3H976XRow4Oy1atCz97W+vpGFDh6WLLhqdfv7Qw+mUk09Jd4+fbOW1MvrjPOrVGrgpRFtYQ6W+o+NhwZjdrbQLlCPqilS4DSEpzY1/oQSLfJ/uEBuhiGJIewqjesbeDIRppoWd+mMFj7r7wQ9+kL72ta/5uT74MQhceuml6fTTT0+/+MUv0uWXX56++c1v+rk2YPLkyemUU05xJYCwYcOGpYUL/7docYaCXBdG5gNtiAPruuaOmQvrQ20rGtDFygJhJC5MA+RKXkFbKH70BAR2CALu521ppX6xKqCdeoZOzggaOXJkYt7Evj7xB7oGDRrkj7qvu+66dP311/vZP4DVgFNPPTX95Cc/8UkBfYH9gOJ9K/43Q57GrH71T+gYQT5AOlEW0fkSbUGC1+F9p62vu1s88HjIHPio+PiRQ/A2UltKC4abEc3C5Fb787qhrRb5OHuxF25Hbq8eVG/0C7Y3aKUbfx7z8pgSuQZoP6DMgeAtPtba7RLcpuUzSEZsXz2xv7Z08BeZHnKdGqZVe814W45r9KcwXq+WByBHftnzEvckb9ZfiRH9zpPYNe6BnVSULuQPiLQEWkqvX4Db7kWYlc0NGduVc5F/99KLafz4cWnQycenBx54IA0dNjTdcN2YNHf2XBsb/pwuu+iydFSf/unBBx5Mo867MN1527j02IwnY/+T5RE8b9ysKVQvAi5LaiYmBW2gYMFnZ5vHwfBDuHhp93Uv+wFGuO+9NMP2DOqHX8LjzvwGryOV+IiduDGRizSRopHGb0RcUzBxmiEFyvOvbHI1dPjQtJ1NrI7u1z/NmzM3nTFsZHr91SXp0UcfTxeOujDt9eG9Uu/eh6cJpjxef92Ndpct0uYcc+8E2i0goSg7OZvv+gVnEUhIAgQYsz82MgptFWaEUjbZzeFaqBc2KsrL7yb+nCo0c1diFDcQCo8ZaayCC0pLYyY6mwUzUHqY2Y3rtAHKWjatkDc6Bshjjz02XXDBBalv377pK1/5in8JHGHALBlhMHr06HTMMcd4HM5SYYbcDH5fLJa93wISKSONBZ6IZqcbY42HVQ8076K8lK29sjejrdyJVgVNF+UnBudHZ8xI990/JY25/po07s4J6Zprr03z5//eFIAFafq0+9Kv//uZdNutY9OECePTsV86Lt103c3pzwtMOfBHgrEqQfF9Mc7zhjbrsD7rKuAkFsLHjf0WtEsxCIWXMhVwsnJa2pSatwI8EB+kAKDQsHo3duxYb8N6pPn88897HRJ2++23+6DPOTmsBqEo8Mh3wIABaeLEib4/4tlnf2Nh91lKo8KK4+yHDlbTEADqmnb7EMq4oTgoD5Lwi/tH/4BnzkADAsaJ9/xBox0UQg3j/DJ35LsqiE866Hz66addWUeRYdVLgDesan7uc5/zjbAIdmb/rGxyltK11hZ4DD5+/Ph08803+7lX5CGU217ZnWPlsLCj+Hh78UeCtAd8jWhXQqAVL/6Ch0rXhoKPDSFZanceH24WvCUOxvfcFWmKPP2XfBowH5c3XohwC/h5uT2DykF1QX/irT0Bf9oEcjCP00DGApGuoTMCMfALvsFzeE+fUN/O+QuIjx91URjvF7oRMp6JFv0DdxG3gYhHCWTa0JY39+dleMqgnAOUU/VIiAzpIiaKEI9jtnlv53TRxZeaLDjG/bfdbpu0fZf3+TEgv37mae+LA44eSIp06KGfTl136+pjBoitBEV+xteyAY0+ngElhdKx+hs8Df8ob8Fj83vT4i13t/kTx8fMtryiBzDZYDXOFEanmSuPqwr6PbrlYYZiRJ/BAAILnmD1uMFt8o4wEPx2m3exKP2d425NH/3IXul755yfju7fN117zVXpsE8fkpYsXpImT7o/7d/zoDTs9BHpq1/9ajrhxEHp7kk/Tq/9bREZmCF/ymd5uYk+rjuuNyAo6Qg5ltuModkgpM2DwRh+QsBEBRfCphEesBD/zY1smdfKxn+K/Lwxb+4HoqFk0778sVpEXAV5gysbdfo999zTVwegkwMEJ02alPr06eMzJN4+4tGfZks8JmCF7NlnOSq8DcozHGYgHUP53KlBElebkS1HI581QHtposkCymjavHW6R37+SOq1/wFpm/d0tgFwun9/5taxN6UPfGDH9MTMp9I++/ZoPPI8/IjD05I3l6X/+vX/mCtWO8gLNYbCO+1eP6oju1KeglxKJhO/wQtShR8wWyMSCcOILr9HZm+G3F+CZf78+S7sWenp0qWL1zHAjlJ78MEHu5vHPKx0ovTyOIgVot69e3u7/+AHP5h69NjPFKZfeptxWPGcr7Rz4yl3xhQkmxGF4W5YGg7xyz0crPREDgbPtogHXW0Zt9lbgDJCP3RwGOa3vvWthgIET9jThwLIYw+E9T333ON0ozShGIl2wMGgHATJIzQAP1rxvxWIHwq+DYhm+PNVLZ+dW17KjquMUNgbXnkcyuF9vxhk5e8MypjEpeGUIwNeMis5MEVCrOV8KwbaBGBCy+NQPu0gsMIH8lUh70NmD2oL2nM+rMSTNtOm/GR8UkaZl0PJ8nBvX7SNmBhFPkUkrO6DRI1HIkruKCxcZBpwBz9ZXu5nbtkxOL3vdUrv3ebd6SMf/kjiVORrrrkmnTr4lLTffv+euu7+ofQ7myxy5MX7tn2PxQ1st33n9Kc/xyqyHwngGbZJ4BzRLwgPu67BPYrRtnrl2bgdP2Lg8vUS+zUXHpnhElRGfWj8wfDFs/gSV+QTMTEgUnmABwavwxl2HFFe7DiKuBjD5p1iJfG5Z+em3Xbd1R+3njRoULpn2r2p/5e+5OcHvjB/Tupm467Q/cN7+evvL/+BTzAZPD9+VDZoj3XD9QJ1Ds7pYBVIbj4twH4BOkwZqrQARcvdTkFYV0E5bgmrJMUhRsisHfKya1WAz3zcdtttvvrD4zCUI14RRWAoDlcGk3xFrCmaktfUcwNAKyNxf+j644IFafbsOa4EXHHFlenEE09MEyfeZfFWpIULX1mpvt/FAWD/tHVa+EoIydDsrBZcSKhzl+tnLWj1pGuR3kD9oux84hOfSGeddZafBI5bChAb+nmzkboFbP7k8dghhxzij4Kofw0GgH7xl7/8tfGIwAcHu0co3wEVm2v7pSe0GZ+apSzczYKaQOVCCerXr1866aSTvC5xq82zmR/FHmWHla+LL77YX4F++eWXPQze5CtG22+/vfcNyYS1RyFIc/pXg7bmIKHyylHmrQFnbpqiHFjOu2XCSkDtg/0/PPpl1ROFl0kf50hp0rNqXUN3Kz6IR+Ld2vJI9yrls5KTNhRepVhNPMrIywtWzQX66TO+KdewjDOnrB8ddNBB1nfm+OQizuZa4Rt9hS234vNIyz09Ww04I2xNodJIDWoDvm3lVrz20FBazIQiI9plgPIFuf2tULq7Ob192R/fLuS7ZlNtcvXHP/4p7b7HHummW25O55xzbnrtdb4huNjPPBKQN4wnS5bwdnje/lSeMKtbsreNvffe24UdeyBQfFj+Z9bHTBLQKLQatGonqRYQBF5hxcDAK//f//7305VXXpkmTJjgy/4MkCgM+apYzgOl7eiIckZ9QbM+XMk+EM4CYf8Le0HY+EvUnC7iQ+9mTWjtqPRTLvY0qI2isFJvUmSlCAE2t19yySWuLHTt2tUfgQHVMSAvBgrRS74yHQ2UUfQDtV+VlTbNniBoZlZ79913O194IwgFjxUz8Qlgh/Ya1QZtQm2AFW5Ws5n4oPyy8n3yySc3Xu7oiO16Q0L087kJ2j7K4VFHHeV9hoNEeUkIP2QE3yAUkKt80V19EOi6KUB8Uxs68MAD08iRI3wV+sILL/QVZ5RHJpjIYwEe4X4rnq13BYi3vr7whS/4BlH2vDAz4LyInXfeeaUCVh1UDrQwSMyePdsHfrRQXtXjbAw2f7OHgtkwH0kV3QykuHlcApRPR0deRuzQyjeheLyB0GODNx/J1OoXj0kElAUGUB6ZACmDeQPuCFDnE6BTZdSALj5oUEfZZaPv0KFDfd8LgH7qORdsbIbHH+WA+1RhEqCyqbwqMwrQEUcc4X0depjZ8iiQx2JshkWI5woPq8D0gyq08xqtQTugP9B/kW/IeJSf/fffP11xxRV+7In6Nv1jU65vaGdsYL/neeed5yfRC6wMIxvgIXKSfXMA3rGixkRayCcSmwKQMbQzlEP4xMq7IDsLKyjfmmgCVt3hH8ple1ivChAFRyB++9vf9oHh+OOPT2PGjHHNV0I0R5U7CGVX+XkU8I1vfMM3ewKWhnkbjlUvVsTY78NHMRkU7r//fn+zho94Vgm58krH5ogDBjyBAZ59AOx3waClSwHgA308GuFDgIB2QF7l9tARQDvNIQFE56LMCsfOm0+sfl122WXpy1/+svsDeIOSy+vhAD6gDLMfRgqQFKuOygPVNaCM0C/aX3zxRX/Li3oVaOMIJfbDQTuPyABtgjA2SNeoPtQuaL882vziF7/oso+PAgtqJ7puymDSw4sCrJgyBrBKzssTn/3sZ/0ROsrOueeemx588EF/1E7fOfzwwz0tPIaHmxIfRSuT5Y9//OPpvvvu80frjJ08bkcx4kPiyFhevkAWMeEijMevTMLbwwb5FhidhD0PCHytdJQBobmQrSJEA7Si8PAohMdefHn8U5/6lK+A0cCpQM5CopGzVMyjEmbMVeIBg6AaJ2VG+EEnA7ve/KFxshmcOr/rrrtcMYR2wvgyeP/+/Rt55Hl1FORlKZeLjga9CCc6GUcdsPzPjIOZCvVOh0TZoYOyKshbUMzw2BfGZmqWcbU3ivwxHZEPqmuVkfOPqGe+xM45P4Sj+D300EOuGPGmG5ucee2fL8qjGLHyi9CCdh6Jc0Iwq0DKt0Y1obqjDUiJF3DnKz+bcj1DO22d1XEmu48//ri/LKCDgnmDkskQYyRhyBZWNHjZYt99923IBUBemwovxTcAb1AakaPwBxnDY1bkKzIYxRLZw1lrLCpw1Ei+etYM6+0kaKFZ9htr5dHh1TgZ+KgsGjj7QFgWZqUEfjAQPPbYYx7GDBnNVukRJFXFM88843tAeFUcmmmcPOqEZlbB2L1Pw4RelD4GQK2kVI1uVjToiBx3QCdDIWC/l2ZpootN0LyWyTkprBBxUCJ049erV6/GoKF20xGhMkIX9YSA5gBPaOARL4McS/Uotig7oo82D1gN5HwgeIQyTBibycmvo9Jco8a6Bu0d0OaZCKHgsHWASQTygn6GEqRtEUykeLxMOvWVTa2/iHaA7GEFmUOGecEEGcL4yZYKxlYeK7KgwAoQ20409oBWfFvvCtCmAlUUlUSFcC0P6jRy+eUVQjopP1Vs4DntZUAzaPbsGppXt1OTf7N4rfzXJ8r3RGDRAVuVQ3VbhhQL0m1oGtYEarfQDUQL5Ve9q/zEzetaacv0ifZmfKlRoypYE/mjuOpHeTr1m3J+iius7r3WNdaEznWJnH7J0TJ/4B1+5TDJZdCq7LUCtI5A5ZQrBuCHwS0/KkpuhVcZooMrfNAAKLcGOdy5vcp0U34MEB2iXbTlbSKnHShOOY+OCCn0eXmB3FxFa5nGPD5h8lPaPH6NGlWD2jfteXWQt3+lUd/B5Pa8nwi4/xFQWf4RyOkHZZ4IZX7JzrVV2WsFaB2CxgsQ6mrIeaXkwl5xVTmqhlYVVQWIZkG0g5xGUOZH1UD58zrLaW9Vz0IeP/fvyKC8qk/oE/1q67oSnocJ+OczNfElj1OjRtVAOxdWpy/n8XOo3+T2PL88bEPjH3nvHDlPVCaQ+yFXNAkFhOXpyqgVoHWEnI2yI9xl5yq3KkMDhtCqkqoC0YPBLpqbYW1oFU9Bnk8r//UB0coVNLtfuf6JoytY32VcV5DiAsplzunBjkEA5Y++8INP4ofaRN5eatSoOmjbwpq26XJa9RewNvm+HWzo+7WHvCzYMeILZZMfdrmF3N2KjloBWodoxXyQV0CzSsGvVSVVCaKjTGPufju0Kj1XdYDVQXv3ahYmv/bCZG8Wl6sUBoVh9FgQNFOacntHA+UXVM6cZkHx8jgAN3ZMWah3ZLpr1FgTqF+D9mRUPhnA5P2l3D8Eucv5Kn35WkbZv1U8QBhGZQSKm6drL491BZWF+2DK9xfysFbXZqgVoBqVgJopwoNDJnnVng1unA/BHhXCcfNWAK9Z8y0uvrEG1AHUGWRw551cV8WTXVAa+VEW2VF6uL/S5SsgxOOtDt6Q4qBIjgeQsCRc+QLsZSFXo0aNjgv6rAz9mDddOQgSOcRbXZJRfAZp11139QMieVuJM5M4MkVpBfLI5UEOhSE/CJOswF2WG4onqHxAVwE3byZzdh3n9fFmWvllHpWFuO3lVSVskHOAatRYW6iz06H5xAKfFuGUaeycB8E5PBywx6uPnL/DIXycrKrOmndidWrCyE8dWH5yy14OJw8JABnlr3BWfLADwubNm+dl5gBAzgrK0ypN7q5Ro0bHB/0WqN/S11Ec+DAsr7Fjp99zVg1Hg6DwcDAsn4jhyjESSiejvGQAciqXKVyJKwVH7jxcsk3+zfKWgQ5eMeeIFk5YRnHjfuU0xMNP98BUGfUKUI3KQI+WdOQ5Z2n07dvXz+Lhcys0ZTou585wFg1nbCCAuLJixFVHo7/00kt+KitCinTqyPhj1+pRriAJuEmDQWAww+OVS86hYOWJcE66ZtVHbs6m4CwgyiXBwooRs0SEIGWRMJOAqVGjRscHckAKSr7yCzgQlxUVPo6MwgOQC0yImAyhKCErSPfEE0/4waEoS5yzxcGxPXr08FO1uQf5MtkjjAMV+ZBq+cPEOUiDXOIUfuQOE0Tud+ihh7osnD59usfDjfzhbB1kFJNIDnpFliI3mWiyck25KINoJX/Q7N5VQa0A1agM6Hi5coDQOPLII/37Q0cffbT7MYu5/PLL/WRVOjlHzXfp0sUFB8oQn6jgAMqHH37YO/jw4cP9G1YIBh3WBxBOHOmPIsR9AJ1ewoZuw3Xs2LEu5MCTTz7pp7Z+8pOf9JNKeeSFkDrttNNc0eFDwJwWzanQnAJO+bgfeXEvvqUGlHeNGjU6NtRXuWKkIOCH4fM3HPrKIaj6dhWP8PnMBavXfDgYGcXhsCgbHCJ7wAEH+EG6fFoIpYQDVnv27OlKFKtJ2267rYfznT3y4ZMP3Jf7A+6LzEJeIQ+Rj4DJGEoVq+MoNEz2Zs2a5YcG8h03TuufNm1auuqqq9L555/vB/mikPFdLRQ27tWvX79V5HCVUU81a1QCEi4SNACFBkhBAQgGlAs6LR/dRPCwMsPX6REYfJ6BlSPcCAeED26uKEZnnnlmOuOMM1zwIBS4B/eVQqKr/BAgfAaCb7x9/etfT1OmTHFFio+D8qkPPofCc3VWijiqndkego0Ts7feeus0YsQIn83x/TBmXzVq1KgWUAiAZEMOyapcRhEfOQB4FIas4XR0Tpbfaaed/DM6fCoGhYSVGxQRJll85oHPKfEZJeQHK8goK9yX++j+uR05xd4jlJ7Ro0e7bGIyyAnTV199tX+TjP1IyEvisrpOWlbRuY4cOdLvy0oUkzrokBzeGFArQDUqA82sBDohfhJAAisrrO7gzzfK+NYO3x5jVYilXh6ZsUrD6hHL0XyfDKWJT1qwgZHVIL4tgyDSIzHA/XLhIpBXnz593DDLY0XpsMMOSwMGDPANz/ryM+VCeFAuFCY+FUK5WL1CcUNQ1ahRozpAFshIPtDHBcms3C+XIfjzbTBkBgoNj8l4kQNZhLzAzeSJVWMMyhDKESs0PKbCIDd0f666J9BKEDKKjc2sArE3ks/UKH+UIeQPZZF8wo/vV6KQIUv5cDX5l1fBMVVGrQDVqAToaHROdXKgaw7FoeNz5Rk5HV9h7Ldh5QUgcDCsFCFIWOblQ3qs4jADQkFSfly5nzq+gF0f+MVOftpnxOoR+4MA/kpHXihmKgd5IliEZnTVqFGjY0L9VTIC6CqFIZcZhCkucgplI1/NLssX8mAPITJkn3328cdhrMgMGjQoDRkyxP0B+eXKD5D8kh/KFPdQGla/Cc/LjptwFB+BfEUHccljY0CtANWoBNSRm4EwATtGCgVp2AiYg44M6MTYUURQlPi6OUvKY8aMSaNGjfIN1jxvl2CQAMjLgV35SQApnCv3wJ/y5GmJJyGieMpHcWrUqFFNqA+j2EgJEiSvFCeXXyDv/7LzBhmPw1gZYsV44MCBvrrMCjaKCooNpgxkT1me4JfLHtyUQfFwoxhxFcp55PGrjFoBqlEZqMPlV5SbXMFB0CAIEDzYeaYtZYh4LPVKGHGlo7PRma+2s9lw8uTJvszM3hz2BQFWh3gcxvN6CQsBQaL7Ux7unQs7wohDeTCkV/kkYLDnwisXPDVq1KgecuWAvYY56O88tpJcYD+Q4iMvkEkC8oq9gbyUwSN8XtpgUzUvczBJQyYh31i5Zk+PFBvJEOQKq0eSL4Rz79zN/XFjJz+VK5dJlAOzscmm+hygGpUCHVCdEEVjzpw5qXv37v7qJkKEzssmY97GYobEfh7equB1d/b3oBD17t3bhQZvXRD/4IMP9vg89po6dWqaOXOmP8ZiwzTPzHmNFOFCPuQp5QUzf/5832BIevDcc8/5WxkILOLh5vVRVpJQpHr16uWChPvyHJ6lZgQcQujAAw/01Sjo2NgETY0amxrow8gZVm+QB6zU4Mfem913390PRWTlmTey2JeDLEDusCcIN/KNR+WEs/LDfkH27CDDSMceQiZugMf3vHGGLCuv5jDBQ0aygoSbPHi1nu0APH5j32K3bt1cRlHWHXfc0d+cZV8Ssg1QLtzkRbmgi7wwVUb9GnyNykCKQd5kmd0gWBAehNE5UTDo2MRjRsU+HISCZjW8DUZc7MTX5mTAGxkoJwgePSdHceGV1cGDB/smapVD9yKe7s/sDeGAAQrHzf0oC+kpC2UkDfcjHuWQYKlRo0Z1IRnFVbIFeQHo3xjJEYAdOSCZo7hKS5hkShmk5TgNJlu8pq57k0cuT+SfyxeVQdcympVD8eRXZdQKUI1KQc2Va94Byx01B3Hz+M0Ekdw5FI+VIpQgNh4C8lEa5Vm+h1aJJLQIw02erdKAPLxGjRrVB308v5blDJBsUFhZDkgBkrzI8yIuq9uEs1JTzou42MtpdZVfngaU08uu+MozT1M11ApQjUpjXTVfdWKEACh3/ryTt3dP4ikNkL2VXzMoXo0aNTYutOrzbwdleQKkxOQypL17Ek/heX7NkOe5cSCl/wdOBx27T6j1fQAAAABJRU5ErkJggg==" style="margin-left: auto; margin-right: auto;" /></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><div align="left" style="border-image: none;">
<a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"></a><span style="font-size: x-small;"><strong>Figure 2.</strong> CTC Rate in Small Blood Vessels. CTCs were continuously monitored with FFC in ear blood vessels for mice with breast cancer. Graph the CTC rates at week 2 after inoculation. Graph b represents the CTC rates at week 5 after inoculation. The grey squares highlight periods of CTC absence in the detection area.</span></div>
</td></tr>
</tbody></table>
</div>
<div style="border-image: none; margin: 0in 0in 0pt;">
<a href="https://www.blogger.com/" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a> The figure above displays the tests done on mice inoculated
with breast cancer. In these tests, CTCs were continually monitored with
fluorescence flow cytometry (FFC) in the small blood vessels of the ear. At
week 2 the CTC rate would quickly rise and fall. Within 15 minutes, the CTC
rate gradually approached its maximum value of 4 CTCs per 5 minutes. However,
this was immediately followed by a 20 minute CTC free gap after which the rate
fell to 1 CTC per 5 minutes. The rate would then fluctuate wildly between these
gap periods. Furthermore there were 4 of these CTC free periods which each
ranged from 15 to 25 minutes. When observed at week 5, the CTC rate appeared
to gradually rise to its maximum value at approximately 55 CTCs per 5 minutes
within 45 minutes and then fall back to 30 CTCs per 5 minutes in 15 minutes. At
this time there was only one 5 minute CTC free period after 35 minutes of
observation.<a href="https://www.blogger.com/" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"></a><a href="https://www.blogger.com/" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"></a></div>
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Most studies comparing the number of CTCs in the blood with
the survivability of cancer utilize a blood draw. Therefore, most go under the
expectation that the concentration of CTCs is constant throughout the bloodstream.
However, both the small and large blood vessel tests implied that the CTCs are
not uniformly distributed within circulating blood and that their amount is not
consistent over a period of time. This is most exemplified by the appearance of
CTC free gaps and the rapidly fluctuating nature of the CTC rate. Nonetheless
both these traits were suppressed over time for both blood vessel types. At the
end of both tests, the CTC rate appeared to fluctuate much more gradually and
the number of CTC free periods decreased. Because these traits also appeared in
several types of cancer, it is implied that they could be universal to CTCs
rather than dependent on one specific type of cancer. However further tests
must be done in order to properly enforce this conclusion. Nonetheless, these
fluctuations imply that either the CTCs are arrested at certain points in the
circulatory system or there are fluctuations in the shedding of CTCs from the
primary tumor. These issues could present a problem with CTC studies as they
have the potential to skew the number of observable CTCs in a blood draw.
However it is possible for this problem to be solved by utilizing larger blood
draws. Nevertheless, more tests must be taken in order to validate these
claims.</div>
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Sources</h3>
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Juratli, Mazen A., Mustafa Sarimollaoglu, Dmitry A. Nedosekin,
Alexander V. Melerzanov, Vladimir P. Zharov, and Ekaterina I. Galanzha. “Dynamic
Fluctuation of Circulating Tumor Cells during Cancer Progression.” Cancers. 6.1
(2014): 128-142. Web. 27 May 2014.</div>
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Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-24691553407942157722014-06-01T21:23:00.001-07:002014-06-01T21:23:35.626-07:00TA-65: An Anti-Aging Drug or a Cancer-Facilitating Drug?<div class="MsoNormal">
There have always been people who have feared growing old
and the decline in health associated with aging. However, people with these
fears may no longer have to worry thanks to TA-65, an anti-aging drug. Isolated
from various species of the Astragalus plant, TA-65 (Cycloastragenol) helps
prevent aging by activating telomerase, which results in increased telomere
length and ensures that cells stay healthy and live on. People have been taking
the drug for a while now, and apparently it works pretty well for them. You can
listen to some of the testimonials of people taking TA-65 <a href="http://www.tasciences.com/testimonials/">here</a>. But for all the
good TA-65 has done for people already, others are very concerned that TA-65 theoretically
increases the risk of oncogene-mediated cancer.</div>
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The obvious question after hearing TA-65 can theoretically
promote cancer is, “how?” TA-65 could induce telomerase activity in cancer
cells that would otherwise have undergone apoptosis. TA-65 could also facilitate
cancer by inducing telomerase activity in pre-immortal cancers, where
telomerase activity is currently not present. Doing this could make otherwise
treatable cancers more untreatable by giving pre-immortal cancers the means to
become immortal. </div>
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Though this risk isn’t fully understood, there are still
those who still stand by the product and doubt that TA-65 does anything
significant to increase the risk of cancer. One reason TA-65 proponents stand
by the drug is the fact that about 85% of cancers express telomerase activity. Therefore,
many cancers already become immortal, and taking a telomerase-inducing drug
like TA-65 isn’t going to make immortal cancers any more immortal. Moreover,
TA-65 is short-lived—if cancer occurred, all one has to do is stop taking TA-65
and their lengthened telomeres will shorten, allowing cancer to be treated
without having to take into account any effects of TA-65. There’s also the fact
that long telomeres ensure that chromosomes are protected, which lessens the
chance of getting cancers that occur when telomeres become too short. Proponents
also point out that there is published evidence that Cycloastragenol (the
active ingredient in TA-65) has been shown to reactivate telomerase expression
in human cells, showing that the drug’s ability to enhance telomerase is not theoretical,
unlike claims that TA-65 facilitates cancer. </div>
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However, there seems to be as many negative arguments for
every positive argument about TA-65. For instance, there is no published
evidence proving that TA-65 causes significant extension of telomere length or
cell life span. Moreover, the ability of TA-65 to induce telomerase activity
could cause cancer by keeping cancer cells caused by oncogene up-regulation
alive when they would have otherwise died. As it stands, your immune system is
responsible for destroying many cancer-like cells on a daily basis. It’s not
crazy to think that TA-65 and its telomerase-inducing effects might help one
cancer cell stay alive and develop into full-blown cancer. Telomere length would
probably have to be significantly longer for this to happen though, and
proponents of telomerase could even use their opponents’ arguments against them
by saying TA-65 only lengthens telomeres by a modest amount. As a result,
cancer cells would not have significant protection that allows for continued
uncontrolled proliferation. However, admitting that TA-65 only lengthens
telomeres by a modest amount begs the question of why it is even being used as
an anti-aging treatment and calls the drug’s efficacy into question. </div>
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Whether TA-65 does or doesn’t cause cancer, there are still
many questions that remain. For example, does TA-65 help enough? Many of the
initial studies of TA-65 were done in mice. There are large concentration
discrepancies between mice and humans when size is taken into account. Are
TA-65 concentrations in humans proportional to what they were in mice when
researchers obtained results that proved the drug’s worth, and if not, is it
safe or even economically feasible to increase the drug’s concentration to
these levels? It already costs a little over $9,000 for the first six months of
the drug between initial testing and the actual supply. Finally, what if TA-65
does cause cancer? Would the risks of cancer outweigh the anti-aging effects for
someone who experiences a noticeably poorer quality of life without the drug? </div>
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In closing, TA-65 shows us how there are two sides to every
story. It’s fair for TA-65 opponents to suggest that the drug causes cancer,
but one must understand that the way it causes cancer is theoretical and hasn’t
been proven. Conversely, TA-65 does seem to have some anti-aging effects, but
one must remember that pharmaceutical companies put a lot of time and money
into developing drugs and will often try to hide side effects or
over-exaggerate the product’s efficacy in order to make a profit. No matter
what the case though, I’d definitely think twice about using TA-65 if I were
given the opportunity. <span style="mso-spacerun: yes;"> </span></div>
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References</div>
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<span style="color: black; mso-bidi-font-size: 16.0pt;">Andrews,
William, and Michael West. "Turning on Immortality: The Debate Over Telomerase
Activation."</span><span style="color: black;"> </span><i style="mso-bidi-font-style: normal;"><span style="color: black; mso-bidi-font-size: 16.0pt;">LifeExtension.com</span></i><span style="color: black; mso-bidi-font-size: 16.0pt;">. Life Extension Magazine, Aug. 2009.
Web. 26 May 2014.<span style="mso-tab-count: 1;"> </span><http://www.lef.org/magazine/mag2009/aug2009_Turning-onImmortality-The-Debate-Over-Telomerase-Activation_01.htm>.</span><span style="mso-bidi-font-size: 10.0pt;"><o:p></o:p></span></div>
Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-76890755771794174472014-06-01T11:20:00.000-07:002014-06-06T15:56:50.864-07:0027HC, CYP27A1, and Breast Cancer<span style="font-family: 'Times New Roman'; font-size: 15px;">Myself and Erik Christensen are investigating the relationship between breast cancer and cholesterol for our Cancer Project. In our presentation we are going to give you a brief overview about what 27HC was, but I wanted to blog a little more in-depth about it. In addition, I wanted to introduc</span><span style="background-color: white; font-family: 'Times New Roman';"><span style="font-size: 15px;">e CYP27A1 and its effect on 27HC and breast cancer as we won't be discussing that aspect of our topic in our presentation.</span></span><br />
<span style="background-color: white; font-family: 'Times New Roman'; font-size: 15px;"><br /></span>
<span style="background-color: white; box-sizing: border-box; font-family: 'Times New Roman'; font-size: 11pt;">The Cholesterol Metabolite 27-hydroxycholestorol (27HC) promotes cell proliferation. Specifically, in this case we are looking at its promotion of ER positive breast tumors. What makes 27HC different is the fact that it is an abundant primary metabolite of cholesterol. Because of its relationship with cholesterol it can attach to and actually stimulate estrogen receptors in the body. Since 27HC is a cholesterol metabolite transported in the same lipoprotein particles as cholesterol, there was a positive association between lipoprotein particles and cholesterol. Patients with ER+ breast cancer have higher amounts of 27HC in breast tissue than women who have not been specifically diagnosed with ER+ breast cancer. Below you can see the process of cholesterol synthesis and where 27HC stands in comparison to cholesterol.</span><br />
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<a href="http://1.bp.blogspot.com/-G23iG90Tt-Q/U5JBV4zWa7I/AAAAAAAAAAs/ev8jXEU4yiI/s1600/F1.medium.gif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-G23iG90Tt-Q/U5JBV4zWa7I/AAAAAAAAAAs/ev8jXEU4yiI/s1600/F1.medium.gif" height="320" width="205" /></a></div>
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<span style="background-color: white; box-sizing: border-box; font-family: 'Times New Roman'; font-size: 11pt;">The precedent behind 27HC that we wanted to try and see was if it really did have an effect on breast cancer. In order to determine if 27HC was indeed a promoter of ER positive breast cancer study was conducted with mice. The goal was to determine if 27HC promoted MCF-7 cell growth (Nelson, et. al. 2013). </span><span style="background-color: white; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px;">As we can see in Figure 1A, 27HC promotes MCF-7 cell growth. Due to </span><span style="background-color: white; box-sizing: border-box; font-size: 10pt;">unesterified plasma levels approximating to 10</span><span style="background-color: white; box-sizing: border-box; font-size: 8pt; vertical-align: 3pt;">−8</span><span style="background-color: white; box-sizing: border-box; font-size: 10pt;">M, the threshold concentration for activation of MCF-7 cell proliferation was 10</span><span style="background-color: white; box-sizing: border-box; font-size: 8pt; vertical-align: 3pt;">−8</span><span style="background-color: white; box-sizing: border-box; font-size: 10pt;">M. This can be seen in figure 1B.</span><br />
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<tr style="box-sizing: border-box;"><td class="captionedImage" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;"><img alt="Screen Shot 2014-06-02 at 6.33.00 PM.png" src="http://islaslab.wikispaces.com/file/view/Screen%20Shot%202014-06-02%20at%206.33.00%20PM.png/512549138/560x427/Screen%20Shot%202014-06-02%20at%206.33.00%20PM.png" style="border: 0px; box-sizing: border-box; height: 427px; padding: 4px; width: 560px;" title="Screen Shot 2014-06-02 at 6.33.00 PM.png" /></td></tr>
<tr style="box-sizing: border-box;"><td class="imageCaption" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;">Figure 1. 27HC promotes MCF-7 cell and Ishikawa cell proliferation, and in vivo 27HC stimulates MCF-7 cell xenograft growth and a uterotrophic response. A–D. Cell proliferation was evaluated by quantifying BrdU (A) or 3H-thymidine incorporation (B–D), n= 4–8. A. Growth responses of MCF-7 cells to E2 (10−8M) or 27HC treatment (10−8 to 10−6M) for 24h were compared. B. The dose-response of MCF-7 cells to 27HC (10−9 to 10−6M, for 24h) was determined. C. The requirement for ERα in the growth response of MCF-7 cells to E2 (10−8M) or 27HC (10−6M) was evaluated in cells treated with methyl-piperidino-pyrazole (MPP, 10uM) for 24h. D.</td></tr>
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<span style="background-color: white; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px;">So with this information it would be wise to see the potential impacts of 27HC on ER+ breast cancer. Since 27HC is a cholesterol metabolite transported in the same lipoprotein particles as cholesterol, there was a predictable positive association between serum 27HC and cholesterol in both controls and cancer patients. We can see that this was eventually proven to be true in Figure 2C and 2D. In addition, compared with controls, there was a 3 fold greater 27HC concentration in normal breast tissue from cancer patients than controls. 27HC levels were 2.3 fold higher in the breast tumor itself than in the breast tissue.</span><br />
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<tr style="box-sizing: border-box;"><td class="captionedImage" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;"><img alt="Screen Shot 2014-06-02 at 7.22.39 PM.png" src="http://islaslab.wikispaces.com/file/view/Screen%20Shot%202014-06-02%20at%207.22.39%20PM.png/512554040/560x860/Screen%20Shot%202014-06-02%20at%207.22.39%20PM.png" style="border: 0px; box-sizing: border-box; height: 860px; padding: 4px; width: 560px;" title="Screen Shot 2014-06-02 at 7.22.39 PM.png" /></td></tr>
<tr style="box-sizing: border-box;"><td class="imageCaption" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;">27HC content is increased in normal breast tissue and tumors from ER+ breast cancer patients, and it is locally modulated. A,B. Serum 27HC (A) and total cholesterol concentration (B) in control and breast cancer patients (n= 17 and 58, respectively). Values for 10 cancer patients with serum 27HC greater than 2SD above the mean value for controls are shown in red. C,D. Relationship of serum 27HC to serum cholesterol concentration in controls (C, n=17) and cancer patients (D, n=58). E. 27HC content in normal breast tissue from controls (n=17) and cancer patients (n=48), and in tumors (n=32). *p<0.05 vs control, †p<0.05 vs cancer patient normal breast. F,G. Relationship of normal breast 27HC content to serum 27HC in controls (F, n=17) and cancer patients (G, n=40). H,I. Relationship of tumor 27HC content to serum 27HC (H) or normal breast 27HC content (I) in cancer patients (n=27).</td></tr>
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<span style="background-color: white; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px;"><br /></span><span style="background-color: white; box-sizing: border-box; font-family: arial, helvetica, sans-serif; font-size: 12pt;">Along the same lines, CYP27A1 is a gene sometimes referred as sterol 27-hydroxylase. Generally, it is expressed in the macrophages of the cell. We are interested in it because it is required for the conversion of Cholesterol into the metabolite 27HC. Interestingly enough, no matter whether macrophages of the breast tissue were malignant or benign, they consistently stained positively and strongly for the CYP27A1 protein. With an already established connection between macrophage infiltration and breast cancer (Wu, et al. 2013), we clamored to try and find other data and studies that incorporated this connection between the macrophage and breast cancer.</span><br />
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<span style="background-color: white; box-sizing: border-box; font-family: arial, helvetica, sans-serif; font-size: 12pt;">There were a couple of important findings from the next set of data we found research. The first was that (bone derived) macrophages were unable to support MCF7 cell proliferation when treated with CYP27A1 inhibitors. More importantly, introducing 27HC could reverse the effects of the CYP27A1 inhibitors. With the reversal process so effective, this indicated that local production of 27HC by macrophages in the tumor has a high impact on tumor pathology. The second observation was that CYP27A1 was expressed in the cancer cells themselves. From the data, the determination can be made that the expression was based on the size of the tumor. This can be seen below.</span><br />
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<tr style="box-sizing: border-box;"><td class="captionedImage" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;"><img alt="Screen Shot 2014-06-06 at 2.08.34 AM.png" src="http://islaslab.wikispaces.com/file/view/Screen%20Shot%202014-06-06%20at%202.08.34%20AM.png/513084056/388x211/Screen%20Shot%202014-06-06%20at%202.08.34%20AM.png" style="border: 0px; box-sizing: border-box; height: 211px; padding: 4px; width: 388px;" title="Screen Shot 2014-06-06 at 2.08.34 AM.png" /></td></tr>
<tr style="box-sizing: border-box;"><td class="imageCaption" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;">Table 1. Overexpression of CYP27A1 increases the likelihood of a higher tumor grade. Results of immunohistochemical analysis of CYP27A1 expression in human breast cancer tissue microarrays are shown. CYP27A1 expression was determined to be low or high and correlated with tumor grade. A Fisher’s exact test was used to determine P values for the likelihood of association. Ordinal logistic regression was used to estimate the odds ratio. N, sample number; N/A, not applicable (because sample number is too small).</td></tr>
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<span style="background-color: white; box-sizing: border-box; font-family: Cambria; font-size: 12pt;">The second main area studied was CYP27A1’s relation to a high cholesterol diet. In order to do this, researchers performed a study on mice where a group of mice was fed a high cholesterol diet from birth and another group on a control diet from birth. In addition to the different diet, both CYP27A1 positive and negative mice were tested on either one diet or another. The results show that CYP27A1 positive mice on a high cholesterol diet developed larger tumors faster and earlier than the mice on the control diet. Furthermore, the tumors were tested and those mice with the high cholesterol diet were found to high much higher levels of 27HC in the tumor than those mice that ate a controlled diet. Most surprisingly, the CYP27A1 negative mice had undetectable levels of 27HC in tumors and tumors formed much later and grew lower. Lastly, if the CYP27A1 negative mice that were fed the control diet were injected with 27HC, they started to produce the same exact results as the CYP27A1 positive mice on the high cholesterol diet. </span><br />
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<tr style="box-sizing: border-box;"><td class="captionedImage" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;"><img alt="Screen Shot 2014-06-06 at 5.17.09 AM.png" src="http://islaslab.wikispaces.com/file/view/Screen%20Shot%202014-06-06%20at%205.17.09%20AM.png/513084350/720x277/Screen%20Shot%202014-06-06%20at%205.17.09%20AM.png" style="border: 0px; box-sizing: border-box; height: 277px; padding: 4px; width: 720px;" title="Screen Shot 2014-06-06 at 5.17.09 AM.png" /></td></tr>
<tr style="box-sizing: border-box;"><td class="imageCaption" style="border: 1px solid rgb(221, 221, 221); box-sizing: border-box; min-height: 20px; min-width: 5px; padding: 0px; vertical-align: top;">Genetic or pharmacological inhibition of 27HC production attenuates hypercholesterolemia- promoted tumor growth in mice. The latency and growth of tumors in the MMTV-PyMT mouse model of breast cancer were evaluated in mice in which the conversion of cholesterol into 27HC was inhibited by disruption of the CYP27A1 gene (CYP27A1−/−). For this study, MMTV-PyMT mice were bred onto a CYP27A1+/+ or a CYP27A1−/− background. (A) Tumor latency and (B) tumor growth were measured in mice on a control diet (CD) or a high-cholesterol diet (HCD) from weaning. Note that in the tumor growth studies, daily injection of 27HC overcame the inhibitory effect of CYP27A1 deletion. Significance between curves is indicated by a connecting black line and an asterisk (P < 0.05, n = 9 to 25).</td></tr>
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<br style="background-color: white; box-sizing: border-box; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px;" />
<span style="background-color: white; box-sizing: border-box; font-family: Cambria; font-size: 12pt;">In my opinion, this is the study’s most significant finding because it indicates that 27HC is the direct breast tumor promoter. </span><span style="background-color: white;"><span style="font-family: arial, helvetica, sans-serif; font-size: x-small;"><span style="line-height: 19px;">In addition, the d at a hints that cholesterol metabolite 27HC stimulates MCF-7 cell growth in mice and lastly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to cancer-free controls, and tumor 27HC abundance is further increased.</span></span></span><br />
<br style="background-color: white; box-sizing: border-box; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px;" />
<span style="background-color: white; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px;">References:</span><br />
<ol style="background-color: white; box-sizing: border-box; font-family: arial, helvetica, sans-serif; font-size: 13px; line-height: 19px; margin: 0.5em 0px 0px; padding: 0px 0px 0px 3em;">
<li style="box-sizing: border-box;"><span style="box-sizing: border-box;"><span style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif;">Nelson, E. R., S. E. Wardell, J. S. Jasper, S. Park, S. Suchindran, M. K. Howe, N. J. Carver, R. V. Pillai, P. M. Sullivan, V. Sondhi, M. Umetani, J. Geradts, and D. P. Mcdonnell. "27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology." Science 342.6162 (2013): 1094-098. Web.</span></span></li>
<li style="box-sizing: border-box;"><span style="box-sizing: border-box;"><span style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif;">Wu, Qian, Tomonori Ishikawa, Rosa Sirianni, Hao Tang, Jeffrey G. Mcdonald, Ivan S. Yuhanna, Bonne Thompson, Luc Girard, Chieko Mineo, Rolf A. Brekken, Michihisa Umetani, David M. Euhus, Yang Xie, and Philip W. Shaul. "27-Hydroxycholesterol Promotes Cell-Autonomous, ER-Positive Breast Cancer Growth." Cell Reports 5.3 (2013): 637-45. Web.</span></span></li>
<li style="box-sizing: border-box;"><span style="box-sizing: border-box;">Umetani, Michihisa, and Philip W. Shaul. "27-Hydroxycholesterol: The First Identified Endogenous SERM." NIH (2011): 1-10. National Institute of Health. Web.</span></li>
<li style="box-sizing: border-box;"><span style="box-sizing: border-box;">Bianchi F, Kaaks R, Viano H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002; 3:565-574. Web</span></li>
</ol>
Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-76023165805820270632014-06-01T10:32:00.000-07:002014-06-03T14:02:43.900-07:00Clinical Trials to Support KRAS Mutations and Cetuximab Resistance<style>
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<span style="font-family: Times,"Times New Roman",serif;">To conclude my series of blog posts, I will focus on the
last important piece of the <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927413/?report=classic#SD1" target="_blank">paper</a> that I have been dissecting. My other posts
focused on the data of the cellular models used to explain the molecular basis
of the secondary acquired resistance. Through two different models, the authors
concluded that KRAS amplification and/or mutation had an effect on resistance
to cetuximab. To determine if these conclusions are clinically relevant, the
researchers examined tumor biopsies from colorectal cancer patients. </span><br />
<a name='more'></a><span style="font-family: Times,"Times New Roman",serif;">The
results are presented in this figure. <span style="mso-spacerun: yes;"> </span></span></div>
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<span style="font-family: Times,"Times New Roman",serif;">This study compares the KRAS mutational statuses of
colorectal cancer patients who had chemotherapy resistant tumors and those with
anti-EGFR resistant tumors. The patients with anti-EGFR resistant tumors have
either been treated with cetuximab or panitumumab. The other group had been
treated by cytotoxic chemotherapy and had not been previously exposed to
anti-EGFR therapies. Through multiple methods of sequencing, KRAS mutations in
the patients’ tumors were identified. Some patients who had anti-EGFR
therapies, shown in table (b), acquired KRAS mutations, while the chemotherapy
patients, table (a), were all wild type for KRAS. </span></div>
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<span style="font-family: Times,"Times New Roman",serif;">The sample size for the chemotherapy group is sufficient
because they all are wild type, but a larger sample size for the anti-EGFR
group would be rewarding and valuable to this study. This could show possibly a
variety of mutations as well as the frequency of these mutations in colorectal cancer
patients. Also, three anti-EGFR patients are KRAS wild type, leading to the
question of what caused their acquired resistance? Would it be similar to the
chemotherapy patients? </span></div>
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<span style="font-family: Times,"Times New Roman",serif;">The molecular experiments focused solely on the drug
cetuximab, but this study allows patients who have also used panitumumab. How
similar are these drugs to assume that panitumumab could also lead to the same
mutations? The authors of this paper made their conclusions in terms of cetuximab,
so incorporating panitumumab data may weaken the strength of their claim. The type
of sequencing also differed for some patients, which could lead to inconsistencies
in the data. </span></div>
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<span style="font-family: Times,"Times New Roman",serif;"><br /></span></div>
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<span style="font-family: Times,"Times New Roman",serif;">The number of mutated reads from sequencing quantifies the
total number of KRAS mutations for the two groups of patients. Graph (c) illustrates
the significant difference between the two groups, including a small p-value,
supporting the significance. However, this study focused on sequencing KRAS in
patients that have already had a form of treatment, but without the knowledge
of their KRAS status before the treatment, one cannot say that anti-EGFR
therapy causes KRAS mutations, leading to resistance. We only know from this
data that there is a correlation, but in combination with the molecular data,
other assumptions can be made.</span><br />
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<span style="font-size: x-small;"><span style="font-family: Times,"Times New Roman",serif;"><b><span style="color: windowtext; text-decoration: none;">References:</span></b></span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Times,"Times New Roman",serif;"><span style="color: windowtext; text-decoration: none;">Sandra Misale</span>,
<span style="color: windowtext; text-decoration: none;">Rona Yaeger</span>,
<span style="color: windowtext; text-decoration: none;">Sebastijan
Hobor</span>, <span style="color: windowtext; text-decoration: none;">Elisa Scala</span>,
<span style="color: windowtext; text-decoration: none;">Manickam
Janakiraman</span>, <span style="color: windowtext; text-decoration: none;">David Liska</span>,
<span style="color: windowtext; text-decoration: none;">Emanuele
Valtorta</span>, <span style="color: windowtext; text-decoration: none;">Roberta
Schiavo</span>, <span style="color: windowtext; text-decoration: none;">Michela
Buscarino</span>, <span style="color: windowtext; text-decoration: none;">Giulia
Siravegna</span>, <span style="color: windowtext; text-decoration: none;">Katia
Bencardino</span>, <span style="color: windowtext; text-decoration: none;">Andrea Cercek</span>,
<span style="color: windowtext; text-decoration: none;">Chin-Tung
Chen</span>, <span style="color: windowtext; text-decoration: none;">Silvio
Veronese</span>, <span style="color: windowtext; text-decoration: none;">Carlo Zanon</span>,
<span style="color: windowtext; text-decoration: none;">Andrea
Sartore-Bianchi</span>, <span style="color: windowtext; text-decoration: none;">Marcello
Gambacorta</span>, <span style="color: windowtext; text-decoration: none;">Margherita
Gallicchio</span>, <span style="color: windowtext; text-decoration: none;">Efsevia
Vakiani</span>, <span style="color: windowtext; text-decoration: none;">Valentina
Boscaro</span>,<sup> </sup><span style="color: windowtext; text-decoration: none;">Enzo Medico</span>,
<span style="color: windowtext; text-decoration: none;">Martin Weiser</span>,
<span style="color: windowtext; text-decoration: none;">Salvatore
Siena</span>, <span style="color: windowtext; text-decoration: none;">Federica Di
Nicolantonio</span>, <span style="color: windowtext; text-decoration: none;">David Solit</span>,
and <span style="color: windowtext; text-decoration: none;">Alberto
Bardelli</span>. “Emergence of <i>KRAS</i>
mutations and acquired resistance to anti EGFR therapy in colorectal cancer.”
Nature (2012) 486:7404. Web May 3, 2014.</span></span></div>
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Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-81254991000768525112014-05-31T20:10:00.002-07:002014-06-02T20:28:42.727-07:00Crohn's Disease as a potential risk factor for Gastrointestinal Cancer developmentAt the age of ten, I was diagnosed with a Gastrointestinal condition known as <a href="http://www.ccfa.org/what-are-crohns-and-colitis/what-is-crohns-disease/">Crohn's Disease</a>. While this introduced several complications such as immune system compromise, severe abdominal pain, and difficulty with weight gain, I have since brought my condition under control, I am for all intents and purposes healthy and stable! Having a condition, however, pushes you to the brink of curiosity. Though I have learned a lot about Crohn's since being diagnosed, I have always wondered if a correlation exists between development of this disease and cancer risk. To my surprise, I stumbled upon a <a href="http://www.jstor.org.libproxy.scu.edu/stable/3553959?seq=5&Search=yes&searchText=breast&searchText=to&searchText=Crohn%27s&searchText=Disease&searchText=relation&searchText=in&searchText=cancer&list=hide&searchUri=%2Faction%2FdoBasicSearch%3FQuery%3Dbreast%2Bcancer%2Bin%2Brelation%2Bto%2BCrohn%2527s%2BDisease%26amp%3Bprq%3D%2528breast%2Bcancer%2Bin%2Brelation%2Bto%2BCrohn%2527s%2BDisease%2529%2BAND%2Biid%253A%252810.2307%252Fi25780653%2529%26amp%3Bhp%3D25%26amp%3Bacc%3Don%26amp%3Bwc%3Don%26amp%3Bfc%3Doff%26amp%3Bso%3Drel%26amp%3Bracc%3Doff&prevSearch=&resultsServiceName=null">study</a> conducted in Denmark looking specifically at patients with Crohn's disease and the resulting risk of cancer development.<br />
<a name='more'></a><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjK_LL0OOK2-nlEJlRPQICwkOr-63iDYbhIuAB36h0-zC0XaKpRvd-cgrTrDbu2AR96PddW-unM7EbZsT5o68IhXjxWPOHstISQ20c8ktDF7Xbtcj_HmGuqiL_KzZiYrT1cVCPdS0KgCm5j/s1600/figure+3.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjK_LL0OOK2-nlEJlRPQICwkOr-63iDYbhIuAB36h0-zC0XaKpRvd-cgrTrDbu2AR96PddW-unM7EbZsT5o68IhXjxWPOHstISQ20c8ktDF7Xbtcj_HmGuqiL_KzZiYrT1cVCPdS0KgCm5j/s1600/figure+3.png" height="320" width="199" /></a></div>
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Before introducing the study itself, a brief introduction to Crohn's Disease is required. Crohn's falls under a category of conditions referred to as <a href="http://www.cdc.gov/ibd/">Inflammatory Bowl Diseases</a>, characterized by significant inflammation and ulceration of the Gastrointestinal tract. These symptoms are caused by the autoimmune nature of Crohn's, the immune system essential targets and attacks healthy cells within the GI tract. In relation to this study, the biological implications of Crohn's relationship with Cancer are unclear; the mechanism of this disease may or may not contribute to uncontrolled cell proliferation and DNA damage.<br />
<br />
The objective of this particular study was to determine the incidence of cancer among a cohort of Crohn's patients in Denmark and compare the observed numbers to the cancer incidence rates in the general Denmark population. 2,645 patients, with equal proportions of men and women, were identified from the Danish National Registry of Patients as having only Crohn's Disease with no additional, potentially confounding, IBD conditions. The study follow-ups began exactly 1 year following each patient's first hospitalization record for Crohn's Disease; this continued until patient's date of death, emigration, or 17 years after the start of the study.<br />
<br />
Interestingly enough what they discover as a result were three unexpected data pairs, denoted by the highlighted regions in Table 2. In comparing the three separate Observed values (Obs) with that of the Expected values (Exp), what can we infer? For the purposes of analyzing the data, the "SIR" value is the <a href="http://www.state.nj.us/health/eohs/passaic/pompton_lakes/pompton_lakes_fs_sir.pdf">standardized incidence ratio</a>, calculated by dividing the observed number of cancers by the expected value; the higher the value the greater the occurrence of cancer. <br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhYbpavgVNesBli4ZwAMUhHm0htfdpiuAktt7_qsmrROqZ6Cgc5IOP5UDOzRiqDfmGWg3iHW6zxLVjg12oHnPDxUGQuuWLdJ_xPolJPdPYFl9WiK5UjfQhDfbuCnZHj9-CO9oiUHYHV0JK6/s1600/figure+1.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhYbpavgVNesBli4ZwAMUhHm0htfdpiuAktt7_qsmrROqZ6Cgc5IOP5UDOzRiqDfmGWg3iHW6zxLVjg12oHnPDxUGQuuWLdJ_xPolJPdPYFl9WiK5UjfQhDfbuCnZHj9-CO9oiUHYHV0JK6/s1600/figure+1.png" height="316" width="400" /></a></div>
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A total of 143 cancers was observed within the participant pool of 2,645 Crohn's patients, a value slightly greater than what was expected. Additionally, the greatest majority of these cancers developed within the Gastrointestinal tract, proposing that the region affected by Crohn's Disease was also most vulnerable to observed cancer development. But most notably, the incidence of cancer within the small intestine yielded the greatest difference between Observed and Expected values. Crohn's Disease is most commonly localized within the small intestine, however can be found additionally in the colon and large intestines. (My particular case involves disease within the small intestines and colon.) Although the study did not receive information regarding the specific location of each patient's Crohn's, it is fair to assume that a good majority of participants had disease primarily affecting the small intestines. According to the study, "cancers of the small intestine occur very rarely in the general population," thus it seems appropriate to surmise that having Crohn's Disease is correlated with developing cancer within the small intestine. <br />
<br />
So let us quickly scan the 5 cases of small intestine cancer observed for any similarities or parallel indications. As denoted in Table 3 below, three cases of Adenocarcinoma and two cases of a Malignant carcinoid resulted. The important value provided is the time between Crohn's and cancer development, similarities in duration offer evidence of a possible correlation. What we observe however is no concrete parallel, in addition to differing histologies, the time between disease development is scattered. While the values observed for cancer within the small intestines in Table 2 indicate a potential correlation between Crohn's presence and cancer development, the values below demonstrate a seemingly random and independent development of cancer.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0G9oExd8ZGFCardlHpoY7XxLzx5uVLPgS_-Ur5Vvdj1Xt_Bbh2ystkt1v1gt9MS6SydkpALzxvwbrxAcPoG2XJmwB6pap64aD-R6zZeFiyE9hE1Dm93np0n9uxKn3F16H21HSdkWtPyuT/s1600/Screen+Shot+2014-05-31+at+7.54.51+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0G9oExd8ZGFCardlHpoY7XxLzx5uVLPgS_-Ur5Vvdj1Xt_Bbh2ystkt1v1gt9MS6SydkpALzxvwbrxAcPoG2XJmwB6pap64aD-R6zZeFiyE9hE1Dm93np0n9uxKn3F16H21HSdkWtPyuT/s1600/Screen+Shot+2014-05-31+at+7.54.51+PM.png" height="193" width="400" /></a></div>
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Now, though the study itself is both fascinating and personally relevant, two issues present itself. Firstly, in regards to Crohn's, the development of disease, date of diagnosis, and first hospitalization record often fall within three different time points. Given that this study followed patients after first date of hospitalization, it is very likely that Crohn's disease had been prevalent in the body many years before. Thus, the method of study follow-up is not accurately measuring the time between Crohn's and cancer development, a variable integral to establishing the correlation between Crohn's and cancer. <br />
<br />
Secondly, though the initial participant pool is large and reliable, the resulting cancer development values present a small and inconsistent data set. While the proportion of Crohn's patients that developed cancer within the small intestines is notable in comparison to the expected proportion, this equates to a mere 5 patients out of 2,645 that demonstrated significant values.<br />
<br />
Even still, as a Crohn's patient, this research is important; I will certainly not dismiss the findings of this study. While there was no evidence of association between Crohn's Disease and development of any extraintestinal cancer, patients within this study demonstrated an increased number of overall cancer development, gastrointestinal cancer, and cancer within the small intestines. Such findings warrant further research and propose that Crohn's Disease may in fact serve as a potential risk factor for Gastrointestinal cancer development.<br />
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<div style="text-align: center;">
<span style="font-family: Times, Times New Roman, serif;">Sources</span></div>
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<span style="color: black;"><span style="font-family: Times, Times New Roman, serif;">Mellemkjær, Lene, et al. "Crohn's
Disease and Cancer Risk (Denmark)." <i>Cancer Causes and Control</i> </span></span></div>
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<span style="color: black;"><span style="font-family: Times, Times New Roman, serif;">11.2 (2000):
145-50. Print.</span><span style="font-family: Times New Roman; font-size: 13.5pt;"><o:p></o:p></span></span></div>
Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-86471427195604857422014-05-31T19:44:00.004-07:002014-05-31T19:44:55.313-07:00A closer look into CYP7B1<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;">As
our project progresses, Matt and I are starting to delve deeper into many of
the topics associated with cholesterol and cancer. One of these very important topics is 7ɑ-hydroxylase
(usually referred to by its gene name CYP7B1), a very important enzyme that works
to hydrolyze the infamous 27-hydroxycholesterol (27HC). 27HC is a cholesterol metabolite that has
recently been shown to promote ER positive breast cancer. This is really all you need to know about
this molecule. However, for more
information on 27HC, you can search the blog for my earlier post <i>Cholesterol and its Promotion of ER+ Breast
Cancer</i>. If you are unable to find my
post, follow this link to another information page for <a href="http://www.scbt.com/datasheet-358756.html">27HC</a>.</span><br />
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<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">TABLE 1</span></b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"><o:p></o:p></span></div>
<div class="MsoNormal" style="background: rgb(238, 238, 238); margin-bottom: 0.0001pt; vertical-align: baseline;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Physiological
roles of CYP7B1</span></b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"><o:p></o:p></span></div>
<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;">
</span><br />
<table border="1" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="background: white; border-collapse: collapse; border: none; mso-border-alt: solid silver 1.5pt; mso-border-top-alt: solid silver .75pt; mso-padding-alt: 0in 0in 0in 0in; mso-yfti-tbllook: 1184;">
<thead>
<tr>
<td style="border-bottom: silver 1.5pt; border-left: #E8E8E8 1.0pt; border-right: #E8E8E8 1.0pt; border-style: solid; border-top: silver 1.0pt; mso-border-bottom-alt: silver 1.5pt; mso-border-left-alt: #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8 .75pt; mso-border-style-alt: solid; mso-border-top-alt: silver .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Role/tissue<o:p></o:p></span></b></div>
</td>
<td style="border-bottom: solid silver 1.5pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: solid silver 1.0pt; mso-border-bottom-alt: silver 1.5pt; mso-border-left-alt: #E8E8E8 .75pt; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8 .75pt; mso-border-style-alt: solid; mso-border-top-alt: silver .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Substrates<o:p></o:p></span></b></div>
</td>
<td style="border-bottom: solid silver 1.5pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: solid silver 1.0pt; mso-border-bottom-alt: silver 1.5pt; mso-border-left-alt: #E8E8E8 .75pt; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8 .75pt; mso-border-style-alt: solid; mso-border-top-alt: silver .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Refs.<o:p></o:p></span></b></div>
</td>
</tr>
</thead>
<tbody>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Bile salt synthesis</span></b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"><o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"> Liver<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">25-Hydroxycholesterol,
27-hydroxycholesterol<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">8</span></sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">, <sup>14</sup>,<sup>29</sup><o:p></o:p></span></div>
</td>
</tr>
<tr>
<td colspan="3" style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Steroid hormone metabolism</span></b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"><o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"> Brain<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Pregnenolone, dehydroepiandrosterone<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">3</span></sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">, <sup>7</sup><o:p></o:p></span></div>
</td>
</tr>
<tr>
<td colspan="3" style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Metabolism of estrogen receptor ligands</span></b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"><o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"> Prostate<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">5α-Androstane-3β,17β-diol<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">19</span></sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">, <sup>20</sup><o:p></o:p></span></div>
</td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"> Prostate<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Dehydroepiandrosterone?<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">23</span></sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">, <sup>24</sup><o:p></o:p></span></div>
</td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"> Vasculature<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">27-Hydroxycholesterol<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">21</span></sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">, <sup>22</sup><o:p></o:p></span></div>
</td>
</tr>
<tr>
<td colspan="3" style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">Immunoglobulin production</span></b><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"><o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom"></td>
</tr>
<tr>
<td style="border-bottom: solid silver 1.0pt; border-left: solid #E8E8E8 1.0pt; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;"> Immune cells<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in;">
<span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">25-Hydroxycholesterol<o:p></o:p></span></div>
</td>
<td style="border-bottom: solid silver 1.0pt; border-left: none; border-right: solid #E8E8E8 1.0pt; border-top: none; mso-border-bottom-alt: silver; mso-border-left-alt: #E8E8E8; mso-border-left-alt: solid #E8E8E8 .75pt; mso-border-right-alt: #E8E8E8; mso-border-style-alt: solid; mso-border-top-alt: silver; mso-border-top-alt: solid silver .75pt; mso-border-width-alt: .75pt; padding: 1.65pt 3.35pt 1.65pt 3.35pt;" valign="bottom">
<div align="center" class="MsoNormal" style="line-height: 13.95pt; margin-bottom: .0001pt; margin-bottom: 0in; text-align: center;">
<sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">25</span></sup><span style="color: #403838; font-family: "Times New Roman","serif"; font-size: 12.0pt; mso-ansi-language: ES-US; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: ES-US;">, <sup>26</sup><o:p></o:p></span></div>
</td>
</tr>
</tbody></table>
<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"><br /></span>
<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<a href="http://www.mybiosource.com/datasheet.php?products_id=1245594&cacheID=0s1vn65tskfee8cb336cttm4j5" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;">CYP7B1</a><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;"> is an enzyme that works to hydrolyze
many different molecules of cholesterol synthesis, including 27HC. It is found in many parts of the body, as
shown in the below table (Table 1). The
different physiological functions of this enzyme are very interesting, such as
its role in the creation of stomach bile.
However, many functions of CYP7B1 are unknown, especially when it comes
to the brain. What is clear is the
effect that CYP7B1 has on 27HC and the effect this function seems to have on ER
+ breast cancer.</span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-m-HZPIAd3ns/U4qInvQ4-QI/AAAAAAAAAB0/7zzT5UcSPr8/s1600/F1.medium.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://3.bp.blogspot.com/-m-HZPIAd3ns/U4qInvQ4-QI/AAAAAAAAAB0/7zzT5UcSPr8/s1600/F1.medium.gif" height="320" width="121" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="fig-label" style="border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; font-weight: bold; line-height: 18.200000762939453px; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">Fig. 1.</span><span style="background-color: #eeeeee; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 18.200000762939453px; text-align: start;"></span><br />
<div style="border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">
Morphological phenotype of 2-week-old mice. (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">A</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">B</em>) Whole-mount staining of mammary glands. In 2-week-old WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">A</em>), there was no elongated side branching of ducts (red arrows), as is seen in CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">B</em>). (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">C</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">D</em>) BrdUrd staining of mammary glands after 2-h BrdUrd treatment. BrdUrd-labeled DNA was visualized with an anti-BrdUrd antibody. In WT mice, very little BrdUrd incorporation could be detected (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">C</em>), but in CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice, there were many BrdUrd-positive nuclei (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">D</em>), suggesting that mammary gland growth in CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice started earlier than in WT mice. The red arrow signifies a BrdUrd labeled cell. (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">E</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">F</em>) Hematoxylin and eosin staining of uterus from WT (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">E</em>) and CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span>(<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">F</em>) mice. There are more glands in the uteri of CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice than in WT mice. (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">G</em>–<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">I</em>) BrdUrd staining of uterus after 2-h BrdUrd treatment. There was more incorporation of BrdUrd into DNA in the uteri of CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">H</em>) than there was in WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">G</em>). The percentage of total epithelial cells, which were BrdUrd stained in WT and CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice is shown in <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">I</em>.(<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">J</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">K</em>) ERα staining of mammary glands. There are more ERα-positive epithelial cells and staining is stronger in CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">K</em>) than WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">J</em>).<br />
<br />
<br /></div>
</td></tr>
</tbody></table>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://1.bp.blogspot.com/-KhsHNFL5kEk/U4qRmuYydCI/AAAAAAAAACI/QOys5vnaNHI/s1600/F2.medium.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://1.bp.blogspot.com/-KhsHNFL5kEk/U4qRmuYydCI/AAAAAAAAACI/QOys5vnaNHI/s1600/F2.medium.gif" height="261" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="fig-label" style="border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; font-weight: bold; line-height: 18.200000762939453px; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">Fig. 2.</span><span style="background-color: #eeeeee; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 18.200000762939453px; text-align: justify;"></span><div class="first-child" id="p-38" style="border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">
Whole-mount examination of mammary glands from 2- to 4-week-old mice. Two-week-old WT (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">A</em>) and CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">B</em>) mice, 3-week-old WT (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">C</em>) and CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">D</em>) mice, and 4-week-old WT (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">E</em>) and CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">F</em>) mice are shown. CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice show more ductal elongation and branching than WT mice at every age. Mammary ducts are encircled in red.</div>
</td></tr>
</tbody></table>
<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;">Before
the link between ER positive breast cancer and 27HC was attained, a paper was
written discussing the effects of limiting CYP7B1 on breast and ovarian growth
in mice. In this paper they discuss
their experiment. In this experiment
they took two types of mice; one group was just normal lab mice who had CYP7B1
expressed (control) and the other group had CYP7B1 knocked out
(experimental). The second group was referred
to as CYP7B1 -/-. The mice were kept in
the same conditions and after a certain amount of time, were killed so that
their cells could be analyzed. What they
found was that the mice who did not have CYP7B1 showed much more cell
proliferation in the mammary glands, also showing growth much earlier in life
as well. In figure 1, we see the greater
cell proliferation, illustrated through the greater branching of the mammary
ducts of the CYP7B1 -/- mice after 2 weeks compared to the control. To solidify this finding, the researchers
used <a href="https://www.google.com/webhp?sourceid=chrome-instant&rlz=1C1CHFX_enUS497US497&ion=1&espv=2&es_th=1&ie=UTF-8#q=what%20is%20BrdUrd">BrdUrd</a> to better monitor the cell proliferation and
to put the results into graphical form (figure 1I). BrdUrd is used to analyze cell proliferation,
with greater amounts of BrdUrd illustrating greater cell proliferation. Later on in the paper they show that this
increased cell proliferation continues for 4 weeks, with the CYP7B1 -/- mice
showing greater ducal elongation and branching when compared to the control
mice at all time points (Fig.2).
Finally, they looked over the long term, going from 6 months to 15
months of age (fig. 3 A-F). At these
time points they monitored the mammary growth, see that for 6 month old mice,
we see the increased branching of the CYP7B1 -/- mice still being
expressed. However, at 15 months, the
researchers saw <a href="https://www.google.com/webhp?sourceid=chrome-instant&rlz=1C1CHFX_enUS497US497&ion=1&espv=2&es_th=1&ie=UTF-8#q=involution%20definition">involution</a> of the mammary glands in CYP7B1 -/- mice as opposed to normal function of the
mammary glands in the control mice. This
illustrates how the early onset of growth in the CYP7B1-/- mice caused for the
earlier involution of the mammary glands.
This experiment was very important in determining the role of CYP7B1 and
its effects on cell proliferation in breast tissue, specifically the mammary
glands. <o:p></o:p></span><br />
<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"></span><br /><span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;"></span>
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<tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-H9OrzOShvWU/U4qSz82_23I/AAAAAAAAACU/l4HYo2jmMx0/s1600/F3.medium.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://3.bp.blogspot.com/-H9OrzOShvWU/U4qSz82_23I/AAAAAAAAACU/l4HYo2jmMx0/s1600/F3.medium.gif" height="320" width="122" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="fig-label" style="border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; font-weight: bold; line-height: 18.200000762939453px; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">Fig. 3.</span><span style="background-color: #eeeeee; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 18.200000762939453px; text-align: start;"></span><div id="p-39" style="border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">
Morphological phenotype of adult CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice. Comparison of mammary glands from 6-month-old WT (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">A</em>) and CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">B</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">C</em>) mice showed a much more extensively branched ductal tree in CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice. (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">C</em>) Higher magnification of the ducts in <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">B</em>. There was no difference between the two genotypes in lobular formation. The mammary glands from 15-month-old mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">D</em>–<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">F</em>) show that, in CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">E</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">F</em>), there are signs of involution (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">F</em>, higher magnification of the ducts in <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">E</em>), whereas ducts appear still to be active in WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">D</em>). (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">G</em>–<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">L</em>) Uteri at the ages of 6 (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">G</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">H</em>),8(<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">I</em> and<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">J</em>), and 15 (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">K</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">L</em>) months. Uteri of 6-month-old CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">H</em>) had larger lumina than did WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">G</em>). Enlarged lumina of the uteri were evident in 8-month-old CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">J</em>) but not in WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">I</em>). By 15 months of age, the lumina of the CYP7B1<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; font-weight: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">–/–</span> mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">L</em>) were extremely enlarged with sclerotic and atrophic glands, whereas the uterine morphology in the age matched WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">K</em>) was essentially similar to that of 6-month-old WT mice (<em style="border: 0px; font-family: inherit; font-size: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">G</em>).</div>
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<span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;">What
this paper finds overall is that the absence of CYP7B1 allows for greater cell
proliferation. This larger amount of
cell proliferation is due to the fact that CYP7B1 is a limiter of 3beta-Adiol,
which is and androgen metabolite that is an inhibitor of </span><a href="https://www.bio.cmu.edu/courses/BiochemMols/ER/ERIntro.html" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;">ER-alpha and ER-beta</a><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%;">
(estrogen receptors alpha and beta) in the presence of CYP7B1. However, when
CYP7B1 is no longer present, 3beta-Adiol becomes estrogenic for both the ER
receptor types and begins to cause increased cell proliferation and early onset
puberty. This is despite the fact that
ER-beta is usually used in cell growth limiting. However, for a reason still unknown to
researchers, the function of the ER-beta, 3beta-Adiol binding becomes growth
promoting in the absence of CYP7B1. What
this does is it causes for increased risk for breast cancer due to the large
increase in cell proliferation, both in the mammary tissue as well as ovarian
tissue. For the purposes of our
research, I have focused the above analysis on mammary tissue. This would explain the reason behind the
better outcomes of ER positive breast cancer patients showing higher levels of
CYP7B1. This fact is supported by what we
learned in class, that areas of the body with more cell proliferation tend to
have higher rates of breast cancer. This
is due to the increase in the number of chances for DNA damage. In organs such as the breast that already
have high cell proliferation, this loss of CYP7B1 can be devastating. It can increase the chances of cancer in an
already cancer susceptible organ. As I
stated in my previous blog, this knowledge can be very helpful in developing
treatments that work to promote CYP7B1.
With treatments that are using native body enzymes, there is less chance
of adverse side effects while still gaining a much better outcome. </span></div>
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<span lang="EN-US" style="font-family: "Times New Roman","serif"; font-size: 12.0pt; line-height: 115%;">Works
Consulted</span></div>
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<ol>
<li><span lang="EN-US" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%; text-indent: -0.25in;">Omoto, Y. "Early Onset of Puberty and Early Ovarian Failure
in CYP7B1 Knockout Mice."<span class="apple-converted-space"> </span></span><i style="box-sizing: border-box; text-align: start; text-indent: -0.25in;">Proceedings of the National
Academy of Sciences</i><span style="background-color: rgba(255, 255, 255, 0.0980392); text-align: start; text-indent: -0.25in;">102.8 (2005): 2814-819. Web.</span><span lang="EN-US" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%; text-indent: -0.25in;"> </span></li>
<li><span lang="EN-US" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%; text-indent: -0.25in;">2.<span style="font-family: 'Times New Roman'; font-size: 7pt; line-height: normal;"> </span></span><span lang="EN-US" style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 115%; text-indent: -0.25in;">Wu, Qian, Tomonori Ishikawa, Rosa Sirianni, Hao Tang,
Jeffrey G. Mcdonald, Ivan S. Yuhanna, Bonne Thompson, Luc Girard,
Chieko Mineo, Rolf A. Brekken, Michihisa Umetani, David M. Euhus,
Yang Xie, and Philip W. Shaul. "27-Hydroxycholesterol Promotes Cell-Autonomous,
ER-Positive Breast Cancer Growth."<span class="apple-converted-space"> </span></span><i style="box-sizing: border-box; text-align: start; text-indent: -0.25in;">Cell Reports</i><span class="apple-converted-space" style="text-indent: -0.25in;"><span style="background-color: rgba(255, 255, 255, 0.0980392); text-align: start;"> </span>5.3 (2013): 637-45. Web.</span></li>
</ol>
<br />Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-27412143187103119092014-05-31T17:12:00.001-07:002014-05-31T17:12:09.445-07:00Oral Contraceptives effect on Breast and Ovarian Cancer Risk In Megan and Christina's presentation, they discussed how the increased level of estrogen and progesterone during pregnancy causes breast tissue to differentiate and ultimately decreases risk of developing breast cancer. Because most combination birth control pills contain both estrogen and progesterone it made me curious about if the use of oral contraceptives can have similar effects of pregnancy and decrease risk of breast cancer. However, the information I found was opposite of what I had anticipated.<br />
<a name='more'></a> Many studies have been conducted that support the notion that oral contraceptives increase one's risk of getting breast cancer. Though this is the opposite of my initial thought, it makes sense when you think about how early menarche and late menopause increase one's risk of getting breast cancer. These hormones cause differentiation in the breast tissue during and after pregnancy. However, increased levels of estrogen outside of pregnancy promotes DNA synthesis and cell proliferation. With increased cell proliferation there is a greater chance that mutations can occur. (1) Also, as Megan and Christina brought up in their presentation, it was seen that parous rats have a G1 phase twice as long as the virgin rats. Even though this extended G1 phase has not yet been proven in humans, it is an advantage that women just taking oral contraceptives would not have. Therefore, women taking oral contraceptives have increased cell proliferation due to the higher levels of hormones, without an extended G1 phase to prevent mutated cells from dividing.<br />
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<a href="http://www.jogc.com/abstracts/full/200703_Editorial_1.pdf">Figure 1.</a> Comparisons of relative risks for breast cancer(2)</div>
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In 1996, the Cancer Epidemiology Unit at Oxford University <a href="http://www.ncbi.nlm.nih.gov/pubmed/8656904">analyzed</a> data from 53,297 women with breast cancer and 100,239 women without breast cancer from around the world and examined use of oral contraceptives as a potential risk factor for breast cancer. The risk of developing breast cancer was found to be the highest in current users (<span style="background-color: white; font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17px;">1.24 [1.15-1.33], 2p<0.00001)</span>. The amount of risk gradually decreases with increasing amount of years since the end of use, until ultimately the risk disappears 10 years after stopping use(3). However, an interesting finding was that the tumors that were found in the women who had been using oral contraceptives were less advanced clinically than women who had never used oral contraceptives. The risk that the cancer had metastasized as opposed to localized tumors was found to be 0.88(<span style="background-color: white; font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17px;">0.81-0.95; 2p=0.002</span>)(3). So, even though oral contraceptives increase one's risk of developing breast cancer, the cancer has a lower risk of metastasizing. </div>
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While the use of oral contraceptives increase the risk of breast cancer, they can decrease the risk of developing ovarian cancer in patients with BRCA1 or BRCA2 mutations. A case-control <a href="http://www.ncbi.nlm.nih.gov/pubmed/17196508">study</a> performed by the Samuel Lunenfeld Research Institute examined oral contraceptive's and parity's effect on ovarian cancer risk of patients with BRCA1/2 mutations. They found that the use of oral contraceptives dramatically decreased the risk in patients with these mutations (BRCA1 <span style="background-color: white; font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17px;">0.56 [95% CI 0.45-0.71]; p<0.0001</span>)(BRCA2 <span style="background-color: white; font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17px;">0.39 [0.23-0.66]; p=0.0004</span>). An interesting finding was that although parity decreases risk of ovarian cancer in those with BRCA1 mutations by about the same amount as use of an oral contraceptive, it increases the risk in BRCA2 mutation carries (<span style="background-color: white; font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17px;">2.74 [1.18-6.41]; p=0.02</span>). Though the results are significant, case-control studies are often subject to bias. In addition, the sample size of those with a BRCA1 mutation was 670 patients, while it was only 128 patients with <span style="font-family: inherit;">BRCA2 mutations(4). This makes me skeptical about the BRCA2 findings, particularly parity increasing the risk of ovarian cancer. </span></div>
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<span style="font-family: inherit;"><span style="background-color: white; line-height: 24px; text-indent: -30px;">1. Conova, Susan. "Estrogens Role in Cancer ." </span><i style="background-color: white; line-height: 24px; text-indent: -30px;">Colombia University Health Sciences</i><span style="background-color: white; line-height: 24px; text-indent: -30px;">. N.p., 26 May 2003. Web. <http://www.cumc.columbia.edu/publications/in-vivo/Vol2_Iss10_may26_03/>.</span></span></div>
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<span style="font-family: inherit;"><span style="background-color: white; line-height: 24px; text-indent: -30px;">2. </span><span style="background-color: white; line-height: 24px; text-indent: -30px;">Reid, Robert L. "Hormonal Contraception and Breast Cancer: Keeping Perspective." </span><i style="background-color: white; line-height: 24px; text-indent: -30px;">JOGC</i><span style="background-color: white; line-height: 24px; text-indent: -30px;"> (2007): 207-09. Web. 31 May 2014. <http://www.jogc.com/abstracts/full/200703_Editorial_1.pdf>.</span></span></div>
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<span style="font-family: inherit;"><span style="background-color: white;">3. </span><span style="background-color: white; color: #333333; line-height: 18px;">Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. </span><i style="background-color: white; color: #333333; line-height: 18px;">Lancet</i><span style="background-color: white; color: #333333; line-height: 18px;"> </span><span style="background-color: white; color: #333333; line-height: 18px;">1996; 347(9017):1713–1727.\</span></span></div>
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<span style="font-family: inherit;">4. Samuel Lunenfield Research Institute: <span style="background-color: white; line-height: 24px; text-indent: -30px;">Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. <i>Lancet</i></span><span style="background-color: white; line-height: 24px; text-indent: -30px;">. N.p., 8 Jan. 2007. Web. 31 May 2014. <http://www.ncbi.nlm.nih.gov/pubmed/17196508>.</span> </span></div>
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<br />Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-8704154899115883822014-05-30T14:48:00.002-07:002014-06-02T20:27:07.629-07:00Tumor Suppressor Functions and Mutations of NOTCH1 in HNSCC<div class="MsoNormal">
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<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://4.bp.blogspot.com/-CP93B5OCscQ/U4d6tkXqGQI/AAAAAAAAACU/DRTPxqgzfsQ/s1600/Screen+Shot+2014-05-22+at+4.51.38+PM.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><span style="font-family: inherit;"><img border="0" src="http://4.bp.blogspot.com/-CP93B5OCscQ/U4d6tkXqGQI/AAAAAAAAACU/DRTPxqgzfsQ/s1600/Screen+Shot+2014-05-22+at+4.51.38+PM.png" height="265" width="320" /></span></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: inherit; font-size: x-small;"><b>Figure 1</b>. Duality of Notch functions in keratinocyte commitment
to differentiation and cell survival. Notch signaling impacts on, and
is regulated by a complex signaling network with an important role
in skin homeostasis and tumor development. Like Notch, many
other components of this network exert a duality of functions,
impinging on keratinocyte growth/differentiation control as well as
cell survival. This has potentially important implications for cancer
therapy. An attractive approach could be the use of selective
inhibitors, which can suppress the Notch prosurvival function
while leaving intact or enhancing its ability to induce differentia-
tion. Alternatively, Notch inhibitors, or inducers, could be used
as part of a combination therapy in conjunction with other
compounds with growth inhibitory and/or pro-apoptotic functions. </span></td></tr>
</tbody></table>
<span style="font-family: inherit;">
</span>
<br />
<a name='more'></a><span style="font-family: inherit;">In the review article, </span><i style="font-family: inherit;">Notch tumor suppressor function</i><span style="font-family: inherit;">, figure 1 is presented,
showing a few of the pathways of how Notch can act as a tumor suppressor in
keratinocyte tumors.<span style="font-size: xx-small;">3</span> Since the figure is somewhat complicated, the first thing
to notice is both the upper and lower parts of the figure. The upper part
diagrams Notch’s tumor suppressor role through inhibitions of stem cell renewal
and cell differentiation signaling pathways and the lower part portrays Notch’s
tumor suppressor role by either inhibition or activation of apoptotic pathways.
A few of the most important pathways to notice are the Notch1, p63, p53, p21,
and Wnts pathway along with the FoxO3a and NF</span><sub style="font-family: inherit;">k</sub><span style="font-family: inherit;">B/Akt pathway. In the
Notch1, p63, p53, p21, and Wnts pathway, Wnts triggers the activation of
products such as Cyclin D1, which is a main component that causes a cell to
enter the cell cycle and go from G1phase into S phase. Therefore the whole
cycle of Notch1, p63, p53, and p21 has a big role in controlling cell’s to
enter the cell cycle. On the other hand, FoxO3a is a pro-apoptotic gene and NF</span><sub style="font-family: inherit;">k</sub><span style="font-family: inherit;">B/Akt
are pro-interferon genes. Notch inhibits FoxO3a and activates NF</span><sub style="font-family: inherit;">k</sub><span style="font-family: inherit;">B,
which essentially creates this balance between stopping cell death and
promoting the immune system to kill those cells that are infected with viruses.
This balance is important for regulating cell’s such that they </span>don't<span style="font-family: inherit;"> enter a
hyperplastic or neoplastic state while still maintaining appropriate levels of cell proliferation. Essentially,
combined with information from previous blogs, mutations in Notch can cause it
to transform into an oncogene or a tumor suppressor, depending on how and where
the mutations take place.</span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="http://1.bp.blogspot.com/-nKwKhnQqjjQ/U4d8Dl1-W6I/AAAAAAAAACc/6h2YurppAw4/s1600/Screen+Shot+2014-05-23+at+12.00.10+AM.png" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><span style="font-family: inherit;"><img border="0" src="http://1.bp.blogspot.com/-nKwKhnQqjjQ/U4d8Dl1-W6I/AAAAAAAAACc/6h2YurppAw4/s1600/Screen+Shot+2014-05-23+at+12.00.10+AM.png" height="270" style="cursor: move;" width="400" /></span></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: inherit; font-size: x-small;"><b>Figure 2</b>. NOTCH gene mutations identified in head and neck cancer. A. schematic diagram of the
domain structure of NOTCH1. (domain structures of NOTCH2 and NOTCH3 are similar). All nonsense mutations occur upstream of the TAD domain, which is required for
transactivation of target genes. Each arrowhead represents a single point mutation in an
individual tumor, of the class indicated to the left. </span><br />
<span style="font-family: inherit; font-size: small;"><br /></span>
<span style="font-family: inherit; font-size: small;"><br /></span>
<span style="font-family: inherit; font-size: small;">
</span></td></tr>
</tbody></table>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://1.bp.blogspot.com/-0-CDEWzA-D8/U4d9d-O2TVI/AAAAAAAAACk/aBp6GbUQQyw/s1600/Screen+Shot+2014-05-29+at+11.32.56+AM.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><span style="font-family: inherit;"><img border="0" src="http://1.bp.blogspot.com/-0-CDEWzA-D8/U4d9d-O2TVI/AAAAAAAAACk/aBp6GbUQQyw/s1600/Screen+Shot+2014-05-29+at+11.32.56+AM.png" height="238" width="400" /></span></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: inherit; font-size: x-small;"><b>Figure 3</b>. Schematic depiction of mutations in NOTCH1. (A) Previously observed NOTCH1 mutations in
hematopoietic malignancies. EGF, epidermal growth factor; LNR, Lin12-Notch repeats; TMD, trans-
membrane domain; RAM, recombination signal-binding protein 1 for J-k (RBPjk) association module;
NLS, nuclear localization signal; PEST, proline, glutamic acid, serine/threonine-rich motifs. Red bars
represent previously described mutation hotspots (amino acids 1575 to 1630 and 2250 to 2550). (B)
Previously observed NOTCH1 mutations in solid tumors. Colored arrow (missense mutation) and “X”
(truncating mutation) depict mutations found in different tumor types: pink, breast cancer; black, glioma;
blue, lung cancer; green, pancreatic adenocarcinoma; red, esophageal squamous cell carcinoma; purple,
tongue squamous cell carcinoma. (C) Mutations in NOTCH1 in HNSCC observed in this study. Black arrow
indicates missense mutation and red “X” indicates truncating mutation (13, 22–24). </span></td></tr>
</tbody></table>
<br />
<span style="font-family: inherit;">Above are two figures that depict
the mutations found in an array of HNSCC cases and previously discovered T-ALL
cases. Each of these figures is created from their own individual study. </span>The study for figure 2, taken from <i style="font-family: inherit;">The Mutational Landscape of Head and Neck Squamous Cell Carcinoma,</i> looked at 92 different HNSCC tumor/normal cell pairs, which about 12 had NOTCH1 mutations.<span style="font-size: xx-small;">4</span> Likewise, this is the same for figure 3 in diagram A of NOTCH1, taken from <i style="font-family: inherit;">Exome Sequencing of Head and Neck Squamous Cell Carcinoma. </i>This study included the exome sequencing of 32 different HNSCC tumors, 21 of with experienced NOTCH1 mutations.<span style="font-size: xx-small;">1</span><span style="font-family: inherit;"> As
seen in figure 2,</span><span style="font-family: inherit;"> T-ALL
mutations happen mostly in the HD region (pink). </span><i style="font-family: inherit;"> </i><span style="font-family: inherit;">Similarly, t</span><span style="font-family: inherit;">he results from figure 3 revealed</span><span style="font-family: inherit;"> inactivating mutations in </span><span style="font-family: inherit; font-style: oblique;">NOTCH1</span><span style="font-family: inherit;"> within this same region. What is important to keep in mind is that this region
and the TM region contain the cleavage sites that release the intra-cellular
domain of NOTCH1 (ICN).<span style="font-size: xx-small;">2</span> Essentially, these mutations disrupt these sites in a
way such that these cleavage sites are no longer protected and can constantly
be cleaved or even to the point where the extracellular and cytoplasmic sides
completely </span>disassociate from each other<span style="font-family: inherit;">. Either way, there is constantly and excess amount of
ICN within T-ALL cells, which in turn triggers cells to turn cancerous. The mutations in the PEST
region are also believed to be contributors to T-ALL but is unknown as to why
because the gene activator region lies within the ANK repeats and TAD regions of
this domain.</span></div>
<div class="MsoNormal" style="margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-autospace: none;">
<span style="font-family: inherit;">In HNSCC, however, the mutations are much more
sporadic and located in regions that have much different physiological
roles. In figure 2, the majority of the mutations in NOTCH1 occur in the
extracellular domain within the EGF-like repeats. This region is the
ligand-binding region. Therefore these mutations cause a loss of function of
NOTCH1 mostly by the inability of ligand-binding. There are some cases too, with nonsense, splice, and deletion </span>mutations<span style="font-family: inherit;"> where there is either a no presence of ICN or no cleavage site. Similarly in figure 3 under diagram C, the sporadic and high concentration
of mutations in the EFG-like region suggests the same idea. However, in this
study, more mutations were found, mainly in the Ankyrin repeats. The Ankyrin
repeats domain is a domain that is essential for proper ICN function, since this is the region that acts as the gene activator. Therefore,
these mutations also create a loss of function in NOTCH1, which gives it its roll in as a tumor </span>suppressor<span style="font-family: inherit;"> in HNSCCs.<o:p></o:p></span></div>
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<span style="font-family: inherit;">When looking at these mechanisms, one might conclude
that creating therapies that could either activate NOTCH1 in HNSCC or deactivate
NOTCH1 in T-ALL could be valid forms of therapy. However, due to the complexity
and duality of the NOTCH1 signaling pathway, doing either of these has
reciprocal problems that could be equal or even worse than the original
carcinoma itself. For example, in T-ALL, a gamma secretase inhibitor was
invented in order to stop the constant production of ICN. However, this
reduction in ICN production led to the formation of skin cancer.<span style="font-size: xx-small;">3</span> Studies
like these have not been done on HNSCC’s yet because no therapy has been made
for NOTCH1 in HNSCC. However, the complex duality of NOTCH1 makes all
reasonable therapies much less possible than they might sound.</span><span style="font-family: Calibri; mso-ascii-theme-font: major-latin; mso-bidi-font-family: Times; mso-hansi-theme-font: major-latin;"><o:p></o:p></span><br />
<span style="font-family: inherit;"><br /></span>
<span style="font-family: inherit; font-size: large;">Work Cited:</span><br />
<span style="font-family: inherit;"><br /></span><span style="background-color: white; color: black; font-family: inherit; font-size: 11px; line-height: 14px; text-decoration: none;">1 <a href="http://www.bibme.org/#" style="background-color: white; color: black; font-size: 11px; line-height: 14px; text-decoration: none;" title="Edit this item">Agrawal, N., Y. Wu, V. E. Velculescu, N. Papadopoulos, D. A. Wheeler, K. W. Kinzler, D. M. Muzny, J. A. Drummond, L. Trevino, M. J. Frederick, C. R. Pickering, C. Bettegowda, L. D. Wood, K. Chang, R. J. Li, C. Fakhry, T.-X. Xie, J. Zhang, J. Wang, N. Zhang, A. K. El-Naggar, S. A. Jasser, J. N. Weinstein, R. H. Hruban, J. N. Myers, W. H. Westra, W. M. Koch, J. A. Califano, R. A. Gibbs, D. Sidransky, and B. Vogelstein. "Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1." <i>Science</i> 333.6046 (2011): 1154-1157. <i>Science</i>. Web. 10 Apr. 2014.</a></span><br />
<span style="font-family: inherit;"><br /></span><span style="background-color: white; color: black; font-family: inherit; font-size: 11px; line-height: 14px; text-decoration: none;">2 <a href="http://www.bibme.org/#" style="background-color: white; color: black; font-size: 11px; line-height: 14px; text-decoration: none;" title="Edit this item">Aster, Jon C, Stephen C Blacklow, and Warren S Pear. "Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies." <i>The Journal of Pathology</i> 223.2 (2011): 263-274. <i>NCBI</i>. Web. 15 May 2014.</a></span><br />
<span style="font-family: inherit;"><br /></span><span style="background-color: white; color: black; font-family: inherit; font-size: 11px; line-height: 14px; text-decoration: none;">3 <a href="http://www.bibme.org/#" style="background-color: white; color: black; font-size: 11px; line-height: 14px; text-decoration: none;" title="Edit this item">Dotto, G P. "Notch tumor suppressor function." <i>Oncogene</i> 27.38 (2008): 5115-5123. <i>Oncogene</i>. Web. 10 May 2014.</a></span><br />
<span style="font-family: inherit;"><br /></span><span style="background-color: white; color: black; font-family: inherit; font-size: 11px; line-height: 14px; text-decoration: none;">4 <a href="http://www.bibme.org/#" style="background-color: white; color: black; font-size: 11px; line-height: 14px; text-decoration: none;" title="Edit this item">Stransky, N., M. Parkin, W. Winckler, K. Ardlie, S. B. Gabriel, M. Meyerson, E. S. Lander, G. Getz, T. R. Golub, L. A. Garraway, R. C. Onofrio, C. Guiducci, M. Romkes, G. Saksena, A. M. Egloff, A. D. Tward, A. D. Kostic, K. Cibulskis, A. Sivachenko, G. V. Kryukov, M. S. Lawrence, C. Sougnez, A. Mckenna, J. L. Weissfeld, E. Shefler, A. H. Ramos, P. Stojanov, S. L. Carter, D. Voet, M. L. Cortes, D. Auclair, M. F. Berger, J. R. Grandis, R. R. Seethala, L. Wang, C. Rangel-Escareno, J. C. Fernandez-Lopez, A. Hidalgo-Miranda, and J. Melendez-Zajgla. "The Mutational Landscape of Head and Neck Squamous Cell Carcinoma." <i>Science</i> 333.6046 (2011): 1157-1160. <i>NCBI</i>. Web. 12 May 2014.</a></span></div>
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Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-59180487801254244452014-05-30T00:33:00.001-07:002014-06-01T10:24:39.196-07:00KRAS Mutations and Acquired Resistance to Cetuximab<style>
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">Throughout my blog posts, I have been looking closely at a
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927413/?report=classic#SD1" target="_blank">paper</a> whose authors claim that KRAS
mutations cause acquired resistance to an anti-EGFR therapy drug called
cetuximab for colorectal cancers. My last blog <a href="http://islaslab.blogspot.com/2014/05/font-definitions-font-face-font-family.html" target="_blank">post</a> examined the data of one of
the cellular models, DiFi, and now I will do the same for the other, Lim1215. These
cellular models are used to help define the molecular basis of this secondary
resistance, which in the future can help prevent such matters. Lim1215 cells
express normal levels of EGFR, while DiFi overexpressed EGFR, but both are similarly
sensitive to cetuximab.</span></span></div>
<a name='more'></a><span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">Graph (a) depicts the relationship between cetuximab
concentration and cell viability, ultimately exhibiting the successful
resistance created in the R lines. The overlap of error bars of the R lines
show that the resistance is similar between the two, despite method of
treatment. Once again, the difference between the R1 and R2 lines isn’t
explained. Just like the DiFi R lines, the Lim1215 R1 line was exposed to a
constant concentration of cetuximab, while R2 was exposed to a concentration
that increased stepwise over time for a year. However, there is a striking
difference between the Lim1215 R lines and the DiFi R lines. The Lim1215 R
lines were exposed to an overall concentration of 1400 nM over a course of 3
months, while DiFi R lines were exposed to an overall concentration of 350 nM
over the course of a year. The specifics and reasons behind this procedure are
unclear, making the comparison between the two cell lines questionable. How
else are the two cellular models different to require different protocols? </span></span></div>
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">According to the Sanger sequencing results in part (b),
which is just a method of DNA sequencing, the two resistant lines show
inconsistencies compared to the control, as pointed out by the arrows. The
other peaks not pointed out do not match perfectly with the control results, but
the peaks seem to be relatively proportional, so they are deemed as insignificant
differences. In Lim1215 R1, the difference turned out to be a G12R mutation,
which means that at position 12 in KRAS, there is an amino acid substitution
from a glycine to an arginine. On the other hand, the difference in Lim1215 R2
is a G13D mutation, where an aspartic substituted a glycine at position 13 in
KRAS. Because the mutation differed in R1 and R2, I would assume that the type
of cetuximab treatment could possibly affect the type of mutation, but the
researchers do not expound further on this topic. </span></span></div>
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<span style="font-size: small;"><a href="http://4.bp.blogspot.com/-ZIjQYLkyLrU/U4gyvvy0LBI/AAAAAAAAAD0/G3sRnaq8Rz0/s1600/Screen+Shot+2014-05-30+at+12.24.40+AM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://4.bp.blogspot.com/-ZIjQYLkyLrU/U4gyvvy0LBI/AAAAAAAAAD0/G3sRnaq8Rz0/s1600/Screen+Shot+2014-05-30+at+12.24.40+AM.png" height="356" width="400" /></a></span></div>
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<span style="font-size: small;"><a href="http://3.bp.blogspot.com/-5fVTcVFp5w0/U4gyzDyULpI/AAAAAAAAAD8/dZT-2BDB3gQ/s1600/Screen+Shot+2014-05-30+at+12.25.06+AM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://3.bp.blogspot.com/-5fVTcVFp5w0/U4gyzDyULpI/AAAAAAAAAD8/dZT-2BDB3gQ/s1600/Screen+Shot+2014-05-30+at+12.25.06+AM.png" height="91" width="400" /></a></span></div>
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">The Western blot analysis in part (c) shows that regardless
of cetuximab exposure, active GTP-KRAS is present in the resistant lines but
not the parent Lim1215 line. All the other protein expression levels seem
similar, emphasizing the significance of the active GTP-KRAS. The evidence of active
GTP-KRAS paired with the KRAS mutations magnifies the possibility that there is
a correlation between KRAS mutation and acquired cetuximab resistance. </span></span></div>
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">The methods to back up the data in parts (d) and (e) are
not focused on much in the paper. Part (d) is a schematic representation of how the
G12R and G13D mutations were “knocked-in” to the genome of Lim1215 parental
cells. The paper does not explain this procedure or its significance further,
but its relationship with the graph in part (e) can help one understand how the
authors come to their conclusions. One can assume that the purpose of knocking-in
the mutations into the genome of the parent cells is to test if the mutations
are the reason why there is resistance, or if they are just side products. Illustrated
in graph (e), the control parent line has significantly lower cell viability as
the cetuximab concentration increases, consistent with the control in graph (a)
as well. The Lim KI G12R, which corresponds to the mutation in Lim1215 R1, has
a similar resistance when compared to graph (a). Lim KI G13D, which corresponds
to the mutation in Lim1215 R2, is still resistant compared to the control, but does
not show the same cell viability compared to R2 in graph (a). Therefore,
another variable may play a role in affecting the resistance in R2. However,
the mutation in Lim1215 R1 seems to be a very strong candidate. </span></span></div>
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">In the DiFi cells, which I went over in my last blog post,
the authors focused on how KRAS amplifications mediate acquired resistance to
cetuximab, but with these Lim1215 cells, KRAS mutations also play a huge role. Overall,
I found the data to be strong enough to support the claim that KRAS mutations can
drive acquired resistance to cetuximab, especially with the knock-in of
mutations to form experimental lines to compare to the control parental line. The
few concerns I have that aren’t clarified in the paper deal with the differences
between the methods of treatment of DiFi and Lim1215 as well as of Lim1215 R1
and Lim1215 R2 to determine if it can explain their difference in resulting
mutations. Insight into these may lead to other interesting findings. In
addition, I question if any other players can affect resistance and KRAS
mutations </span></span></div>
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<span style="font-size: small;"><span style="font-family: Times,"Times New Roman",serif;">From the results of these two cellular models, the authors
then needed to determine if KRAS mutation and amplification are clinically
relevant. In my next blog, I will dive into the clinical data set. </span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Times,"Times New Roman",serif;"><b><span style="color: windowtext; text-decoration: none;">References:</span></b></span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Times,"Times New Roman",serif;"><span style="color: windowtext; text-decoration: none;">Sandra Misale</span>,
<span style="color: windowtext; text-decoration: none;">Rona Yaeger</span>,
<span style="color: windowtext; text-decoration: none;">Sebastijan
Hobor</span>, <span style="color: windowtext; text-decoration: none;">Elisa Scala</span>,
<span style="color: windowtext; text-decoration: none;">Manickam
Janakiraman</span>, <span style="color: windowtext; text-decoration: none;">David Liska</span>,
<span style="color: windowtext; text-decoration: none;">Emanuele
Valtorta</span>, <span style="color: windowtext; text-decoration: none;">Roberta
Schiavo</span>, <span style="color: windowtext; text-decoration: none;">Michela
Buscarino</span>, <span style="color: windowtext; text-decoration: none;">Giulia
Siravegna</span>, <span style="color: windowtext; text-decoration: none;">Katia
Bencardino</span>, <span style="color: windowtext; text-decoration: none;">Andrea Cercek</span>,
<span style="color: windowtext; text-decoration: none;">Chin-Tung
Chen</span>, <span style="color: windowtext; text-decoration: none;">Silvio
Veronese</span>, <span style="color: windowtext; text-decoration: none;">Carlo Zanon</span>,
<span style="color: windowtext; text-decoration: none;">Andrea
Sartore-Bianchi</span>, <span style="color: windowtext; text-decoration: none;">Marcello
Gambacorta</span>, <span style="color: windowtext; text-decoration: none;">Margherita
Gallicchio</span>, <span style="color: windowtext; text-decoration: none;">Efsevia
Vakiani</span>, <span style="color: windowtext; text-decoration: none;">Valentina
Boscaro</span>,<sup> </sup><span style="color: windowtext; text-decoration: none;">Enzo Medico</span>,
<span style="color: windowtext; text-decoration: none;">Martin Weiser</span>,
<span style="color: windowtext; text-decoration: none;">Salvatore
Siena</span>, <span style="color: windowtext; text-decoration: none;">Federica Di
Nicolantonio</span>, <span style="color: windowtext; text-decoration: none;">David Solit</span>,
and <span style="color: windowtext; text-decoration: none;">Alberto
Bardelli</span>. “Emergence of <i>KRAS</i>
mutations and acquired resistance to anti EGFR therapy in colorectal cancer.”
Nature (2012) 486:7404. Web May 3, 2014.</span></span></div>
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</span>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-56742026838142125122014-05-29T23:52:00.003-07:002014-05-30T11:29:55.472-07:00Autocrine Motility Factor<div class="MsoNormal">
Our project’s topic illustrates how <a href="http://jhc.sagepub.com/content/54/2/231.full.pdf+html" target="_blank">AMF</a> induces phosphorylation
of the HER2 receptor and thus activates its signaling pathway. HER2 breast
cancer is when the breast cancer cells have an amplification of HER2 2 receptors
on the surface of the cell. With this increased number of receptors cell proliferation is
increased resulting in cancer. HER2 breast cancer is often treated with
the Trastuzumab(Herceptin) drug. This drug works by first attaching onto the
HER2 receptor on the extracellular side, which then stops the receptors from
signaling downstream. Many patients who take Herceptin become resistant to its
effects. My group will explore the theory that the interaction between AMF and
HER2 causes the resistance to the drug. AMF’s phosphorylation of HER2 activates
phosphoinositide-3-kinase and mitogen-activated protein kinase signaling. This
happens regardless of Herceptin involvement. This is important because the <a href="http://cancerres.aacrjournals.org/content/73/4/1411.long" target="_blank">AMF-HER 2</a> interaction may be a viable target for therapeutic treatment of
patients with breast cancer. <o:p></o:p></div>
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AMF has many other aliases; these include
glucose-6-phosphate, the enzyme that catalyzes the conversion of
glucose-6-phosphate into fructose 6-phosphate in the second step of glycolysis,
and neuroleukin which is a neurotrophic factor for spinal and sensory neurons.
Though AMF and the others, GPI and NLK, have differing functions they all come
from the same gene. AMF monomers are made of two domains, both these domains
are in a alpha-beta-alpha conformation. The smaller domain contains a
five-stranded beta-sheet surrounded by alpha helices. The larger domain has a
six-stranded beta sheet. The functional AMF dimer is composed of two identical
monomers. The active site of each monomer is created by a cleft between the to
domains and the dimer interface. <o:p></o:p></div>
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AMF is part of a group of cytokines that stimulates tumor
cell motility in an autocrine fashion. This protein factor is expressed and
secreted by cancer cells via an autocrine route. This action has been known to
stimulate the motility of cancer cells. Malignant tumors can often be
characterized by their unregulated growth, invasion into local areas, and
their eventual growth into distant organs. One can conclude that for any of
these goals to be accomplished the tumor needs to have an efficient cell migration
mechanism. AMF was distinguished among the cytokines due to its ability to
stimulate directional and random motility of AMF producing cells. <o:p></o:p></div>
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Recent trials conducted by the forerunners of AMF research found that AMF and its receptor AMFR have a direct link with breast cancer. High levels of AMF and AMFR were found in patients who died of breast cancer, and also in those who had reoccurrence. Also a significant relationship was found between high levels of AMF and long-term survival. The researchers concluded that AMF and AMFR are overexposed in breast cancer and have a negative association with the patients long term outcome. This confirms their belief that the AMF-AMFR complex has a significant role in the progression and severity of breast cancer. Along with these characteristics AMF also protects cancer cells from undergoing apoptosis and is involved in up regulation of cyclin dependent kinase activity, which we learned about in the beginning of this quarter.</div>
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In a recent immunohistochemical staining of AMF test the scientists found evidence that AMF and AMFR levels had a direct link to the growth of tumors. In stromal and endothelial cells the staining for AMF was weak, while in tumor tissues the staining was high in both the cytoplasm and the nucleus. Vascular endothelial cells and larger vascular vessels in tumor tissues also had a high degree of staining. This means that AMF and its receptor were prevalent in the vascular system, which confirms that AMF does indeed have a connection to metastasis. The graph above shows the actual immunohistochemical staining data of tumor cells versus normal cells. The AMF is were the black arrows are, and they are clearly present in the tumor cells but not in the normal cells. </div>
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Knowing what we know about AMF we can conclude that the AMF
and HER 2 relationship may be a target for future therapeutic drugs. If we can
design a drug that can either disrupt AMF so that it loses its affinity for HER
2 or one that deactivates AMF all together we may be able to actually stop this
resistance to herceptin from forming. Another method may be in finding a way to disrupt one of the many signaling pathways such as MAPK, which are triggered from HER2 phosphorylation, but that is another topic.<o:p></o:p><br />
<br />
Sources:<br />
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<span style="color: #252525; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">1. </span>Liotta
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<span style="background: white; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">3. Silletti S, Raz A
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<span style="background: white; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">4. Watanabe H, Takehana
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Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-39446949819509840512014-05-29T17:25:00.000-07:002014-05-29T17:25:11.750-07:00Beyond Standard Therapies in Metastatic Colorectal CancerAfter all standard therapies for treating metastatic colorectal cancer are exhausted, there are no interventions to improve the quality or length of life of the patient. However, patients with cancer that progresses despite therapy are possible candidates for further intervention. One therapy that can be used is multikinase inhibitors. They block intracellular and cell surface kinases, some of which are involved in tumor growth and the metastatic progression of cancer. These multikinase inhibitor drugs can reduce cell replication and tumor growth and are used to treat cancer in advanced stages. For metastatic colorectal cancer, a <a href="http://clinicaltrials.gov/ct2/show/NCT01103323">phase 3 trial</a> was done internationally for the multikinase inhibitor <a href="http://www.stivarga-us.com/hcp/?ecid=stivarga:ppc:ggl:brd:2">Regorafenib</a>.<br />
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The authors of the study were conducting the trail in 16 countries and 114 centers. Having large groups of patients is necessary for a phase 3 trial, whose main functions are to assess the drugs effectiveness, side effects, compare it to commonly used treatments, and gain information that will allow the drug to be used safely. The funding was completely done by Bayer, in hopes of getting the drug on the market. </div>
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Overall, 760 people over the age of 18 were randomized in the trial, with 505 getting regorafenib treatment (5 of which actually did not) and 255 getting placebo (2 of which did not). The patients chosen must have had cancers that progressed over 3 months while not receiving any form of therapy. The trial was also double blind; the randomization and statistics were kept hidden from the patients and investigators (and the sponsor) throughout the trial. The trial profile further illustrates the selection, randomization, and analysis of the patients.</div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEin7OG7oWZjqkT6m5jqe4rFqXv3m1lVG6cBbK50hNcU2GKAVP6seA0QcIGuFTpiDQkAkOQBsdBsWWIgEmMTCp-nmHry27ipFNyNqc4ObuUqQBDLCIQWjKZRH4YVdt4vyKhF8iwnzccrnAAp/s1600/RegorafenibFigure1.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEin7OG7oWZjqkT6m5jqe4rFqXv3m1lVG6cBbK50hNcU2GKAVP6seA0QcIGuFTpiDQkAkOQBsdBsWWIgEmMTCp-nmHry27ipFNyNqc4ObuUqQBDLCIQWjKZRH4YVdt4vyKhF8iwnzccrnAAp/s1600/RegorafenibFigure1.png" height="320" width="281" /></a></div>
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All patients received as equal supportive care as possible while retaining efficacy. Additionally, each patient was given 160 milligrams of Regorafenib or matching placebo orally once a day over 3 weeks (of a 4 week cycle). After every 2 weeks the patients were assessed to determine if they should continue treatment. While no crossing over of treatment occurred, some patients did require a reduction in drug dosage due to treatment related toxic effects. Nevertheless the majority of baseline characteristics were the same in the Regorafenib and placebo groups, including the interventions given to the patients previously before the trial. In fact, all patients in the study had received Bevacizumab (a anti-VEGF therapy) sometime after their initial diagnosis of colorectal cancer. Thus the idea of different responses in patients because of different previous therapies can be ruled out.</div>
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The mean duration of treatment was 2.8 months for the group receiving Regorafenib and 1.8 months for the group taking placebo. After 432 deaths the primary analysis was obtained. The primary analysis was overall survival, defined as the time (in days) from the point of randomization to the time of death of any cause. The median overall survival for patients in the regorafenib group was 6.4 months, whereas the median survival for the placebo group was 5.0 months. </div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjsUxg-nMxb_U1Q_6X0wSEqFtdW21oQCWPLe9a1T7b_C4Ua7FtT-YmXdhB0fRGiGeAuBCAX6TCjtT-XvQocSwZW9mhr9vPKuhurZqQwvFocmLJhHSMdoB7R5Nrd0ICqCVgh7m017XktbojI/s1600/RegorafenibFigure11.png.jpg" imageanchor="1" style="clear: right; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjsUxg-nMxb_U1Q_6X0wSEqFtdW21oQCWPLe9a1T7b_C4Ua7FtT-YmXdhB0fRGiGeAuBCAX6TCjtT-XvQocSwZW9mhr9vPKuhurZqQwvFocmLJhHSMdoB7R5Nrd0ICqCVgh7m017XktbojI/s1600/RegorafenibFigure11.png.jpg" height="158" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="font-size: 13px; text-align: center;">Figure 1: Overall Survival</td></tr>
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Over the trial period, it appears regorafenib was helpful in treating patients, but the long term survival rate shows the opposite. In fact, after a year of therapy, the placebo has a greater long term overall survival percentage then the group treated with regorafenib. However, it is important to keep in mind the number of individuals in the study is much lower by 12 months. Only 3 patients of the placebo group are in the trial after a year (only 7 in the Regorafenib group). One may infer that regorafenib hinders too much cell replication over time compared to a placebo. In which case the repeated cell death is causing the lack of long-term survival compared to the placebo. Another possibility is that more patients, especially late in the trial, died due to treatment-related side effects.</div>
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There were treatment-related adverse effects in 465 patients (93%) taking regorafenib and 154 (61%) in those taking placebo (Table 2). The most common adverse effect with regorafenib is hand-foot skin reaction and fatigue. Based on the high percentage of hand-foot skin reactions, it appears that regorafenib might inhibit cell surface kinases in the extremities (Table 2). In the placebo the most common side effects were fatigue and anorexia. However, most adverse effects occurred in the beginning of treatment. If the start of treatment is monitored carefully the drug can possibly be used more safely. Also, when a patient has colorectal cancer at such an advanced stage, their life will be difficult regardless. Therefore, having 6.4 months versus 5.0 months on average is a significant improvement for patients without any previous way of treating their late-stage cancer. Some patients will gladly take an extra month of life. </div>
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<br /></div>
<div>
Following <a href="http://www.cancer.gov/cancertopics/druginfo/fda-regorafenib">FDA regulation</a> last year, Bayer developed regorafenib into their drug <a href="http://www.stivarga-us.com/hcp/?ecid=stivarga:ppc:ggl:brd:2">Stivarga</a>. Researchers hope it will be the basis for a new standard of care for patients with late-stage metastatic colorectal cancer. There are still some challenges, such as identifying the exact mechanism of the reaction between regorafenib and tumors. And researchers need to understand why there were differences in the responses of some subgroups. With all of this research underway, regorafenib (Stivarga) and other multikinase inhibitors are leading the way for therapy in patients with treatment-refractory cancer. </div>
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<u>References:</u></div>
<div>
1. <span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 17.1200008392334px;">"The Lancet." </span><i style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 17.1200008392334px;">Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer (CORRECT): An International, Multicentre, Randomised, Placebo-controlled, Phase 3 Trial : The Lancet</i><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 17.1200008392334px;">. N.p., n.d. Web. 29 May 2014.</span></div>
<div>
<span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 17.1200008392334px;">2. </span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">"Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy." </span><i style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">Home</i><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">. Bayer, n.d. Web. 29 May 2014.</span></div>
<div>
<span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">3.</span><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;"> "The Next Proven Step." </span><i style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">STIVARGA® for Professionals</i><span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">. Bayer, n.d. Web. 29 May 2014.</span></div>
<div>
<span style="font-family: 'Times New Roman', serif; font-size: 12pt; line-height: 18pt; text-indent: -42pt;">4. </span><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -3.5em;"> </span><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -3.5em;">"FDA Approval for Regorafenib."</span><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -3.5em;"> </span><i style="box-sizing: border-box; font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -3.5em;">National Cancer Institute</i><span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -3.5em;">. NCI, n.d. Web. 29 May 2014.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0.0980392); font-family: 'Times New Roman', Times, serif; font-size: 16px; line-height: 24px; text-indent: -3.5em;"><br /></span></div>
Anonymoushttp://www.blogger.com/profile/03710620971265452062noreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-87897485666628419932014-05-29T06:53:00.000-07:002014-06-07T17:58:31.394-07:00Notch1 Helps or Hinders Tumor Formation in Conjunction with HPV?<div class="MsoNoteLevel1CxSpFirst" style="margin-left: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: 0in;">
<div class="MsoNormal" style="margin-bottom: 0in;">
<!--EndFragment--><span style="line-height: normal; text-indent: 0in;"><span style="text-indent: 0in;"><span style="background-color: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">In HPV positive cervix cancer, one cannot
develop cancer solely from having HPV; additional mutations, such as </span><i style="color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">NOTCH1</i><span style="background-color: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;"> mutations, are necessary to
instigate tumorigenesis. Different studies have yielded contradictory results
of whether Notch1 acts as either a tumor suppressor protein or an oncoprotein
in HPV positive cervical cancer. In this </span></span><a href="http://www.ncbi.nlm.nih.gov/pubmed/14695182" target="_blank">article</a></span><span style="line-height: 115%; text-indent: 0in; vertical-align: super;">1</span><span style="background-color: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">, the authors observed that when Notch1 is
expressed excessively, it acts as a tumor suppressor in HPV positive cervical
cancer; however, when it is expressed in moderate amounts </span><span style="background-color: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">in conjugation with constitutively active PI3K, it presented oncogenic properties.</span><br />
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<span style="font-size: xx-small;">Figure 1. Effects of overexpression of Notch1-IC
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<span style="font-size: xx-small;"> in HeLa, C4-1, and C-33 </span><span style="font-size: xx-small; text-indent: 0in;">cell lines evaluated by thymidine </span></div>
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<span style="font-size: xx-small; text-indent: 0in;">incorporation</span><span style="font-size: xx-small; text-indent: 0in;"> assay analysis. Cells were either transfected with</span></div>
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<span style="font-size: xx-small; text-indent: 0in;">Experiment 2 is a replication of experiment 1.</span></div>
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<!--StartFragment--><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; font-size: 10pt;">In order to observe how overexpression of Notch1
influences cell proliferation, the authors transfected HeLa and C4-I cell
lines, which both are derived from HPV 18 infected cervical cancer lesions,</span> and a C-33 cell line, which is made up of HPV-negative keratinocytes, with
a vector containing a gene coding for Notch1-IC (active form of Notch1). The
vectors contain a cytomegalovirus early promoter, which promotes the
overexpression of Notch1-IC. In order to evaluate cell proliferation, thymidine
uptake, which increases when cells proliferate, was evaluated by</span><span style="background: white; font-family: 'Trebuchet MS'; font-size: 10pt;"> </span><a href="http://www.perkinelmer.com/resources/technicalresources/applicationsupportknowledgebase/radiometric/thymidine.xhtml" target="_blank">thymidine incorporation assays</a>. </span><span style="background-color: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">The thymidine uptake of cell lines that were
transfected with Notch1-IC DNA were compared to the same cell lines without
Notch1-IC DNA transfection (control). It appears that the C4-1 cells yield the
most variable and unreliable data out of the 3 cell lines, which is apparent
because of the difference in the data between experiment one and two, which
have the same variables, and the big error bars on the control data (figure 1).
The data suggests that Notch1-IC expression reduced cell proliferation in all
the cells sampled, and this reduction was more significant in cells with HPV
DNA, which indicates that Notch1’s ability to prevent cell proliferation is
more prominent in cervical cancer cells that are infected with HPV than healthy
keratinocytes (figure 1). These results support that Notch1 can act as a tumor
repressor protein in HPV positive cervical cancer when expressed
excessively.</span><br />
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<span style="font-size: xx-small;">Figure 2. Anchorage-independent growth in soft
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<span style="font-size: xx-small;">foreskin keratinocytes that infected with HPV 16 in
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<span style="font-size: xx-small; text-indent: 0in;"> (without Notch1-IC or abnormal PI3k, moderate presence of </span></div>
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<span lang="EN" style="font-size: xx-small; text-indent: 0in;"> 2 weeks of incubation. Labels
correspond to DNA integrated into the</span></div>
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transduction. FSKE6/7 represents </span></div>
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<span lang="EN" style="font-size: xx-small; text-indent: 0in;">P110</span><span style="font-size: xx-small; text-indent: 0in;">αCAAX DNA represents p110α DNA (constitutively active PI3k). </span></div>
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<!--StartFragment--><!--EndFragment--><span lang="EN" style="text-indent: 0in;"><span style="background-color: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">In order to see if moderate levels of Notch1
expression contribute to tumorigenesis, the authors virally transduced
Notch1-IC DNA, which allows Notch1-IC to be expressed moderately. They also
observed how overactivated PI3K influenced tumorigenesis by virally transducing
a gene into that codes for a constitutively active p110α domain of PI3K into
cells. Primary human foreskin keratinocytes (FSK) infected with HPV 16 were
exposed to retroviruses that contained the Notch1-IC gene, p110α gene, both of
these genes, or none of these genes (control). The cells were incubated onto
soft agar and the authors observed </span><a href="http://www.cellbiolabs.com/news/soft-agar-assays-anchorage-independent-cell-growth" target="_blank">anchorage-independent growth</a></span><span lang="EN" style="background: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">, </span><span style="background: white; color: #666666; font-family: 'Trebuchet MS'; font-size: 10pt; text-indent: 0in;">which indicates growth of transformed tumor cells, and the
results are shown in figure 2. I can infer from these pictures that overactivated
PI3K in HPV positive cervix cells induces the creation of aggressive, fast
growing tumors, while the moderate expression of Notch1 increases the likelihood
that cells undergo abnormal growth, however, this growth is slower than
overactivated PI3K induced growth (figure 2). These pictures reflect that HPV
infection, moderate expression of Notch1, and overactivated PI3K alone do not
significantly contribute to tumorigenesis,but the synergy of these factors
express robust oncogenic characteristics.</span><br />
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<span style="color: #666666; font-family: "Trebuchet MS"; font-size: 10.0pt; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">This is
a fairly robust study, however, the authors derived many of their conclusions
from the soft agar analysis in figure 2, which slightly obscures their conclusions
because evaluating tumor growth by observing colony growth is very subjective. One
cannot derive quantitative data, which hinders their ability to support their
claims with statistical evidence, from these pictures except for colony count,
which the authors did not include. Robust conclusions are made from the soft
agar assay, however, because healthy cells simply cannot grow efficiently
independent of a physical attachment to a substrate. I believe the thymidine
uptake assay analysis in figure 1 obtained fairly robust data because the
assays were run in triplicate and the non-control assays were run in triplicate
twice. There seemed to be a significant difference between the control and
experiment data, however, the authors did not provide the statistical evidence (p
values) to support this difference. Also, the conclusions are further obscured
by solely using constitutively active Notch1 (Notch1-IC). Overall, the data did
support their conclusions, however, due to their omission of critical data and
use of Notch1-IC, I am skeptical. Because other research suggests contradictory
functions of Notch1’s influence on tumorigenisis in HPV positive cervix cancer,
these authors offer a plausible explanation for this contradiction— Notch1
could act as a tumor suppressor protein or an oncoprotein depending on its
amount of expression—but more research, especially in vivo, must be conducted
to support these claims.<o:p></o:p></span></div>
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<div style="line-height: normal;">
<span style="color: black; font-family: Times; font-size: 13.5pt; mso-fareast-font-family: "Times New Roman";">References:</span></div>
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<span style="color: black; font-family: "Times New Roman"; font-size: 12.0pt;">1. Lathion,
Stéphanie, Janina Schaper, and Peter Beard. "Notch1 Can Contribute to
Viral-Induced Transformation of Primary Human Keratinocytes." <i>Cancer
Research</i> 63: 8687-694. Web. 27 May 2014.</span><span style="color: black; font-family: Times; font-size: 13.5pt;"><o:p></o:p></span></div>
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<span style="color: black; font-family: "Times New Roman"; font-size: 13.5pt;">2. Min Jie
Alvin Tan, Elizabeth A. White, Mathew E. Sowa, J. Wade Harper, Jon C. Aster,
and Peter M. Howley. "Cutaneous β-human papillomavirus E6 Proteins Bind
Mastermind-like Coactivators and Repress Notch Signaling" </span><i><span style="color: black; font-family: "Times New Roman"; font-size: 12.0pt;">PNAS</span></i><span style="color: black; font-family: "Times New Roman"; font-size: 12pt;"> 109.23:</span><span style="color: black; font-family: "Times New Roman"; font-size: 13.5pt;">1473–E1480. </span><span style="color: black; font-family: "Times New Roman"; font-size: 12.5pt;">Web. 27 May
2014.</span><span style="color: black; font-family: Times; font-size: 13.5pt;"><o:p></o:p></span></div>
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<b style="mso-bidi-font-weight: normal;"><u><span style="font-family: "Times New Roman";"></span></u></b><span style="font-family: "Times New Roman";">In my recent
blog post, I discussed the p53 gene, and experiments testing sunscreens effect
on p53 in mice. In this blog post, I will discuss a study testing sunscreen’s
relation to p53 protein production done on humans. From 1992-1996, the <a href="http://aje.oxfordjournals.org/content/163/11/982.full" target="_blank">NambourSkin Cancer Prevention Trial</a> conducted a study to test the association of time
spent outdoors and the expression of p53, as well as its relation to the use of
sunscreen. Researchers predicted that sunscreen counteracts p53 production, and
carried out their research on over 160 random participants for 6 months. There
were four different treatment groups: 1. Application of SPF 16 sunscreen daily
+ beta-carotene supplementation, 2. Application of SPF 16 sunscreen daily +
placebo tablets, 3. Beta-carotene only, 4. Placebo only. <a href="http://www.nlm.nih.gov/medlineplus/druginfo/natural/999.html" target="_blank">Beta-carotene</a> is a
type of pigment called a carotenoid, and produces Vitamin A, which helps
prevent cell damage. It’s thought to be possibly effective for people who are
sensitive to sun exposure in order to help prevent sunburn, but the exact
efficiency is not known. </span>
</div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: "Times New Roman";"></span></b><a href="http://aje.oxfordjournals.org/content/163/11/982/F1.expansion.html" target="_blank"><img alt="http://aje.oxfordjournals.org/content/163/11/982/F1.expansion.html" border="0" src="http://1.bp.blogspot.com/-7-cdaBe1Q4o/U4aXDIxPbrI/AAAAAAAAACM/SQTmEsSptb0/s1600/F1.large.jpg" height="252" width="320" /></a><b style="mso-bidi-font-weight: normal;"><span style="font-family: "Times New Roman";"></span></b></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: "Times New Roman";"> </span></b><b style="mso-bidi-font-weight: normal;"><span style="font-family: "Times New Roman";">Figure 1. </span></b><span style="font-family: "Times New Roman";">Proportion of p53-positive cells in the
whole epidermis (n=139) of participants’ dorsal hand. </span></div>
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<br /></div>
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<span style="font-family: "Times New Roman";">Based on the above
graph, it seems like there’s a high frequency of individuals with <5% of
their cells being p53 positive, and that the frequency for p53 positive cells
becomes relatively low after 25%. What this graph leaves unclear is what the
frequency represents—is it measured by number of individuals who had that
amount of p53 positive cells? Does it carry forward? For example, if a person
is 80% positive, will they be counted into the frequency for 0-5, 5-10, 10-15,
etc. in addition to 75-80? If so, this could be why the data looks so skewed
toward a higher frequency for lower levels of p53 positive cells. The study
says that 61% of participants had over 5% of p53 cells and 22% had over 20%,
but 17% had <5%, and so I would think that the frequencies would correlate
with these numbers but it doesn’t seem like it does. Not to mention, does it
make a difference that they took biopsies from the hand and not other areas of
the body? Different parts of the body will most likely have different
susceptibilities to sunburn or sensitivity to UV exposure due to their cell
makeup, so does using the hand also skew the data</span></div>
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="http://aje.oxfordjournals.org/content/163/11/982/T1.expansion.html" target="_blank"><img alt="http://aje.oxfordjournals.org/content/163/11/982/T1.expansion.html" border="0" src="http://2.bp.blogspot.com/-RsXLcB_i5HI/U4aXYfmy1qI/AAAAAAAAACY/6rzJQx6Sjxc/s1600/Screen+Shot+2014-05-28+at+6.14.59+PM.png" height="393" width="400" /></a></div>
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<span style="font-family: "Times New Roman";">Table 1 shows
that there is a significant difference in having p53 positive cells when
comparing males to females (p<0.01), as well as females smokers to male
smokers (p<0.05). One thing the researchers could control if they were to
repeat the study would be to not accept past smokers, whose history could affect
the results of the trial. It is indicated that the subsequent analysis were
adjusted for sex and smoking status, which could also affect the data by making
p53 percentages higher even though they might not be attributed to UV exposure.
According to the table, it seems like other variables such as age, skin color,
skin type, and cancer history did not significantly influence the proportion of
p53-positive cells. </span></div>
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<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="http://aje.oxfordjournals.org/content/163/11/982/T3.expansion.html#xref-fn-11-1" target="_blank"><img alt="http://aje.oxfordjournals.org/content/163/11/982/T3.expansion.html#xref-fn-11-1" border="0" src="http://2.bp.blogspot.com/-r2m9xH83pmY/U4aXYcBcsFI/AAAAAAAAACc/CLrlb1t__Ek/s1600/Screen+Shot+2014-05-28+at+6.11.20+PM.png" height="231" width="400" /></a></div>
<span style="mso-spacerun: yes;"></span><br />
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<span style="font-family: "Times New Roman";">Table 3 (above) shows
the effect of sunscreen on proportion of p53-positive cells. The study found
that when sunscreen is the only variable used to compare participants, there is
no significant difference in proportion of p53 positive cells. But they also
conducted a multivariable model to take into account time spend outdoors, sex,
smoking status, skin type, and skin color. </span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: "Times New Roman";">Overall, the
researchers concluded that sunscreen is independently associated with lowering
p53 protein production, and I somewhat agree with their argument. What makes
the data difficult to interpret is the amount of external factors that could
contribute. Also, the numbers in Table 3 suggest that there is a significant
difference between the groups, but between never wearing sunscreen and wearing
sunscreen 7 days per week, there appears to be the same percentage of p53
positive cells, but when comparing sunscreen use from 1-6 days, it appears that
there is a lower proportion in the 5-6 range, which is confusing. Another downside
to the experiment is that it was done in Australia, which is known as the “skin
cancer capital of the world,”<a href="http://www.cancer.org.au/policy-and-advocacy/position-statements/sun-smart/" target="_blank">(3)</a> and so another variable could be location of the
homes of these individuals. The paper also did not differentiate results for
the four different groups, and did not go into depth about why they also used
beta-carotene. Wouldn’t that add another variable other than sunscreen when
analyzing data? As a result, I don’t fully trust the conclusion of the paper
because there are so many variables that could contribute to the experiment,
and there are also parts of the experiment that aren’t fully explained, which
makes it difficult to interpret the data and propose conclusions. </span></div>
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<br /></div>
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<br /></div>
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<span style="font-family: "Times New Roman";">Sources:</span></div>
<div class="MsoListParagraphCxSpFirst" style="mso-add-space: auto; mso-list: l0 level1 lfo1; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.25in;">
<span style="font-family: "Times New Roman"; mso-bidi-font-style: italic; mso-fareast-font-family: "Times New Roman";"><span style="mso-list: Ignore;">1.<span style="font: 7.0pt "Times New Roman";"> </span></span></span><span style="font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">Jolieke
C. van der Pols, Chunxia Xu, Glen M. Boyle, Peter G. Parsons, David C.
Whiteman, and Adele C. Green. Expression of p53 Tumor Suppressor Protein in
Sun-exposed Skin and Associations with Sunscreen Use and Time Spent Outdoors: A
Community-based Study <i>Am. J. Epidemiol. (1 June 2006) 163 (11): 982-988
first published online April 19, 2006 doi:10.1093/aje/kwj137</i></span></div>
<div class="MsoListParagraphCxSpMiddle" style="mso-add-space: auto; mso-list: l0 level1 lfo1; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.25in;">
<span style="font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><span style="mso-list: Ignore;">2.<span style="font: 7.0pt "Times New Roman";">
</span></span></span><span style="font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">"Beta-carotene." <i>U.S
National Library of Medicine</i>. U.S. National Library of Medicine, 19 July
2011. Web. 26 May 2014. <http://www.nlm.nih.gov/medlineplus/druginfo/natural/999.html>.</span></div>
<div class="MsoListParagraphCxSpLast" style="mso-add-space: auto; mso-list: l0 level1 lfo1; mso-margin-bottom-alt: auto; mso-margin-top-alt: auto; text-indent: -.25in;">
<span style="font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><span style="mso-list: Ignore;">3.<span style="font: 7.0pt "Times New Roman";">
</span></span></span><span style="font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";">"SunSmart." <i>Cancer
Council Australia</i>. Cancer Council Australia, 19 Nov. 2013. Web. 25 May
2014.
<http://www.cancer.org.au/policy-and-advocacy/position-statements/sun-smart/>.
</span></div>
Unknownnoreply@blogger.comtag:blogger.com,1999:blog-418450701778072512.post-63029528296371786542014-05-28T01:07:00.004-07:002014-05-28T01:08:46.648-07:00The CRISPR/Cas9 genome editor and its therapeutic potentialIn the first few weeks of the quarter we had a lengthy discussion on the origins of cancer cells. Loss of function mutations in tumor suppressor genes and gain of function mutations in oncogenes lead to the deregulation of the cell cycle and eventually uncontrolled cell proliferation. Gene therapy has been considered as an option to rehabilitate these genes back to a functional state. Unfortunately, the methods researched in the last three decades since the principle discovery of gene therapy, such as retroviral vectors, have been incredibly inefficient and have a low ceiling due to inherent low indel (nucleotide insertions or deletions) specificity. Within the last fifteen years though, three restriction enzymes (used to cut DNA at relatively specific sites) have been heavily researched in hopes of finding a mechanism to make the ultramodern form of gene therapy a reality.<br />
<div class="p2">
<span class="s1"></span><br />
<a name='more'></a><br />
<span class="s1">The first of three enzymes discovered, the Zinc-finger nuclease (ZFN) has been reengineered and researched so heavily in the last decade that a couple of months ago a paper was published in the <i>NEJM</i> (<a href="http://www.nejm.org/doi/full/10.1056/NEJMe1400593">Kay <i>et al. </i>2014</a>) outlining how ZFNs were used to introduce a 32bp deletion in the <i>CCR5</i> gene of an HIV patient as a way of introducing HIV-resistance in the patient’s T-cells. TALENs, the second endonuclease, has proven to be a much easier enzyme to work with and appears to have a higher ceiling than ZFNs due to enhanced sequence specificity, but has not reached the level that ZFNs have in being used as a gene therapeutic. The newest, and by far the most exciting, of the three enzymes is known as the CRISPR/Cas9 endonuclease system. This endonuclease, discovered in the bacteria responsible for the fermentation of dairy, <i>Streptococcus thermophilus</i>, is used as a method of protecting the bacteria from viral infection by explicitly targeting viral DNA in the bacterial cytosol and introducing double strand breaks in the viral genome, thereby halting viral reproduction. This enzyme has two notable domains to focus on, a domain that cuts DNA, and a single guide RNA (sgRNA) domain that guides the CRISPR/Cas9 enzyme to the matching viral sequences. This guiding RNA in the CRISPR/Cas9 is what makes it such an exciting discovery that will inevitably affect all fields of biology. When engineering the CRISPR/Cas9 endonuclease to cut a specific sequence, all that needs to be altered is the short (20bp) RNA sequence in the protein, much easier than altering the protein structure of both ZFNs and TALENs. This versatility of CRISPR/Cas9 allows libraries of the enzyme to be engineered cheaply and opens up the future of gene therapy to masses. One of the head researchers involved in discovering the system has publicly praised her enzyme by stating that the CRISPR/Cas9-system “could potentially be as powerful as the Polymerase Chain Reaction (PCR).”</span></div>
<div class="p1">
<br /></div>
<div class="p2">
<span class="s1">Without going into detail, the combined CRISPR/Cas9-system was discovered in 2007 and in the last seven years, the “CRISPR Craze” (Figure 1) has lead to scientists flocking to study this system. With only seven years since its discovery, CRISPR/Cas9 is far from being used in human therapy. Current research is focused on removing some of the limitations of the enzyme and proving that the enzyme has functionality in eukaryotic cells. </span></div>
<div class="p1">
<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-zEDRgUjJbEg/U4WDPQtDetI/AAAAAAAAADM/EW9GQjOgbXw/s1600/Screenshot+2014-05-18+22.03.23.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://3.bp.blogspot.com/-zEDRgUjJbEg/U4WDPQtDetI/AAAAAAAAADM/EW9GQjOgbXw/s1600/Screenshot+2014-05-18+22.03.23.png" height="111" width="200" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure 1. <b>CRISPR Craze.</b> Dramatic increase in CRISPR <br />
related research since 2007, with an estimated 314 publications in <br />
2014 (Source: Web of Science, March 17, 2014).</td></tr>
</tbody></table>
<span class="s1"></span><br /></div>
<div class="p2">
<span class="s1">Interestingly though, a recent paper (Yin <i>et al.</i> 2014) claims that it is the proof of principle that the CRISPR/Cas9 endonuclease can be utilized as a therapeutic <i>in vivo</i>. To investigate the efficacy of CRISPR/Cas9 in a mammalian system the researchers studied a mouse model with a fatal mutation in the fumarylacetoacetate hydrolase (<i>Fah</i></span><span class="s2"><sup><i>mut/mut</i></sup></span><span class="s1">), the last enzyme in the tyrosine catabolic pathway. <i>Fah</i></span><span class="s2"><i><sup>mut/mut</sup></i></span><span class="s1"><i> </i>have a mutation in exon 8 of the gene (G—>A) that results in the skipping of the exon and an detrimentally truncated protein. To fix the resulting lethal phenotype, severe liver damage, the mice were injected with a plasmid vector expressing the Cas9 enzyme and one of three sgRNA targeting the <i>Fah</i> locus (FAH1, FAH2, or FAH3), and a high concentration of ssDNA containing the wild type <i>Fah</i> gene, which can serve as a template for the DNA repair process once CRISPR/Cas9 cuts the mutant gene. </span><br />
<span class="s1"><br /></span>
<br />
<div style="text-align: left;">
<span class="s1">Figure 2 shows that although the phenotype was improved, relative to the control, a fraction of the cells in the FAH2 treated group were saved. The paper states that only ~0.4% of hepatocytes responded to the treatment, possibly due to the vector used or indirect injection of treatment. However, the extent of the damage, as shown in figure 3, is clearly enhanced to a significant extent. Demonstrating that in treated cells, the phenotype is functionally rescued to the level of control NTBC treated mice. Finally, figure 4 illustrates that treated cells show an 8-36% level of expression relative to WT mice, which again shows that this article is landmark only for the sake of proof of principle, not efficacy. </span></div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-6NV7wrKsbr8/U4WFzIrmvOI/AAAAAAAAADw/sa_M8BI5yiI/s1600/Screenshot+2014-05-27+23.43.58.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img alt="" border="0" src="http://3.bp.blogspot.com/-6NV7wrKsbr8/U4WFzIrmvOI/AAAAAAAAADw/sa_M8BI5yiI/s1600/Screenshot+2014-05-27+23.43.58.png" height="128" title="" width="200" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><div style="text-align: center;">
Figure 2. <b>Histological stain of mouse </b></div>
<b></b><br />
<div style="text-align: center;">
<b><b>hepatocytes show improved phenotype in </b></b></div>
<b>
<div style="text-align: center;">
<b>Cas9 + sgRNA treated cells (FAH2).</b> </div>
</b><br />
<div style="text-align: center;">
W<span style="font-size: x-small; text-align: start;">ild-type mice (</span><i>Fah</i><span class="s2" style="font-size: xx-small; text-align: start;"><sup><i>+/+</i></sup></span>), control mice </div>
<div style="text-align: center;">
(<i>Fah</i><span class="s2" style="font-size: xx-small; text-align: start;"><sup><i>mut/mut</i></sup></span> + Unguided Cas9), Cas9 + sgRNA </div>
<div style="text-align: center;">
treated mice (<i>Fah</i><span class="s2" style="font-size: xx-small; text-align: start;"><sup><i>mut/mut</i></sup></span> + FAH2).</div>
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<tr><td class="tr-caption" style="text-align: center;">Figure 4. <b>Quantitative-PCR measurement of wild-type</b><b><br />mRNA (G allele) expression in wild-type mice (WT), <i>Fah</i><span class="s2" style="font-size: xx-small; text-align: start;"><sup><i>mut/mut </i></sup></span>mice (Mut), and in treated mice <br />(FAH1, FAH2, and FAH3).</b> </td></tr>
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Figure 3. <b>Liver damage marker (aspartate </b></div>
<b></b><br />
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<b><b>aminotransferase (AST), alanine aminotransferase </b></b></div>
<b>
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<b>(ALT), and bilirubin) levels show over three-fold </b></div>
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<b>decline in treated mice. </b>NTBC is an upstream inhibitor </div>
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of the tyrosine catabolic pathway that alleviates the <i>Fah</i><span class="s2" style="font-size: xx-small; text-align: start;"><sup><i>mut/mut</i></sup></span> </div>
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phenotype; "NTBC on" mice are liver damage control group </div>
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within the <i>Fah</i><span class="s2" style="font-size: xx-small; text-align: start;"><sup><i>mut/mut </i></sup></span>genotype, "NTBC off" are untreated </div>
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mice with full extent of lethal phenotype; "NTBC off + FAH2" </div>
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are treated mice. * <i>P</i> < 0.01, <i>n </i>= 3 mice.</div>
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Relative to the <span style="font-family: TradeGothicLTStd;">hereditary tyrosinemia</span> in these mice, most cancers are much more heterogeneous (read: more complicated) leading one to think that the methods from taking this therapy from reaching 0.4% cells and expressing 8-36% WT-mRNA in said affected cells to an efficacious standard in cancer patients are far from being reached. However, the CRISPR/Cas9-system has excited thousands of scientists around the world for many reasons and research will keep advancing on the system in the coming years at a dramatic rate. Currently, though, the value of the system as a gene therapeutic in humans can only be measured in its potential and not in its capability.</div>
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<b><u>References</u></b></div>
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<ol>
<li>Yin, H., Xue, W., Chen, S., Bogorad, R. L., Benedetti, E., Grompe, M., et al. (2014). Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. <i>Nature Biotechnology</i>. doi:10.1038/nbt.2884</li>
<li>Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. <i>Science</i>, <i>337</i>(6096), 816–821. doi:10.1126/science.1225829</li>
<li>Kay, M. A., & Walker, B. D. (2014). Engineering Cellular Resistance to HIV. <i>New England Journal of Medicine</i>, <i>370</i>(10), 968–969. doi:10.1056/NEJMe1400593</li>
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