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<h2>3. DNA Origami</h2>
<h2>3. DNA Origami</h2>
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<figcaption><font size="2">Figure 4: Scaffolded DNA Origami [x]</font></figcaption>
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<a name = "references"></a>
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Revision as of 19:46, 23 October 2014

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     <li><a href="http://openwetware.org/wiki/Biomod/2014/OhioMOD/project">Background</a></li>

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<h1>Background</h1>

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<A HREF="#scroll1">1. CANCER AND CLL</A> </br> <A HREF="#scroll2">2. miRNA & PTEN</A> <A NAME="scroll1"></A></br><A HREF="#scroll3">3. DNA Origami</A> </br> <A HREF="#scroll4">4. References</A>



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<h2>1. CANCER AND CLL</h2> <p1>Cancer is a group of diseases broadly characterized by the uncontrolled growth and spread of abnormal cells. In 2013, there were approximately 1.6 million new cases of cancer, and about 580 thousand people were expected to die of the disease. However, cancer isn’t necessarily fatal. The five year survival rate of all cancers diagnosed between 2002 and 2008 is 68%, up from 49% in 1977. (Why did this happen? Better drugs? Better diagnosis?) </p1>

<figure> </br><img src="http://openwetware.org/images/6/61/IIFig1.png"height="479" width="664"/> <figcaption><font size="2">Figure 1: Mortality rates of different classes of cancer in the United States 1930-2009[1].</font></figcaption> </figure>

</br></br><p1>Leukemia is a type of cancer that develops when the bone marrow produces abnormal stem cells, which would normally differentiate into white blood cells. The abnormal cells don’t differentiate, reproduce continuously, and do not die. The unhealthy cells crowd out healthy cells in the blood, resulting in complications which can be fatal. Chronic lymphocytic leukemia (CLL), one specific type of the disease, is characterized by the buildup of abnormal, mature lymphoid progenitor cells. CLL typically grows slowly, affecting cells in the lymph nodes. It is the most common form of leukemia in the western hemisphere, accounting for nearly 38% of all leukemia cases. In 2013, around 16 thousand new cases were diagnosed, with about 4,500 estimated deaths. Over 60% of those diagnosed were in adults over 65 years of age. The outlook for CLL has improved dramatically over the last three decades. The 5-year survival rate is 82%, and most patients live for 10 years or more if the cancer is detected in stage A. CLL is clearly less of a threat than other types of cancer. However, it is ideal for studying potential cancer therapeutics for several reasons.</p1> </br></br><p1>The OSU-CLL cell line is an immortalized cell line created by Dr. John Byrd and his team at The Ohio State University to promote mechanistic in vitro and in vivo studies of CLL. OSU-CLL cells displace aberrant co-expression of CD5 protein, and trisomy in chromosomes 12 and 19, all of which are common indicators of CLL. Studies have also shown that OSU-CLL cells show similar motility and proliferation behaviors when compared to primary CLL cells. OSU-CLL is also readily transferable to mice for in vivo studies. (ADD A COUPLE EXAMPLES OF RESEARCH DONE WITH OSU-CLL?) (WHAT SHOULD I DO WITH THE “CAUSE” SECTION?)</p1>

</br></br><p1>Chemotherapy refers to the use of chemical therapeutics to kill or attack cells which divide rapidly. Along with radiation therapy and surgery, chemotherapy is one of the most commonly used methods of cancer treatment, prescribed to 22% of cancer patients. There are numerous common chemotherapeutics, but they have some common characteristics. Their mechanism of action typically involves disrupting the mechanisms of cellular reproduction. This makes them more toxic to cells which divide rapidly, perfect for treating cancer. However, this also causes some unfortunate side effects. Cells in the bone marrow also divide rapidly, and are responsible for producing the white blood cells which are central to the human immune system. Chemotherapy usually attacks these cells, making the body extremely vulnerable to infection. Hair follicles and digestive tissues also divide rapidly, so hair loss and severe digestive problems are other side effects. Other complications surround the application of chemotherapy, including drug resistance. The Blood-Brain Barrier also poses a huge challenge in the treatment of brain cancers. </p1> </br></br><p1>There are other complications surrounding the application of chemotherapy. In brain cancer, the blood brain barrier prevents most free drugs from reaching the tumor through the circulatory system. Nonspecific chemotherapy also suffers because the drug is distributed throughout the body. Biocompatibility can also be an issue. If the drug provokes an immune response from the body, or is broken down in the circulatory system, it won’t function as a chemotherapeutic agent, despite potentially attractive cytotoxic characteristics. Cancer cells are also capable of developing resistance to chemotherapeutic agents through a variety of methods, most of which stem from the idea of natural selection. For any tumor, a small amount of cells will probably be resistant to any given chemotherapeutic. If this drug is administered consistently, those cells will reproduce more and the whole tumor will become resistant.</p1> </br></br><p1>Clearly, chemotherapy is not a perfect system. However, nanotechnology may hold the key to solving a lot it’s problems. Most cancer cells show a modified protein expression profile, expressing some surface proteins at a much greater rate than normal cells. For instance, Beta Folate Receptors are significantly overexpressed in myeloid leukemia. This folate receptor has been targeted by liposomal drug carriers in the past to great effect <a href="#references">[1]</a> and it should be possible to incorporater targetting into other nanoparticle therapeutics. Targeting allows for higher doses of chemotherapy with fewer side effects (CITATION). Encapsulation of therapeutics has also been shown to increase their viability in the circulatory system and increase efficacy of therapy in vitro (http://pubs.rsc.org/EN/content/articlelanding/2013/tb/c2tb00063f/unauth#!divAbstract). Encapsulation of chemotherapeutics can also be used to apply multiple drugs to one tumor, which significantly lowers the chance of resistance developing.</p1> One specific type of chemotherapy, antisense therapy, utilizes complementary base pairing to block RNA strands in cancerous cells. In all cells, messenger RNA is translated in the ribosomes to produce proteins, which regulate and catalyze all processes in the cell. In cancerous cells, proteins responsible for growth and division are overexpressed, while those responsible for inducing cell death (apoptosis) and regulating growth are underexpressed. Antisense therapy involves targeting a specific mRNA strand that is overexpressed in cancerous cells (the sense strand) and introducing a complementary strand (the antisense strand) to the cell to bind with it and block it’s translation. One study targeted the growth inducing protein Bcl-2. The authors found that, in live patients, Bcl-2 antisense therapy showed a positive tumor response and an improvement in symptoms. The drawback to antisense therapy lies in the structure of DNA. It is naturally degraded in the body, so it needs to be modified to make it a viable <A NAME="scroll2"></A>treatment (http://pubs.acs.org/doi/abs/10.1021/jm00059a007).</p1></br></br>


<h2>2. miRNA & PTEN</h2> <p> 

MicroRNAs (miRNAs) are small, single stranded RNA molecules which have a vital role in regulating almost all cellular processes. They are imperfect complements to messenger RNA strands, allowing them to bind to mRNA and block protein expression. The first miRNA strand, Lin-4 was discovered in 1993. Researchers noticed that the lin-4 gene could regulate the expression of another gene, lin-14. They also discovered that lin-4 didn’t code for a protein, and that a 22 bp sequence of it’s transcript was complementary to part of the lin-14 sequence. The researchers hypothesized that the lin-4 transcript was blocking the expression of the lin-14 gene. This breakthrough led other scientists to start studying how genes might regulate other genes, and thousands of miRNAs have been identified since.

<figure> </br><img src="http://openwetware.org/images/3/33/BgmiPt1.pictClipping"height="300" width="300"/> <figcaption><font size="2"> <a href="#references">[Figure 1]</a>: Life Cycle of miRNA</font></figcaption> </figure> </br></br>MicroRNA are coded by portions of the genome previously regarded as “junk DNA”. Some miRNAs are coded for by portions of the genome that don’t code from proteins, while others are translated from introns which have been spliced from mature RNA. MiRNAs which have their own genes are transcribed as long strands of primary miRNA (Pri-miRNA). Pri-miRNA can be several hundred base pairs long, and can include several miRNA strands. Each individual miRNA has a hairpin-loop structure on the pri-miRNA. Two enzymes are responsible for recognizing and cutting out the hair-pin structures, which are known as pre-miRNA. The pre-miRNA are exported from the nucleus to the cytoplasm, where the RNase enzyme DICER cuts the loop from the pre-miRNA. Cutting the pre-miRNA results in two mostly complementary RNA strands, which are then processed by the RNA-induced silencing complex (RISC). </br></br>The RISC selects an individual miRNA strand and the other strand is usually degraded. The strand that is less thermodynamically stable has been found to generally be selected for further processing (http://www.jbc.org/content/279/40/42230.full.pdf+html). The RISC then uses an argonaute protein to bind with the single stranded miRNA and orient it to bind with the target mRNA. If the miRNA is a perfect complement to the target mRNA, the duplex will be destroyed by the argonaute protein. In the case of imperfect binding, the miRNA simply blocks expression of the mRNA. miRNA’s don’t need perfect complementary to block mRNA, so an individual miRNA can block the expression of several genes. </br></br>MicroRNAs have been implicated in most cellular processes, including growth, development, and apoptosis. Because of their ubiquitous nature, miRNA dysregulation is a factor in most human disease. In cancer, some miRNA are overexpressed, while other are underexpressed. Predictably, miRNAs which should limit growth and proliferation are underexpressed in cancer, while those which limit apoptosis and cell cycle control are overexpressed. In Chronic Lymphocytic Leukemia (CLL), miR - 21 and miR - 155 are chronically overexpressed (https://docs.google.com/file/d/0B2iZyjmlaa9KNFowY0VYSUhrelU/edit). miR - 21 targets genes such as PTEN and Bcl2, both of which are tumor suppressors (MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer), ("Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells") With elevated levels of miR - 21, PTEN and Bcl2 are suppressed, allowing cells to grow uncontrollably. <figure> </br><img src="http://openwetware.org/images/3/3a/BgmiPt2.png"height="300" width="300"/> <figcaption><font size="2"> <a href="#references">[Figure 2]</a>: PTEN and its effects on the Akt/PKB pathway.</font></figcaption> </figure> </br></br>PTEN stands for Phosphatase and Tensin Homolog. It plays an integral part in the Akt/PKB signalling pathway, which controls cell death. PTEN catalyzes the dephosphorylation of PIP3, a phospholipid in the cell membrane, resulting in the product PIP2. This reaction inhibits the Akt/PKB pathway, leading to cell death. PTEN is a vital regulator of the Akt/PKB pathway because it controls many downstream regulatory processes. In many types of cancer, including CLL, PTEN activity is nonexistent. Without PTEN cell death doesn’t occur and cells divide uncontrollably, leading to <A NAME="scroll3"></A>cancer. </p>


<h2>3. DNA Origami</h2> <figure> </br><img src="http://openwetware.org/images/0/0f/IV_Fig4.png"height="479" width="664"/> <figcaption><font size="2">Figure 4: Scaffolded DNA Origami [x]</font></figcaption> </figure> <br><br> <a name = "references"></a>


<h2>4. References</h2> <a href="http://pubs.acs.org.proxy.lib.ohio-state.edu/doi/pdf/10.1021/bm0506142">[1]</a> IEEE Citation here blah blah blah blah. <br>[Figure 1]: JWF Catto, Et al. MircroRNA in Prostate, Bladder, and Kidney Cancer: A Systematic Review. European Eurology, 2011. <br>[Figure 2]: S Phin, Et al. Genomic Rearrangements of PTEN in Prostrate Cancer. Frontiers in Oncology, 2013.

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