Dec 8, 2017

Effects of Telomerase Inhibitor Imetelstat (GRN163L) on the Lifespan of Human Pancreatic Cancer Cells

Michaela Androff '18

Telomerase is present in 85% of cancer cells and is essential for a cell’s unlimited lifespan. Telomerase inhibitors are a common use for treatment of cancer due to their selectivity and inhibition mechanisms. They inhibit Telomerase through three methods: dsRNA, siRNA, and oligonucleotides. This paper focuses on second generation N3’-P5’ thio-phosphoramidate oligonucleotide (GRN-163L) and its effects on the lifespan of human pancreatic cancer cells. They hypothesized that long term exposure of GRN-163L to human pancreatic cancer cells will lead to a limited cellular lifespan. This study tested 10 cell lines that all presented with different telomerase activity levels, but very short telomeres. Continued exposure of GRN163L to CAPN1 and CD18 cells led to crisis and maintenance of short telomeres. However, with the removal or GRN163L led to the reactivation of telomerase in these cells and re-elongation of the

telomeres. This demonstrates that exposure of GRN163L can limit the lifespan of human pancreatic cancer cells.

ALDH1A1 as a potential biomarker for pancreatic cancer

Alexandra Ehlens '18

ALDH1A1 has been identified as a cancer stem cell (CSC) in breast, colon, lung, and head and neck squamous cancer. ALDH1 has also been found to provide tumor cells with drug protection and radiation resistance by detoxifying specific therapeutic agents involved. Recent studies have found that an increased expression of aldehyde dehydrogenase 1A1 (ALDH1A1) in pancreatic cancer is correlated with worsened prognosis. The same study also reported ALDH1A1 to be an adequate prognostic marker in pancreatic cancer by using micro tissue arrays. By evaluating the expression of ALDH1A1 in whole mount pancreatic cancer tissue slides, immunohistochemistry was performed to determine the expression of ALDH1A1, verifying the results by qRT-PCR and western blot. In order to keep the study free of bias, staining intensity, and proliferation rate was evaluated by independent researchers and pathologists. Using various survival analysis methods, researchers were able to correlate the results with clinical and histopathological data such as tumor stage, lymph node status, and whether or not the patients underwent adjuvant chemotherapy to overall survival, as well as recurrence- free survival. Final results concluded that a higher expression of ALDH1A1 correlated to a higher overall survival and higher recurrence free survival when compared to those with a lower expression of ALDH1A1. These results contradicted the previous study that found a dismissal prognosis with increased expression of ALDH1A1.

Genetics of Gambling: Background and Potential Epigenetic Mechanisms

James Whelan '18

Pathological gambling, recently redefined as Gambling Disorder is described as, “Persistent and recurrent problematic gambling behavior leading to clinically significant impairment or distress, as indicated by the individual exhibiting four (or more) of the following in a 12month period.” (American Psychiatric Association, 2013). Gambling Disorder is a large and moreover growing problem in the United states (Callado et Griffiths, 2016); as of 2004 54 billion was being spent annually on gambling disorder and associated treatment. Governing states and specifically researchers have tried to unearth the characteristics of, and more importantly, the general mechanisms surrounding individual’s gambling disorder. There has, as of now, been a significant amount of interest in using modern genetic approaches to elucidate these aforementioned mechanisms for which gambling may be heavily implicated (Ibanez et al., 2003; Lobo & Kennedy, 2009). More recently, intrigue has grown around epigenetic and molecular approaches to try to identify other progressive and implicating mechanisms relating to gambling disorder. This is especially because of the fact that no pharmacological compounds exist currently which specifically treat gambling disorder. I reviewed an article “Down-Regulation of Serotonin and Dopamine Transporter Genes in Individual Rats Expressing a Gambling-Prone Profile: a Possible Role for Epigenetic Mechanisms.” Using a rat model, the researchers found differential regulation of intuitive and commonly tested genetic and other biological markers: serotonin, tyrosine hydroxylase and dopamine transporter. More specifically, these factors were, as predicted, down regulated in rats which (with a preceding screen) fit a gambling-prone profile. With all of this information in mind, the researchers for this study found corroborating molecular evidence. Significant and selectively increasing methylation, common of heterochromatin- formation, inaccessibility of DNA, and thus transcriptional down regulation was also observed at serotonin and dopamine genes in the various parts of the brain which were test (prefrontal cortex, ventral striatum, etc). Of all brain regions tested for molecular profiles, not all yielded significant results for the matrix which was formed when testing these areas for all biological transcriptional factors. This study presents interesting and probably very important correlative data which may be used for manipulative purposes going forward.