Author Interviews, Genetic Research, Nature / 10.05.2016

MedicalResearch.com Interview with: Serena Nik-Zainal MD PhD Wellcome Beit Fellow & Honorary Consultant in Clinical Genetics CDF Group Leader Wellcome Trust Sanger Institute United Kingdom  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Nik-Zainal: We have used the massive improvement in speed of "sequencing" (reading the human genetic material) in order to obtain comprehensive whole genome maps of 560 human breast cancer patients. This is the largest whole genome sequencing study of a single cancer type in the world. We wanted to forensically search these cancers, find all the important genes that drive breast cancer, find all the important mutation patterns that tell us something about why breast cells turn into cancer cells and then to pull it altogether for each patient. We wanted to be able to "profile" each cancer patient, to see if we could further our understanding of personal cancer genomes. In all, we had 556 female and four male patients, and they were sought from all over the world – USA, Europe and Asia. (more…)
Author Interviews, BMJ, Diabetes, Genetic Research / 08.05.2016

MedicalResearch.com Interview with: Wenpeng You, PhD student Biological Anthropology and Comparative Anatomy Research Unit University of Adelaide | School of Medicine Adelaide, Australia  Maciej Henneberg, PhD, DSc, FAIBiol Wood Jones Professor of Anthropological and Comparative Anatomy University of Adelaide School of Medicine; Institute for Evolutionary Medicine, University of Zurich Editor in Chief, Journal of Comparative Human Biology HOMO MedicalResearch.com: What is the background for this study? What are the main findings? Response: Type 1 diabetes disease has very strong genetic background. Prevalence of type 1 diabetes has been increasing globally. Previous studies focusing on regional genetics and environmental factors cannot fully explain this phenomenon. Due to insufficient medical knowledge up until early 20th century, people with type 1 diabetes disease would most commonly die during their teens or early 20s. Therefore, they did not have the opportunity to pass on their genes providing background for the development of type 1 diabetes to their next generations. Since discovery and introduction of insulin to modern medicine in early 1920s, more and more type 1 diabetes patients have been able to survive their reproduction cycle (up until and past 50 years of age). This has made more and more genes related to type 1 diabetes to accumulate in human populations. We applied the Biological State Index which measures a probability to pass genes on to the next generation at population level.  We found that the rapid increase in type 1 diabetes over the last few decades was correlated with increases of the Biological State Index and its proxy, human life expectancy, especially in more developed world in which natural selection has been relaxed most. This correlation was found after statistically excluding differences in countries income, levels of urbanization, sugar consumption and obesity prevalence. (more…)
Author Interviews, Genetic Research, Science / 04.05.2016

MedicalResearch.com Interview with: Lluís Ribas de Pouplana, Ph.D IRB Barcelona Barcelona 08028 MedicalResearch.com: What is the background for this study? What are the main findings? Response: Ever since the discovery of the genetic code it became obvious that the system had not grown to its full theoretical potential of making proteins with 63 different amino acids. Francis Crick called the code 'a frozen accident', but it was unclear what had actually froze it. In this article we offer an explanation to that, and we validate it experimentally. What we find is that the central pieces of the genetic code, the transfer RNAs, are unable to incorporate enough specific elements for the system to be able to use 63 of them without confusion. Since you need a new tRNA for each new amino acid, once the tRNA identification limit is reached you also reach the maximum number of usable amino acids. This limit happened to be reached at 20, and that's where it has stayed for 3 billion years. (more…)
Author Interviews, Genetic Research, PLoS, Vitamin D / 27.04.2016

MedicalResearch.com Interview with: Haidong Zhu, MD, PhD Associate Professor of Pediatrics Georgia Prevention Institute Medical College of Georgia Augusta University MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Zhu: Vitamin D plays an important role in a wide range of body functions beyond bone health. Vitamin D deficiency is associated with increased risk of cancer and cardiovascular disease. Vitamin D deficiency is common among darker skin individuals, particularly African-Americans, which could contribute to health disparity. We want to understand underlying molecular mechanism (i.e. global DNA methylation) for how vitamin D deficiency causes cancer, cardiovascular disease and impaired immune function. DNA methylation, a chemical modification to our genome, is one of the ways that our body adapts to the environment. Low rate of global DNA methylation is a common event in cancer, which may lead to disturbances in the genome, make the genome more vulnerable to environmental damage and increase disease risk. Our study shows that majority of black teens are vitamin D deficient and have a lower rate of global DNA methylation than white teens. We further demonstrate that vitamin D3 supplementation for 16 weeks increases global DNA methylation in black teens and young adults. Our study provides an important piece of evidence that vitamin D plays a role in epigenetic regulation in humans, which could be an underlying mechanism for vitamin D-deficiency related disease risk and health disparity. (more…)
AACR, Author Interviews, Cancer Research, Genetic Research, MD Anderson, Weight Research / 20.04.2016

MedicalResearch.com Interview with: Dr. Xifeng Wu, MD PhD Department Chair, Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences Director, Center for Translational and Public Health Genomics Professor, Department of Epidemiology Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center, Houston, Texas Medical Research: What is the background for this study? What are the main findings? Dr. Wu: Obesity is a well-established risk factor for renal cell carcinoma (RCC), the most common form of kidney cancer. It has been estimated that more than 40% of RCC incident cases in the US may be attributed to excessive body weight. Growing body of evidence suggests that obesity may also influence clinical outcome of RCC; however, the findings are sometimes conflicting. So far, the molecular mechanism linking obesity to RCC risk or prognosis is not well understood. In this study, we evaluated the promoter CpG site methylation of 20 candidate obesity-related genes and their association with RCC risk and recurrence in a two-phase study of 240 newly diagnosed, previously untreated RCC patients. Pyrosequencing was conducted on paired RCC tumor and normal adjacent tissues to measure promoter methylation. Among the 20 markers, we found NPY, LEP and LEPR showed significant differential methylation levels between tumors and normal adjacent tissues, and methylation was significantly higher in tumors in both discovery and validation groups. Consistent with our findings, we also found lower expression of LEPR in tumor tissues compared to normal adjacent tissues in data obtained from The Cancer Genome Atlas. Additionally, high LEPR methylation in tumors was associated with more advanced tumor features, such as high pathologic stage, high grade and clear cell RCC histology, and increased risk of recurrence compared to the low methylation group. These results suggest that tissue changes in promoter methylation in obesity-related genes may provide some biological basis for the association between obesity and RCC outcome, and that LEPR may be an independent prognostic indicator of recurrence in RCC patients. Further research in larger study population and functional studies are warranted to validate our findings and to elucidate the underlying causal mechanisms. (more…)
Author Interviews, Exercise - Fitness, Genetic Research / 20.04.2016

MedicalResearch.com Interview with: Nicholas Jones BSc (Hons) MSc ISAK CSCS ASCC DNA Sports Performance Ltd Director MedicalResearch.com: What is the background for this study? Response: Coaches and trainers all know that individuals can respond differently to the same stimulus. One person may be a super responder to X training method, another may be a none-responder to the very same training method. The reasons for this have never been fully explained, however genetics have been discussed and thought to play a role for some time. MedicalResearch.com: What are the main findings? Response: At the beginning of the eight weeks of training, the participants were set two fitness tests to measure their power and endurance. Power was measured by a countermovement jump (CMJ) and endurance by an aerobic three minute cycle test (known as Aero3). After eight weeks, those whose training had been matched to their genes improved their CMJ power test of 7.4% compared to just a 2.6% increase in the mismatched group. In the cycle endurance test, those who trained to their genetic strengths saw an average 6.2% improvement compared to 2.3% for the mismatched group. (more…)
Author Interviews, Autism, Brigham & Women's - Harvard, PLoS / 09.04.2016

MedicalResearch.com Interview with: Ya Wen PhD TRANSCEND Research, Neurology Department Massachusetts General Hospital, Charlestown, Massachusetts, Harvard Medical School, Harvard University, Boston, Massachusetts Higher Synthesis Foundation, Cambridge, Massachusetts MedicalResearch.com: What is the background for this study? Dr. Ya Wen: At the time of this study (December 2014), the SFARI (Simons Foundation Autism Research Initiative) Gene-Human Gene Module recorded 667 human genes implicated as relevant to Autism spectrum disorders (ASDs). Now the number is close to 800. We sought to address the challenge of making sense of this large list of genes by identifying coherent underlying biological mechanisms that link groups of these genes together. To do this, we used information from several existing and well established databases and created a “demographics” of autism genes and pathways. MedicalResearch.com: What are the main findings? Dr. Ya Wen: From these hundreds of autism genes, we first found the relatively most important pathways, and then we generated a pathway network by mapping the pathway-pathway interactions into an Autism Pathway Network. Our systems analyses of this network converged upon an important role in autism pathophysiology for two pathways: MAPK signaling and calcium signaling, and specifically the process where they overlap, “calcium-protein kinase C-Ras-Raf-MAPK/ERK”. Our study also illuminated genetic relationships between autism and several other kinds of illness, including cancer, metabolic and heart diseases. Many of the significant genes and pathways were associated with vulnerability in the processing of challenging environmental influences. (more…)
Author Interviews, Genetic Research, JAMA, Schizophrenia / 26.03.2016

MedicalResearch.com Interview with: S. Hong Lee, PhD Queensland Brain Institute, The University of Queensland, Brisbane School of Environmental and Rural Science, University of New England, Armidale Australia  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Previous studies reported increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for schizophrenia tend to have children at an earlier or later age. We found evidence for a significant overlap between genetic factors associated with risk of schizophrenia and genetic factors associated with Age at First Birth (AFB). We observed a U-shaped relationship between schizophrenia risk and maternal AFB, consistent with the previously reported relationship between schizophrenia risk in offspring and maternal age when not adjusted for age of the father. (more…)
Allergies, Author Interviews, Genetic Research / 26.03.2016

MedicalResearch.com Interview with: Dr Gabrielle A. Lockett PhD Postdoctoral Research Fellow Asthma Genetics Laboratory, Faculty of Medicine, University of Southampton MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Lockett: Season of birth has been known for decades to influence a huge range of traits, such as height and lifespan, as well as the risks of diseases such as allergy and schizophrenia. But until now the mechanism for season of birth effects was unknown. This study discovered that epigenetic marks (specifically DNA methylation) on the genome are associated with season of birth in 18-year-olds, suggesting that this could be a mechanism for such long-lasting birth season effects. Epigenetic marks on the genome are known to both influence gene expression and to change in association with environmental exposures. This study is the first to identify DNA methylation associated with season of birth. This discovery therefore extends our knowledge of environmental exposures that are able to affect the epigenome. The study also went on to further examine the genes identified to contain birth season-associated DNA methylation. Groups of these genes have functions related to development, cell death and the cell cycle, suggesting that season of birth alters the epigenetic regulation of these processes in particular. There was also suggestive evidence that season-associated DNA methylation could be on the functional pathway to allergic disease outcomes. (more…)
Alcohol, Author Interviews, Breast Cancer, Genetic Research, PLoS / 18.03.2016

MedicalResearch.com Interview with: Chin-Yo Lin, Ph.D. University of Houston Center for Nuclear Receptors and Cell Signaling Department of Biology and Biochemistry Science and Engineering Research Center (SERC) Houston, TX 77204-5056  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Lin: Many studies have established that alcohol consumption is a risk factor for breast cancer. Breast cancers associated with drinking tend to be hormone receptor-positive, the type is commonly treated with the drug tamoxifen which blocks the actions of estrogen in driving tumor growth in pre-menopausal women. Alcohol consumption has also been shown to increase the risk of disease recurrence in patients. Our study shows that alcohol can enhance the effects of estrogen by increasing cancer cell division and also reduce the efficacy of tamoxifen. The key mechanistic insight from the study is that alcohol treatment of breast cancer cells increased the expression of BRAF, a cancer-causing gene that is commonly mutated and activated in other types of cancers. (more…)
Author Interviews, Brain Injury, Genetic Research / 09.03.2016

MedicalResearch.com Interview with: Dr. Jane McDevitt Temple University in Philadelphia MedicalResearch.com: What is the background for this study? Dr. McDevitt: During a head impact there is a mechanical load that causes acceleration and deceleration forces on the brain within the cranium. The acceleration and deceleration causes stress to the neurons and initiates a neurometabolic cascade, where excitatory neurotransmitters such as glutamate are released and depolarize the cell.  This triggers protein channels to open and allow ions into and out of the cell.  Increases in calcium persist longer and have greater magnitude of imbalance than any other ionic disturbance. One channel responsible for allowing calcium into the cell is r-type voltage-gated calcium channel.  One of the main proteins within this voltage-gated calcium channel is the CACNA1E protein produced by the CACNA1E gene. This protein forms the external pore and contains a pair of glutamate residues that are required for calcium selectivity.   It is also responsible for modulating neuronal firing patterns. A variation within this gene (i.e,CACNA1E ) that regulates expression levels of CACNA1E could be associated with how an athlete recovers following a concussion injury. Upwards of 20% of the concussed population fall into the prolonged recovery category, which puts these athletes at risk for returning to play quicker than they should. Variation in recovery depends on extrinsic factors like magnitude of impact, and sport, or intrinsic factors like age or sex. One intrinsic factor that has not been definitively parsed out is genetic variation. Recovery is likely to be influenced by genetics because genes determine the structure and function of proteins involved in the cell’s resistance and response to mechanical stress. Due to CACNA1E’s relationship to calcium influx regulation, a single nucleotide polymorphism (SNP) could modify the expression level of the protein responsible for regulating calcium. Altered protein levels could lead to athlete’s responding to concussive injuries differently. The main objective of this study was to examine the association between CACNA1E SNPs with concussion recovery in athletes. (more…)
Author Interviews, Biomarkers, Cleveland Clinic, Genetic Research, Personalized Medicine, Prostate, Prostate Cancer, Urology / 07.03.2016

MedicalResearch.com Interview with: Eric A. Klein, MD Chairman, Glickman Urological and Kidney Institute Cleveland Clinic MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Klein: Prostate cancer is an enigma. While this tumor is the second leading cause of cancer death among American men, most newly diagnosed disease detected by PSA screening is biologically indolent and does not require immediate therapy. Currently, the main clinical challenge in these men is to distinguish between those who can be managed by active surveillance from those who require curative intervention. Current clinical and pathological tools used for risk stratification are limited in accuracy for distinguishing between these scenarios. An abundance of research in the last decade has provided evidence that genomics can offer meaningful and clinically actionable biological information to help inform decision making, and current National Comprehensive Cancer Network (NCCN) guidelines on prostate cancer endorse the use of commercially available genomic tools for men considering active surveillance.[1] It has been previously shown that the 22-gene genomic classifier, Decipher, accurately predicts the likelihood of metastasis and prostate cancer specific mortality when measured on tissue from radical prostatectomy specimens.[2] In multiple validation studies, it performed with higher accuracy and discrimination compared to clinical risk factors alone. The current study[3] is the first to examine whether the use of Decipher might aid decision making when measured on biopsy tissue at the time of diagnosis. Men with available needle biopsy samples were identified from a study cohort that previously had Decipher performed on their matched radical prostatectomy tissue. In this cohort of mixed low, intermediate and high risk men, Biopsy Decipher predicted the risk of metastasis 10 years post RP with high accuracy, outperforming NCCN clinical risk categorization, biopsy Gleason score and pre-operative PSA. Furthermore, this study showed that Decipher reclassified 46% of patients into lower or higher risk classification compared to NCCN classification alone. The study also showed that Biopsy Decipher can identify men that are at high risk for adverse pathology as defined by the presence of primary Gleason pattern 4 or greater. (more…)
Author Interviews, Breast Cancer, Cancer Research, Genetic Research / 06.03.2016

MedicalResearch.com Interview with: Rong Li, Ph.D., Professor Holder of the Tom C. & H. Frost Endowment Department of Molecular Medicine Institute of Biotechnology Co-Leader, Cancer Development and Progression Program Cancer Therapy & Research Center University of Texas Health Science Center at San Antonio  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Li: The breast cancer susceptibility gene BRCA1 is well known for its function in double strand break DNA repair. However, the ubiquitous role of BRCA1 in DNA repair may not be sufficient to explain its tissue-specific tumor suppressor function in vivo. Using the “awesome power” of mouse genetics, we identified a previously unappreciated crosstalk between BRCA1 and a transcription regulator in mammary gland development. Importantly, we provide compelling evidence that this BRCA1 function is independent of its well-established DNA repair activity. MedicalResearch.com: What should clinicians and patients take away from your report? Dr. Li: The newly identified DNA repair-independent function of BRCA1 may provide new tools and targets for early prevention of BRCA1-associated breast cancer. (more…)
Author Interviews, Genetic Research, Heart Disease, JACC / 04.03.2016

MedicalResearch.com Interview with: Silvia G Priori ,MD, PhD and Andrea Mazzanti, MD Medical Research: What is the background for this study? What are the main findings? Response: The study investigates a novel therapeutic approach for Long QT Syndrome type 3: a malignant varian of long QT Syndrome a disease in which the risk of arrhythmias is proportional to the prolongation of QT interval. LAQT3 is caused by gain of function mutations in the gene SCN5A that encode for the alpha subunit of the cardiac sodium channel. These mutations increase the late sodium current (INa late) that prolongs the QT interval and predisposes the heart to develop life-threatening ventricular arrhythmias. In 1996 we demonstrated in an animal model of Long QT Syndrome type 3 that administration of mexiletine was able to shorten QT interval and the same results were obtained in LQT3 patients treated with mexiletine : these data provided rational for the adoption in clinical practice guidelines to recommend the use of mexiletine to shorten QT interval in LQT3 patients with the expectation that shortening QT interval would reduce the risk of arrhythmic death. In this setting, our study is the first to provide data in support of the view that mexiletine shortens QT interval and reduces the probability to experience arrhythmic events. (more…)
Author Interviews, Genetic Research, MD Anderson, Nature, Prostate Cancer / 01.03.2016

MedicalResearch.com Interview with Dr. Dingxiao Zhang Ph.D Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Smithville, TX 78957, USA MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Zhang: Prostate cancer (PCa) is a heterogeneous malignancy harboring phenotypically and functionally diverse subpopulations of cancer cells. To better understand PCa cell heterogeneity, it is crucial to dissect the biology of normal prostate epithelial lineages. The background for the current study is to annotate the gene expression profiles of normal prostate epithelial cells, through which we hope to gain insight on Prostate cancer subtypes and the cellular heterogeneity in PCa. The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. In this study, we have performed a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. One of our major findings is that the differential gene expression profiles in basal versus luminal prostate epithelial cells account for their distinct functional properties. Specifically, basal cells preferentially express gene categories associated with stem cells, MYC-transcriptional program, neurogenesis, and ribosomal RNA (rRNA) biogenesis regulated by Pol I. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene expression profile is enriched in advanced, anaplastic, castration-resistant, and metastatic prostate cancers. Therefore, we link the cell-type specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. (more…)
Author Interviews, Genetic Research, Sleep Disorders / 28.02.2016

MedicalResearch.com Interview with: Alice Gregory PhD Department of Psychology Goldsmiths, University of London London, UK Medical Research: What is the background for this study? What are the main findings? Dr. Gregory: Sleep paralysis involves a total inability to move just as someone is falling asleep or waking up. This experience typically ends within seconds to minutes and is not usually a sign of any wider problem – yet it can be extremely frightening. This is in part because this experience is often accompanied by hallucinations. To understand what is happening during episode of sleep paralysis it is useful to understand that there are different stages of sleep. One distinction is between Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep. During REM sleep the body is paralysed. Dreaming often occurs during REM sleep, so it has been proposed that this paralysis keeps us safe, by preventing us from ‘acting out our dreams’. During an episode of sleep paralysis, someone may have woken up but has retained certain features of REM sleep (specifically the paralysis and sometimes dream-related hallucinations). While sleep paralysis is rather common and the public seem incredibly interested in learning more about this, it is surprising that there is such little research on this topic. Certain risk factors for sleep paralysis have been proposed previously, such as experiencing stress. However, those suffering from this experience are keen for more information, which is currently unavailable. For this reason, we wanted to see whether we could identify other factors which were associated with sleep paralysis. Furthermore, in reviewing the literature, we were stunned that while it seems obvious that genetic differences between people are likely to be important in explaining why certain people experience sleep paralysis and others do not – there was almost no work on this topic. We decided to investigate this further as well. (more…)
Author Interviews, Genetic Research, UCLA / 26.02.2016

MedicalResearch.com Interview with: April D. Pyle PhD Associate Professor, Microbiology, Immunology & Molecular Genetics Molecular Biology Institute Center for Duchenne Muscular Dystrophy Edythe Broad Center of Regenerative Medicine and Stem Cell Research University of California, Los Angeles, CA Medical Research: What is the background for this study? What are the main findings? Dr. Pyle: We have developed a CRISPR/Cas9 gene editing platform that is applicable for approximately 60 percent of Duchenne muscular dystrophy patients. Duchenne is a devastating muscle wasting disorder affecting approximately1 in 5000 boys worldwide. It is caused by lack of the dystrophin protein. In our study, we demonstrate that we can restore the dystrophin reading frame by deleting up to 725kb of the DMD gene between exons 45 and 55, the largest deletion shown to date in this gene, which results in a functional dystrophin protein being expressed. We demonstrated feasibility of this platform in Duchenne patient-derived human induced pluripotent stem cells differentiated to skeletal and cardiac muscle cells. (more…)
Author Interviews, Breast Cancer, Genetic Research, JAMA / 25.02.2016

MedicalResearch.com Interview with: Dr. Shoshana Rosenberg ScD, MPH Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts Medical Research: Why would BRCA testing rates have increased among younger women with cancer?   Dr. Rosenberg: There has been increasing awareness surrounding genetic testing for breast cancer in more recent years, likely contributing to the trend that we saw over time  in our cohort. This has included more media attention, most notably Angelina Jolie’s sharing her story in 2013. Medical Research: Is this increase in testing a good thing? Dr. Rosenberg: Young women who are diagnosed with breast cancer should be getting tested so the fact that an increasing proportion of women have been undergoing BRCA testing in recent years indicates patients (and the physicians who treat them) are following recommendations. (more…)
Author Interviews, Autism, Genetic Research / 23.02.2016

MedicalResearch.com Interview with: Li ZENG, Ph.D. Principal Investigator Neural Stem Cell Research Lab National Neuroscience Institute Singapore Medical Research: What is the background for this study? What are the main findings? Dr. Zeng: Autism Spectrum Disorders (ASDs) are a group of highly inheritable behavioural disorders that pose major personal and public health concerns. Patients with ASDs have mild to severe communication difficulties, repetitive behaviour and social challenges. Such disorders significantly challenge an individual’s ability to conduct daily activities and function normally in society. Currently there are very few medication options that effectively treat ASDs. Therefore, there is a need to better understand the biology of that produces Autism Spectrum Disorder symptoms. In the study, we found how one brain-specific microRNA (miR-128) plays a key role in causing abnormal brain development. MicroRNAs are small molecules that regulate gene expression in the human body to ensure proper cellular functions. Although it was known that miR-128 is misregulated in some patients with autism, what that meant and how it functioned was not known. We showed that miR-128 targets a protein called PCM1 that is critical to the cell division of neural precursor cells (NPCs). NPCs during early brain development have two fates - they either stay as NPCs and undergo self-renewal or become neurons through differentiation. The dysfunctional regulation of PCM1 by misregulated miR-128 impairs brain development, which may underlie brain size changes in people with Autism Spectrum Disorders. (more…)
Author Interviews, Genetic Research, JNCI, Melanoma / 21.02.2016

MedicalResearch.com Interview with: Nancy E. Thomas, MD PhD Department of Dermatology, University of North Carolina Chapel Hill, NC 27599 Medical Research: What is the background for this study? Dr. Thomas: Melanoma had been thought for some time to arise from at least two causal pathways, a ‘chronic sun exposure pathway’ and a ‘nevus pathway’. However, the role of inherited genetic variation in development of melanoma along these pathways had not previously been studied. Thus, we chose to examine the association of SNPs in putative low-penetrance melanoma susceptibility loci with histologic markers of divergent pathways. Medical Research: What are the main findings? Dr. Thomas: Within the large Genes, Environment and Melanoma Study, we investigated the relationship of germline variants in newly identified low-penetrance melanoma risk loci to histologic markers of divergent causal pathways in melanoma. We present strong evidence that the IRF4 rs12203592*T genotype is positively associated with chronic sun exposure-related melanoma and inversely associated with nevus-related melanoma. We also found that the IRF4 rs12203592 genotype is linked to the bi-model age distribution known to occur in melanoma and which is related to the divergent pathways. IRF4 rs12203592 is a functional variant known to affect IRF4 expression in human skin and melanoma cell lines. We conclude that IRF4rs12203592 is likely, at least in part, to determine pathway-specific risk for melanoma development. (more…)
Author Interviews, Cancer Research, Columbia, Genetic Research / 19.02.2016

MedicalResearch.com Interview with: Jeanine D'Armiento, M.D., Ph.D. Associate Professor of Medicine in Anesthesiology Director of the Center for Molecular Pulmonary Disease in Anesthesiology and Physiology and Cellular Biophysics Director, Center for LAM and Rare Lung Disease New York, NY 10032 Medical Research: What is the background for this study? What are the main findings? Dr. D'Armiento: I am the Director of the Center for Lymphangiomyomatosis (LAM) and Rare Lung Disease at Columbia University; the Center focuses on this proliferative lung disease, which arises spontaneously or as the pulmonary manifestation of the Tuberous Sclerosis Complex (TSC). We have one of the largest cohorts of these patients in the country. Through an understanding of the pathogenesis of LAM our research aims to identify novel therapeutic targets of the disease to improve the care of these patients. Building on our previous research we demonstrated that the HMGA2 gene and its signaling pathway (the route of information which begins an action within cells), are required to produce tumors in the lung and kidneys in individuals with Tuberous Sclerosis Complex. (more…)
Author Interviews, Biomarkers, Genetic Research, Ophthalmology / 11.02.2016

MedicalResearch.com Interview with: Dr Shi Song Rong PhD and Guy Li-Jia CHEN MBBS, MMed, MRCSEd (Ophth), PhD Assistant Professor Department of Ophthalmology & Visual SciencesPrince of Wales Hospital Faculty of Medicine The Chinese University of Hong Kong Medical Research: What is the background for this study? What are the main findings? Response: Glaucoma is a leading cause of irreversible blindness worldwide. Primary angle-closure glaucoma (PACG) as a major form of glaucoma accounts for about half of the cases blinded from the disease. So far, more than 50 genes/loci have been assessed for their associations with PACG and a wider spectrum of relevant conditions, primary angle-closure disease (PACD).  In the article, we summarize the statistical associations of individual genes varying across different study cohorts and conducted meta-analysis to evaluate the associations of 28 polymorphisms in 11 genes/loci with PACD and its subtypes, including PACG, primary angle-closure (PAC) and/or primary angle-closure suspect (PACS). Thus, we affirmed the association of PACG and combined PACS/PAC/PACG with 10 polymorphisms in 8 genes/loci as potential biomarkers. Among them 3 were identified in the genome-wide association study (COL11A1,PLEKHA7 and PCMTD1-ST18), and 5 (HGF, HSP70, MFRP, MMP9 and NOS3) in candidate gene studies. (more…)
Author Interviews, Brain Cancer - Brain Tumors, Genetic Research, Pediatrics, University of Pennsylvania / 04.02.2016

MedicalResearch.com Interview with: Dr. Adam C. Resnick, Ph.D Assistant Professor of Neurosurgery Faculty, Abramson Cancer Center Director of Children's Brain Tumor Tissue Consortium Division of Neurosurgery Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery Children's Hospital of Philadelphia   Payal Jain, PhD Candidate Division of Neurosurgery, Children's Hospital of Philadelphia Department of Neurosurgery Cell and Molecular Biology Graduate Group Gene Therapy and Vaccines Program Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania   Medical Research: What is the background for this study? What are the main findings? Response: This study originates from our long-standing interest in studying pediatric low-grade gliomas (PLGGs), which are the most commonly diagnosed brain tumor in children. While several PLGGs have been found to harbor mutations/gene fusions driving the mitogen-associated protein kinase (MAPK) pathway leading to clinical trials testing MAPK inhibitors, these tumors remain poorly categorized and not enough is known about specific genetic mutations driving different tumor sub-types and the potential for specific targeted therapeutics. Our current study encompasses analysis of the largest combined genomic dataset of pediatric low-grade gliomas samples.  In doing this we, identified the MYB-QKI gene fusion, a non-MAPK related event, as the common genetic event driving a rare PLGG sub-type, called angiocentric gliomas. We have reported a novel tri-partite mechanism by which MYB-QKI mediates its oncogenic effect, this being the first report of a single gene rearrangement utilizing three different paths to cause cancer.
  • First, this gene rearrangement activates MYB, which is a proto-oncogene that is normally not expressed in the developed brain.
  • Second, we found that the rearrangement leads to translocation of QKI-related enhancers close to MYB’s promoters, thereby driving MYB-QKI expression in these tumors. Furthermore, MYB-QKI can also regulate its expression in a positive feedback loop.
  • Third, the tumor suppressor activities of QKI are disrupted in MYB-QKI. Such collaboration of genetic and epigenetic dysregulation in a single genetic rearrangement has previously not been reported.
(more…)
Author Interviews, Autism, Genetic Research, JAMA, Schizophrenia / 30.01.2016

MedicalResearch.com Interview with: Andrea J. Gonzalez-Mantilla, M.D. Postdoctoral Fellow Andres Moreno-De-Luca, M.D. Investigator I Autism & Developmental Medicine Institute Department of Radiology Geisinger Health System Danville, PA 17822 Medical Research: What is the background for this study? What are the main findings? Response: Developmental brain disorders (DBD), such as autism, intellectual disability, and schizophrenia are a group of heterogeneous conditions characterized by deficits that affect multiple functional domains, such as cognition, behavior, communication, and motor skills. Previous studies provide strong evidence of common underlying molecular pathways and shared genetic causes among apparently different DBDs. Large-scale genomic studies of individuals with developmental brain disorders have found that identifying multiple, independent de novo pathogenic loss-of-function (pLOF) variants in the same gene among unrelated individuals is a powerful statistical approach to reliably identify disease-causing genes. However, genomic data from smaller cohorts and case reports are not routinely pooled with data from larger studies. Moreover, most previous studies have been restricted to cohorts of individuals ascertained based on a single diagnosis (e.g., a study will focus on only individuals with a diagnosis of autism and not consider other genomic data from individuals with a different diagnosis). Therefore, genomic data from individuals across DBD are not being jointly analyzed in search of pLOF variants in the same gene that may help build evidence for a causative role in developmental brain disorders. In this study, we carried out data mining of previously published data to identify genes related to the DBD phenotype. We expanded the aforementioned method and developed a multilevel data-integration approach, which capitalizes on three genotype-phenotype data sources: (1) genomic data from structural and sequence pLOF variants, (2) phenotype data from six apparently distinct DBD (autism, intellectual disability, epilepsy, schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder), and (3) data from large scale studies, smaller cohorts, and case reports. We identified 241 candidate genes for developmental brain disorders, including 17 genes that had not previously been associated with developmental brain disorders. (more…)
Author Interviews, Cancer Research, Genetic Research, PNAS / 28.01.2016

MedicalResearch.com Interview with: Nina Bhardwaj, MD, PhD and Director of Immunotherapy and professor of Hematology and Medical Oncology Benjamin Greenbaum, PhD Assistant Professor The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai   Medical Research: How did the discovery of the group of non-coding RNA molecules in cancer cells that sets off an immune response come about? Dr. Greenbaum: Our work is a collaboration between my lab, which is computational, and the Bhardwaj lab, focused on cancer immunology. I had previously made the observation that certain RNA viruses were avoiding certain motifs, such as CpG dinucleotide containing motifs, and the Bhardwaj lab tested whether those motifs could set off an immune response. Recent work had shown that tumors transcribe unusual RNA with immunological consequences, so we investigated whether the same sort of approaches we had used for viral RNA worked here. Dr. Bhardwaj: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses. We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory. Medical Research: What are the main findings? Dr. Bhardwaj: We used a novel quantitative approach, derived from methods in statistical physics, to characterize all of the non-coding RNA transcribed by normal tissue and compared them to the non-coding RNA found in tumors. We found that while the non-coding RNA transcribed in normal tissue displays patterns of motif usage consisting with that of coding RNA, the RNA transcribed in tumors, yet rarely found in normal tissue, can have motif usage more typically associated with viral and bacterial genomes. We predicted a handful of such RNA are immunostimulatory and validated this prediction in antigen presenting cells. We then showed that this sensing may come from a subset of the innate immune system associated with pathogen RNA sensing. We called these RNA “i-ncRNA”, for immunostimulatory non-coding RNA. (more…)
Author Interviews, Duke, Genetic Research, Infections / 24.01.2016

MedicalResearch.com Interview with: Ephraim L. Tsalik, MD MHS PhD Assistant Professor of Medicine Division of Infectious Diseases Center for Applied Genomics & Precision Medicine Duke University Medical Center Emergency Department Service Line Durham VA Medical Center  Medical Research: What is the background for this study? What are the main findings? Dr. Tsalik: This study was motivated by the convergence of two research interests.  The first was spearheaded by Dr. Sack, leading our collaboration at Johns Hopkins.  Dr. Sack and his colleagues have a long history and expertise in studying enteric infections such as E. coli.  The second is our group here at Duke’s Center for Applied Genomics & Precision Medicine as well as the Durham VA Medical Center.  Specifically, we have an interest in studying the host response to infectious disease.  One of the ways we’ve done that historically is through challenge studies where healthy volunteers are exposed to a pathogen in a controlled setting.  Despite everyone getting the same exposure, not everyone gets sick.  That observation gives us a unique opportunity to study the host biology of symptomatic individuals, asymptomatic individuals, and what distinguishes the two from each other.  That is precisely what we did here. Volunteers ingested Enterotoxigenic E. coli (ETEC), which is a common cause of traveler’s diarrhea.  Some subjects became ill with diarrhea while others remained well.  In this study, we focused on gene expression patterns, which is a snapshot of how genes in the body are being used in response to this infection.  Some genes are more active, some are less.  The pattern of those changes that occur in response to infection is what we call a “signature”. This approach allowed us to generate some key findings.  First of all, we were able to define the genes involved in the body’s response to this type of E. coli infection.  Second, we discovered genes that were differentially expressed at baseline that could distinguish people who would go on to become ill from those that would remain healthy.  Although this study was not designed to identify the mechanism for that resilience to infection, it does focus our attention on where to look.  We suspect the genes we identified are likely to play a role in infectious disease resilience and susceptibility based on their known immune function roles.  We also have data, which wasn’t published in this study, that implicates some of these genes in the resilience to other infections such as influenza. The last major finding was something called Drug Repositioning Analysis.  This is a tool that allowed us to identify drugs and drug classes that could be used to mitigate infections caused by ETEC.  That analysis highlighted some compounds already known to be effective such as Zinc.  But it also identified several other drug classes that have not previously been investigated and could be important tools to combat such infections especially as antibiotic resistance looms. (more…)
Author Interviews, Breast Cancer, Genetic Research, NYU / 16.01.2016

More on Breast Cancer Research on MedicalResearch.com MedicalResearch.com Interview with: Dr. Benjamin Neel MD PhD Professor, Department of Medicine Director Perlmutter Cancer Center NYU Langone Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Neel:  Over the past 10 years, there have been major advances in cancer genomics--i.e., defining what changes in genes are found in different types of cancer cells.  Sometimes, such studies have resulted in the identification of new drug targets, such as EGF receptor mutations or EML-ALK translocations in lung cancer, RAF mutations in melanoma and hairy cell leukemia, and KIT or PDGFR mutations in GIST.  More often, though, either the genetic changes that genomic studies reveal are difficult to target by conventional small molecule drugs or we dont know which of the many mutations found in a given tumor are critical to its proliferation/survival. "Functional genomics" is a parallel approach to tumor genomics, that aims to use large scale screening technology to identify which genes are essential to cancer cell survival/proliferation.  This approach can reveal which genetic changes in cancer cells "drive" the cancer--but it also can find genes on which the cancer becomes dependent because of the other "driver" genes.  One major approach to functional genomics uses short hairpin RNAs (a type of RNAinterference/RNAi) to "knock down" the expression of each gene in a cell.  Scientists can generate a "library" of designer virus particles, each of which expresses a different hairpin that can "knockdown" a different gene.  A large population of tumor cells is then infected with the virus, and scientists use gene sequencing or array based approaches to see which shRNAs become depleted from the starting population of shRNAs; this type of screen is called a "dropout screen". Earlier studies, including by our group, performed dropout screens on smaller numbers of cancer cell lines.  Yet because these screens involved only a few cell lines, they could not represent the large number of sub-types knownt to occur in, for example, breast cancer.  Our study, by using 77 breast cancer lines, has adequate power to survey the landscape of breast cancer. Furthermore, by obtaining parallel genomic information, as well as some information on the breast cancer cell "proteome" (the proteins in these cells), we can couple genomic analysis with functional genomics. In addition, we had drug response information for a large number of these lines, and so were able to make some predictions for drugs that might prove additive for breast cancer therapy. The result is a large number of potential new targets linked to genetic information, as well as new insights into how the different sub-types of breast cancer "rewire" their respective signaling diagrams compared with normal cells. (more…)
Author Interviews, Genetic Research, UT Southwestern / 09.01.2016

MedicalResearch.com Interview with: Rhonda Bassel-Duby, Ph.D. and Dr. Chengzu Long, PhD Department of Molecular Biology UT Southwestern Medical Center Dallas, TX 75390-9148 Medical Research: What is the background for this study? What are the main findings? Response: Duchenne muscular dystrophy (DMD), which was first described by Duchenne de Boulogne (1806-1875) in 1860s, is one of the most severe and common type of muscular dystrophy. DMD is caused by mutations in the gene for dystrophin (DMD) on the X chromosome and affects approximately 1 in 3500 to 5000 boys. Without dystrophin, a large cytoskeletal protein, muscles degenerate, causing myopathy. Symptoms can be visible between 1 to 6 years old. Most Duchenne muscular dystrophy patients are confined to a wheelchair by age 12. Death of DMD patients usually occurs by age 25, typically from breathing complications and cardiomyopathy. Hence, therapy for  Duchenne muscular dystrophy necessitates sustained rescue of skeletal, respiratory and cardiac muscle structure and function. Although several gene therapies have been tested, there is no curative treatment so far. Duchenne muscular dystrophy arises from a monogenic mutations in dystrophin gene. This makes DMD an ideal disease model for CRISPR-mediated gene editing therapeutics, a major breakthrough in gene engineering in the past three years. This system can remove the defect within the gene. In 2014, in a first proof of concept study, Olson’s team used CRISPR-mediated gene editing to correct the dystrophin gene mutation in the germline of DMD mouse model. In this new paper, we advanced the same technology to postnatal muscle tissues by delivery gene editing components via a harmless adeno-associated virus. Skeletal and cardiac muscle showed progressive rescue of dystrophin protein. (more…)