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Author Interviews, BMC, BMJ, Genetic Research / 03.12.2015

MedicalResearch.com Interview with: Hatem A. Azim MD PhD Breast Cancer Translational Research Laboratory Institut Jules Bordet Université Libre de Bruxelles Brussels, Belgium Medical Research: What is the background for this study? What are the main findings? Dr. Azim: As at breast cancer diagnosis is known to impact prognosis, with young patients having worse outcome. On the other hand, elderly patients are less studies in general and little is known on their tumor characteristics. In this study, we aimed to define the pattern of genomic aberrations in different age groups. This can result in identifying if key potentially targetable genomic alterations are more specific to particular age groups and thus could open the door to design particular studies targeting these aberrations in these age groups. We found that  age is associated with unique biological features at the DNA level, independent of tumor stage, histology and breast cancer molecular subtype. Of particular mention, the higher prevalence of GATA3 mutation in younger patient, a known driver mutation associated with endocrine resistance. In addition, age at diagnosis appears to impact the tumor transcriptome confirming previous observations, but also highlighting novel findings, of particular relevance the higher expression of stem cell related genes in young patients. (more…)
Author Interviews, Genetic Research, Nature, Weight Research / 26.11.2015

MedicalResearch.com Interview with: Dr. Andrew Whittle, joint first-author of the paper and a postdoc in the Prof. Vidal-Puig’s lab at the time the research was conducted. Medical Research: What is the background for this study? Dr. Whittle: Antonio Vidal-Puig heads the disease model core of the University of Cambridge Metabolic Research Laboratories at the Wellcome Trust-MRC Institute of Metabolic Science (IMS). His laboratory has a long-standing interest in the mechanisms that regulate how adipose tissue stores, burns or releases energy. The group studies mice that have increased or reduced susceptibility to obesity and its metabolic complications, in order to dissect the molecular pathways that underpin these phenotypes. Their long-term goal is to develop more effective strategies to manipulate the body’s own regulatory pathways, both to reduce obesity itself or limit the negative impact that excess lipids have on other important metabolic organs. Professor Hideaki Bujo from Toho University Medical Center in Japan has been working for a number of years to understand the role of specific lipoprotein receptors in vascular biology. Specifically he has shown that LR11 is cleaved to release a short soluble for of the protein, sLR11, which can effect changes to vascular smooth muscle cell migration. To further his studies he generated a knock-out mouse model completely lacking LR11. One of the first observations his group made was that these mice remained leaner than control animals. I and Meizi Jiang (a postdoc in the Bujo lab) conducted a collaborative study of the LR11 knockout mice (Lr11-/-), to investigate the mechanisms by which a lack of LR11 resulted in mice being protected from diet-induced obesity.  (more…)
Author Interviews, Genetic Research, Pediatrics / 25.11.2015

MedicalResearch.com Interview Grant S Schulert MD, PhD Clinical Fellow, Division of Rheumatology Cincinnati Childrens Hospital  Medical Research: What is the background for this study? What are the main findings? Dr. Schulert: Influenza infection causes millions of illnesses annually, but most of those are relatively mild.  In a subset of cases, patients can become critically ill, even if they are relatively young and healthy.  Several previous reports had observed in these critically ill patients features of a hyperinflammatory syndrome known as HLH (hemophagocytic lymphohistiocytosis) or MAS (macrophage activation syndrome).  This hyperinflammation can be triggered by other infections as well as in a subtype of juvenile arthritis, but there is also a familial form occurring in early childhood with known genetic causes.  Our questions with this study were 1) how often are features consistent with HLH/MAS seen in fatal H1N1 influenza infections and 2) do patients with fatal H1N1 infection have genetic mutations associated with HLH/MAS? Our collaborator Paul Harms, MD, and his team at the Michigan Center for Translational Pathology, University of Michigan Medical School identified 16 cases of fatal H1N1 influenza infection.  Based on their clinical features, between 41-88% of these patients could be categorized as having a hyperinflammatory HLH/MAS.  We then used processed tissue samples from the patients for whole exome genetic sequencing, which reads the entire genetic code of every gene in a person. Five patients carried mutations in genes which cause HLH, and several others carried mutations in genes linked to MAS.  This suggests that there may be genetic risk factors for developing fatal hyperinflammatory syndromes in H1N1 infection. (more…)
Author Interviews, Critical Care - Intensive Care - ICUs, Genetic Research, Pulmonary Disease / 20.11.2015

MedicalResearch.com Interview with: Dragana Vidovic and Marianne Carlon Laboratory for Molecular Virology and Gene Therapy KU Leuven, Belgium Medical Research: What is the background for this study? What are the main findings? Response: Cystic fibrosis (CF) or mucoviscidosis is a genetic disorder caused by mutations in the CFTR gene which codes for a chloride/bicarbonate channel that regulates fluid secretion across the epithelium in different organs, for instance, the airways and the gastrointestinal tract. In the cells of CF patients, these anion channels are dysfunctional or even absent leading to the formation of sticky mucus. Persistent airway infection is the major clinical manifestation. The symptoms can be treated, but there is no cure for the disorder. Gene therapy holds promise to cure the disease. Previous studies suggested that the treatment is safe, but largely ineffective for Cystic fibrosis patients. However, as gene therapy has recently proven successful for inherited disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for CF. Here we developed an improved gene therapy treatment based on inserting the CFTR gene into the genome of a recombinant AAV viral vector (rAAV), which is derived from the relatively innocent AAV virus. We used this vector to “smuggle” a healthy copy of the CFTR gene into the affected cells. We administered rAAV to CF mice via their airways. Most of the mice recovered. In patient-derived intestinal cell cultures or organoids, chloride and fluid transport was restored. Medical Research: What does the study add to the field? Response: Development of Cystic fibrosis gene therapy requires a thorough preclinical examination of a candidate vector in relevant cell and animal models before being administered to humans. Here, both in mice with Cystic fibrosis and in mini-guts or intestinal organoids derived from Cystic fibrosis patients, this approach yielded positive results setting the stage for further validation in large animal models which mimic the CF patient situation more faithfully. We believe that our study will revive the interest in CF gene therapy as a promising, mutation-independent approach to ultimately cure Cystic fibrosis. (more…)
Author Interviews, Genetic Research, JAMA, Neurological Disorders / 17.11.2015

MedicalResearch.com Interview with: Kevin M. Biglan, M.D., M.P.H Professor of Neurology and the Associate Chair for Clinical Research Department of Neurology and the Center for Human Experimental Therapeutics University of Rochester School of Medicine and Dentistry Rochester, New York  Medical Research: What is the background for this study? What are the main findings? Dr. Biglan: A therapeutic goal of research in Huntington Disease (HD) is the identification of treatments that delay the progression of disease and onset of illness in individuals at risk for developing manifest HD. Designing such efficacy trials is challenging. A major hurdle is the lack of practical primary outcome measures to assess the effect of an intervention on delaying disease onset. Use of the dichotomous endpoint of clinical diagnosis as the primary outcome requires large sample sizes and long duration of follow up in order to show a significant therapeutic effect on delaying disease onset. Continuous measures that can reliably distinguish cytosine-adenine-guanine (CAG) expanded individuals in the pre-manifest period may allow for the identification of potential disease modifying therapies using relatively smaller cohorts followed for shorter periods of time. The Prospective Huntington At-Risk Observational Study (PHAROS) represents the largest observational study to clinically evaluate pre-manifest Huntington Disease wherein both research participants and investigators were unaware of Huntington Disease mutation status. Accordingly, PHAROS was uniquely designed to address, in an unbiased manner, those clinical features most associated with the CAG expansion during the prodromal phase in  Huntington Disease.  The identification of continuous outcome measures that are associated with HD in the pre-manifest period may facilitate the design and powering of future studies of potential disease modifying therapies prior to traditional motor diagnosis. (more…)
Author Interviews, Cancer Research, Genetic Research, JAMA / 14.11.2015

MedicalResearch.com Interview with: Samuel Klempner, M.D. Assistant Professor Division of Hematology/Oncology UC Irvine Health Orange, CA 92868  Medical Research: What is the background for this study? What are the main findings? Dr. Klempner: The background for our series is the concept that little is known about the genetic landscape of rare tumors such as acinic cell tumors, and that understanding genetic changes in tumors can identify treatment options.  This paradigm can, and should, be extended beyond rare tumor types and many researchers are currently studying various tumor types.  Another important background idea is that tumor genomic alterations may be more important than that anatomic site of origin. For example, I would argue that a breast cancer that harbors an EGFR mutation common to lung cancer could be treated similar to a lung cancer based on the genomic changes. In our study we found another way that the BRAF protein and its downstream signaling may become activated through duplicating part of the protein called the kinase domain.  This genetic event causes the pathway to be always "on" which is not normal, and likely drives cancer growth.  However, BRAF kinase domain duplication appears sensitive to currently available drugs that target the BRAF pathway, as evidenced by the response in our patient.  Thus, finding this change is important and may be able to guide a more personalized therapy choice.  Importantly, we found BRAF kinase domain duplication across multiple different tumor types, suggesting this may be a recurrent event in some cancers.  A very similar finding, involving duplication of the EGFR kinase domain, was also just reported (Cancer Discovery 2015;5:1155-1163) lending further validation to this mechanism of pathway activation in cancer. (more…)
Author Interviews, Brigham & Women's - Harvard, Genetic Research, JAMA, Neurological Disorders, Schizophrenia / 12.11.2015

MedicalResearch.com Interview with: Frederick W. Vonberg, MA, MBBS Research Fellow in Neurocritical Care Boston Children's Hospital and Harvard Medical School Medical Research: What is the background for this study? What are the main findings? Response: An association between schizophrenia and epilepsy has long been suspected, ever since people noticed similarities in some aspects of the presentation of the two conditions, and in their epidemiology. For example, people with epilepsy are thought to be more at risk of developing schizophrenia. Furthermore, a psychosis resembling schizophrenia can characterize some forms of epilepsy. Whether this link reflected an overlap in the genetics of the two conditions has remained a mystery, however. In this study, we used a recently developed computational technique to show that there is a significant positive correlation between the genetic variants that are associated with epilepsy and with those that are associated with schizophrenia. (more…)
Author Interviews, Genetic Research, Race/Ethnic Diversity, Weight Research / 06.11.2015

MedicalResearch.com Interview with: Joan C. Han, MD Director, Pediatric Obesity Program, Le Bonheur Children’s Hospital Associate Professor, Division of Pediatric Endocrinology Department of Pediatrics, University of Tennessee Health Science Center Memphis, TN 38103 Medical Research: What is the background for this study? What are the main findings? Dr. Han: Obesity has become a world-wide epidemic. Our research group studies the genetic factors that contribute to the development of obesity. Brain-derived neurotrophic factor (BDNF) is a protein that plays a key role in regulating appetite. We found that a common genetic variant of the BDNF gene is associated with lower expression of this gene in the hypothalamus, a region of the brain that controls energy balance. The mechanism of this reduced gene expression appears to be due to diminished binding of the transcription factor hnRNPD0B. We also observed that this genetic variant is associated with higher body mass index and higher body fat in children and adults. The obesity-predisposing variant of the BDNF gene occurs more commonly in people of African-American or Hispanic backgrounds, which could have important clinical implications given the higher rates of obesity in these populations. (more…)
Author Interviews, Colon Cancer, Genetic Research, Journal Clinical Oncology / 03.11.2015

MedicalResearch.com Interview with: Hans F.A. Vasen, MD Department of Gastroenterology Leiden University Medical Center and Netherlands Foundation for the Detection of Hereditary Tumours Leiden, the Netherlands Medical Research: What is the background for this study? Dr. Vasen: People with familial colorectal cancer (CRC) have a 3-6 fold increased risk of colorectal cancer. It has been estimated that about 2% of the population have familial CRC (about 2.7 million people in the US). Previous studies showed that colonoscopic surveillance reduces the CRC-mortality by >80%. In people with hereditary CRC, i.e., Lynch syndrome (10 fold increased risk of CRC), an intensive screening program with colonoscopy 1x/1-2 years, is recommended. In familialcolorectal cancer, the optimal screening program  is unknown. Medical Research: What are the main findings? Dr. Vasen: In this randomized trial with 528 individuals at risk for familial CRC, we compared screening intervals of 3 and 6 years. We found that patients had significant more high-risk adenomas (precursor lesions of CRC) at 6-years-follow-up compared to at 3-years-follow-up. However, because of the relatively low rate of high-risk adenomas at 6 years (7%) and the absence of colorectal cancer in the 6-years group, we consider a 6-year-interval safe. (more…)
Author Interviews, Genetic Research, Kidney Disease, Nature, Stem Cells / 24.10.2015

MedicalResearch.com Interview with: Benjamin Freedman, Ph.D. Assistant Professor | University of Washington Department of Medicine | Division of Nephrology Member, Kidney Research Institute Member, Institute for Stem Cell and Regenerative Medicine Seattle WA 98109  Medical Research: What is the background for this study? What are the main findings? Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy. Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney 'organoids' that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific 'symptoms' of these two different diseases in the petri dish. (more…)
Author Interviews, Endocrinology, Genetic Research, Weight Research / 22.10.2015

Urszula T. Iwaniec, Ph.D. Associate Professor Skeletal Biology Laboratory School of Biological and Population Health Sciences Oregon State University Corvallis, OR 97331MedicalResearch.com Interview with: Urszula T. Iwaniec, Ph.D. Associate Professor Skeletal Biology Laboratory School of Biological and Population Health Sciences Oregon State University Corvallis, OR 97331 Medical Research: What is the background for this study? What are the main findings? Dr. Iwaniec: Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related bone loss.  Leptin, a hormone produced by fat cells plays an essential role in weight regulation. Delivery of leptin directly into the hypothalamus by gene therapy normalizes body weight. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature female rats and determined the impact of leptin-induced weight loss on bone. Our findings show that hypothalamic leptin gene therapy reduced body weight with minimal effects on bone mass or microarchitecture. (more…)
Author Interviews, Genetic Research, Lancet, Macular Degeneration, Ophthalmology / 12.10.2015

Professor P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute AustraliaMedicalResearch.com Interview with: Professor  P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute Australia Medical Research: What is the background for this study? Prof. Rakoczy: Wet age related macular (wet-AMD) is the major cause of blindness in the developed world. It is treated with frequent anti-VEGF injections into the eye. Our preclinical studies demonstrated that following the subretinal injection of a recombinant adeno-associated vector (rAAV) carrying a natural inhibitor of neovascularization (sFlt-1), leaky new, abnormal vessels can be controlled and retinal anatomy improved. The rAAV.sFlt-1 based Ocular Biofactory™ platform has potentially significant advantages over existing technologies as it is designed to provide sustained production of a naturally occurring antiangiogenic agent, sFlt-1, in situ in the eye. In this trial we investigated the safety of rAAV.sFlt-1 in patients diagnosed with wet-AMD. (more…)
Author Interviews, Cancer Research, Genetic Research / 10.10.2015

Huma Q. Rana, MD Clinical Director, Cancer Genetics and Prevention Dana-Farber Cancer Institute in BostonMedicalResearch.com Interview with: Huma Q. Rana, MD Clinical Director, Cancer Genetics and Prevention Dana-Farber Cancer Institute in Boston Medical Research: What is the background for this study? What are the main findings? Dr. Rana: -        Li-Fraumeni syndrome (LFS) is thought to be a rare, inherited condition that  causes high lifetime risks for multiple cancers.  It is caused by mutations in the TP53 gene.  Traditionally, only people with striking personal or family histories of cancer underwent genetic testing for TP53 mutations, as there are well-established testing criteria.   This gene was usually tested for in isolation, meaning not combined with testing of other genes.  Due to technological advances, namely multi-gene panels (MGP), many more people are having their TP53gene analyzed.    This included a patient of mine who somewhat surprisingly  tested positive for a TP53 mutation.    This led us to investigate whether people who test positive for TP53 mutations on MGPs are different from ones who test positive on traditional or single-gene (SG) testing. We compared individuals tested for TP53 single gene versus multigene panel testing to determine if there were differences in the percent of mutation carriers meeting current testing criteria for LFS.   Our data showed that 73% of individuals sent in for single gene testing of TP53 met Classic or Chompret (2009) criteria for LFS, whereas only 30% of those sent in for multi-gene panel testing met criteria (p=0.0000001).  When we looked at the most up-to-date testing criteria, which includes Classic, Chompret, or a personal diagnosis of early-onset breast cancer (age at ≤35), 85% of individuals in the single gene group who were positive met criteria, while only 53% of the mutation carriers identified on a multi-gene panel did.   These data suggest that multi-gene panel testing enables us to identify TP53 mutation carriers who may not have otherwise been identified if testing were limited to those who meet established LFS criteria. (more…)
Author Interviews, Fertility, Genetic Research / 09.10.2015

Rajiv McCoy, PhD Dept. of Genome Sciences Univ. of WashingtonMedicalResearch.com Interview with: Rajiv McCoy, PhD Dept. of Genome Sciences Univ. of Washington Medical Research: What is the background for this study? What are the main findings? Dr. McCoy:  Aneuploidy—the inheritance of extra or missing chromosomes compared to the typical 46-chromosome set—is extremely common in human embryos. The vast majority of aneuploidies result in preclinical pregnancy loss, often before the pregnancy is even recognized by the mother. This is thought to be the primary reason why only ~30% of all conceptions result in successful live birth. Many aneuploidies arise during egg formation, with the frequency increasing with maternal age. In addition to meiotic errors, a large proportion of aneuploidies affecting cleavage-stage embryos are mitotic in origin, arising during the initial post-fertilization cell divisions. These initial divisions are controlled by machinery contributed by the mother in the egg (before the embryo's genome has been activated). While these mitotic errors are frequent in cleavage-stage embryos, we found that they are rare in embryos at day-5 of development (the blastocyst stage), suggesting that embryos and/or cells with extensive mitotic errors do not survive to day 5. We discovered that some women have a greater propensity to produce embryos with mitotic errors than others, and our idea was that maybe differences in the mitotic machinery could help explain this. Using data from in vitro fertilized embryos screened by our collaborators at Natera, we found that women who have a particular version of a gene called PLK4 tend to produce more aneuploid embryos, regardless of age. This genetic variant is actually very common—more than half of people carry at least one copy—and is present in nearly all populations. PLK4 has a well-known role in ensuring the proper distribution of chromosomes. We also found that patients referred for embryo screening due to previous IVF failure had higher rates of mitotic error, which underscores the clinical importance of this form of whole-chromosome abnormality. (more…)
Author Interviews, Genetic Research, Lung Cancer, PLoS / 07.10.2015

MedicalResearch.com Interview with: Keiji Tanimoto, D.D.S., Ph.D Assistant Professor Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan Medical Research: What is the background for this study? Dr. Tanimoto: Hypoxia-inducible factor-2α (HIF-2αor EPAS1) is important for cancer progression, and its overexpression is considered a putative biomarker for poor prognosis in patients with lung cancer. However, molecular mechanisms underlying EPAS1 overexpression are not fully understood. Recently, several SNPs of EPAS1 have been reported to be associated with the development of various diseases including cancer. Therefore, we focused on SNPs within EPAS1, and examined the roles of these SNPs in regulation of EPAS1 gene expression and the association of these SNPs with prognosis of non-small cell lung cancer (NSCLC) patients by bioinformatics analyses. Medical Research: What are the main findings? Dr. Tanimoto:
  • The SNP within the EPAS1 intron 1 region (rs13419896) may affect EPAS1 gene and protein expression;
  • The fragment with A allele of the SNP showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun;
  • The median survival time of NSCLC patients with at least one A allele of rs13419896 was significantly shorter than that with the G/G homozygote (28.0 vs. 52.5 months, P = 0.047, log-rank test);
  • The possession of A allele of rs13419896, along with clinical stage, was an independent variable for risk estimation of overall survival for NSCLC patients [hazard ratio (HR) = 2.31, 95% CI = 1.14-4.81, P = 0.021], after adjustment for age, gender, stage, histology, tumor size, and differentiation.
(more…)
Author Interviews, Genetic Research, Nutrition, Weight Research / 05.10.2015

Jacqueline Alvarez-Leite MD, Ph.D Full Professor, UFMG Moore Laboratory Massachusetts General HospitalMedicalResearch.com Interview with: Jacqueline Alvarez-Leite  MD, Ph.D Federal University of Minas Gerias in Brazil Medical Research: What is the background for this study? What are the main findings? Dr. Alvarez-Leite : Obesity is now a global epidemic and bariatric surgery is now the main therapeutic option for those individuals with extreme obesity in which clinical treatments failed. However, a significant proportion of those patients regain the weight lost 3-4 years after surgery. Therefore, some metabolic or genetic trait may be related to weight regain. The rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity- associated (FTO) gene is one of the most studied genes involved in obesity. However, few studies have been conducted on patients who underwent bariatric surgery. In our study, we evaluated the influence of  this FTO SNP on body weight and composition, and weight regain in 146 patients during a 60-mo follow-up period after bariatric surgery. We observed that there was a different evolution of weight loss in individual with obesity carriers of the FTO gene variant after bariatric surgery. However, this pattern is evident at only 2 y post bariatric
 surgery, inducing a lower proportion of surgery success (percentage of excess weight loss >50%) and greater and earlier weight regain after 3-y of follow-up. Multiple regression 
analyses showed that the variation in rs9939609 was a significant and independent predictor for regaining weight during the 
5-y follow-up period. (more…)
Author Interviews, Genetic Research, Ophthalmology / 05.10.2015

MedicalResearch.com Interview with: Dr. Annabel Christ PhD Max-Delbrueck-Center for Molecular Medicine Berlin, Germany Medical Research: What is the background for this study? Dr. Christ: The development and function of the retina in all vertebrate species follow the same principles. Still, there is one important feature that distinguishes the mammalian eye from that of others inasmuch as it does not grow much after birth. In contrast, in fish or reptiles, the retina continuously grows, even in adults. The mechanism that restricts the growth of the mammalian eye remains enigmatic. Yet, understanding this mechanism may offer therapeutic strategies to block eye growth in cases of severe nearsightedness or to induce growth of the retina in patients with retina degeneration. To explore the mechanisms that control human eye growth we studied a genetic form of extreme eye overgrowth (buphthalmia). It is caused by an inherited defect in the gene encoding LRP2, a receptor in the retina. We reasoned that this exceptional form of eye disease might tell us something about the concepts governing eye growth in all humans. (more…)
Author Interviews, Cancer Research, Colon Cancer, Genetic Research, JNCI, Mayo Clinic, Race/Ethnic Diversity / 05.10.2015

Harry H. Yoon, MD Mayo Clinic Rochester, MN 55905MedicalResearch.com Interview with: Harry H. Yoon, MD Mayo Clinic Rochester, MN 55905 Medical Research: What is the background for this study? What are the main findings? Dr. Yoon: In the U.S., the survival of patients with colon cancer is known to differ by race, with individuals of black race having worse outcomes than those of white race. However, it has been difficult to tease apart why the differences in survival exist. It is generally believed that social or other non-biologic factors (eg, decreased access to care, suboptimal treatment) contribute to the discrepancy.  It’s also known that differences in the general medical condition of patients could affect how long a patient lives. However, it is unknown whether there are race-based differences in the biology of colon tumors themselves.  This biology can be reflected in the genetic composition of tumors, as well as by whether and how quickly the cancer returns after the patient has undergone surgery and chemotherapy. In addition, it is unknown whether race-based differences in biology may be related to the age of the patient at the time of diagnosis.  Blacks with colorectal cancer typically have an earlier age of onset than whites do. A major barrier to addressing these questions are that there are very few large populations of colon cancer patients where everyone had the same disease stage and received uniform treatment, and where patients were monitored for years afterward specifically to see whether the cancer returned.  It is much harder to measure whether cancer has returned (ie, cancer recurrence), as compared to simply knowing whether a patient is alive or dead.  This difference is important, because knowing about cancer recurrence sheds more light on cancer biology than only knowing about patient survival, since many factors unrelated to cancer biology (eg., heart disease) can affect whether a person is alive or dead. The most reliable data on cancer recurrence (not just patient survival) generally comes from patients who have enrolled in a clinical trial.  In the Alliance N0147 trial, all patients had the same cancer stage (ie, stage III), underwent surgery and received standard of care chemotherapy (ie, “FOLFOX”) after surgery.  Patients had uniform, periodic monitoring after chemotherapy to see if the cancer returned. In other words, examining racial outcomes in this cohort largely eliminates some of the key factors (eg, decreased access to care, suboptimal treatment) that are believed to contribute to racial discrepancies, and provides a unique opportunity to determine if differences in cancer biology between races may exist. This study was done to see if colon cancers are genetically different based on race, and whether race-based differences exist in cancer recurrence rates. The study found that tumors from whites, blacks, and Asians were different in terms of the frequency of mutations in two key cancer-related genes, BRAF and KRAS.  Tumors from whites were twice as likely to have mutated BRAF (14% in whites compared to 6% in Asians and 6% in blacks).  Tumors from blacks had the highest frequency of KRAS mutations (44% in blacks compared to 28% in Asians and 35% in whites).  Tumors from Asians were the mostly likely to have normal copies of both genes (67% in Asians compared to 50% in blacks and 51% in whites). Next, the study found that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites.  However, this discrepancy was only evident among young patients (ie, aged less than 50 years).  Almost 50% of younger black patients experienced colon cancer recurrence within 5 years, compared to ~30% of black patients over age 50, or compared to white or Asian patients regardless of age. The worse outcome among young blacks remained evident even after adjusting for many potential confounding factors, such as tumor grade, the number of malignant nodes, or the presence of BRAF or KRASmutations.  Because this question was examined in a clinical trial cohort of uniform stage and treatment, the role of multiple important potential confounders was diminished. To our knowledge, this is the first report indicating that colon cancers from young black individuals have a higher chance of relapsing after surgery and chemotherapy, compared to those from white individuals. (more…)
Author Interviews, Depression, Genetic Research, JAMA / 03.10.2015

Dr. David Brent MD Department of Psychiatry Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center Pittsburgh, PennsylvaniaMedicalResearch.com Interview with: Dr. David Brent MD Department of Psychiatry Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Medical Research: What is the background for this study? Dr. Brent: Youth with a parent with a history of depression are at increased risk for having a depressive episode themselves. Medical Research: What are the main findings? Dr. Brent: Those who received a cognitive behavioral educational group program were less likely to have had a depressive episode, and were functioning better than those who did to receive the program 6 years later, especially if their parent was NOT depressed at the time that they received the program. If the parent was depressed then the program was no better than usual care. (more…)
Author Interviews, Breast Cancer, Chemotherapy, Genetic Research, NEJM / 29.09.2015

Dr. Kathy D. Miller, MD Indiana University Melvin and Bren Simon Cancer CenterMedicalResearch.com Interview with: Dr. Kathy D. Miller, MD Indiana University Melvin and Bren Simon Cancer Center Medical Research: What is the background for this study? What are the main findings? Dr. Miller: Previous studies had found a small but real benefit with the addition of chemotherapy to anti-estrogen treatment in patients with hormone sensitive disease. The challenge for patients and clinicians has always been that the benefit of chemotherapy is quite small and the toxicity can be substantial. The Oncotype Dx recurrence score assay was developed to identify patients who could safely be treated with anti-estrogen therapy alone (and conversely those who truly need and would derive a much larger benefit from chemotherapy). When the Oncotype Dx RS was applied to samples stored from a previous randomized trial, patients with low risk scores didn't seem to benefit from chemotherapy. While those initial results had some impact on treatment, many were concerned about eliminating chemotherapy on the basis of one small retrospective trial. The overall trial enrolled 10,253 women. 1626 (15.9%) had a Recurrence Score of 0-10 and were assigned to receive antiestrogen therapy alone without chemotherapy. After five years 99.3% (98.7, 99.6%) for were free of distant relapse (that is to say, 99.3% of women had NOT had recurrence of breast cancer at distant sites in the body). Overall survival was 98%. (more…)
Author Interviews, Breast Cancer, Brigham & Women's - Harvard, Genetic Research, Journal Clinical Oncology, Race/Ethnic Diversity / 20.09.2015

Aditya Bardia MBBS, MPH Attending Physician, Massachusetts General Hospital Cancer Center, Assistant Professor, Harvard Medical School Boston, MA 02114MedicalResearch.com Interview with: Aditya Bardia MBBS, MPH Attending Physician, Massachusetts General Hospital Cancer Center, Assistant Professor, Harvard Medical School Boston, MA 02114   Medical Research: What is the background for this study? What are the main findings? Response:  Multiple studies have consistently shown that African American women with cancer, including breast cancer, have worse outcomes than Caucasian counterparts. While socioeconomic issues, including access to care plays an important role, the contribution of tumor biology has been less clear. In this study, utilizing exome sequencing data, we linked the racial distribution of primary breast cancer with tumor genotypic traits, including somatic mutations, gene-expression profiles and intra-tumor heterogeneity. We observed that in addition to having a higher prevalence of triple negative breast cancer than Caucasian women (something that has been documented in the literature), African American women had a significantly higher prevalence of TP53 mutations, TNBC basal-like 1 and mesenchymal stem-like tumors, and intratumor genetic heterogeneity, and all of which suggest more aggressive tumor biology, suggesting that differences in tumor genomic profile contribute, at least partly, to the known racial disparity in survival between African Americans and Caucasians breast cancer patients. (more…)
Author Interviews, Cancer Research, Case Western, Colon Cancer, Genetic Research / 16.09.2015

Ahmad M. Khalil, PhD Department of Genetics School of Medicine Case Western Reserve University Cleveland, Ohio 44106-4955 MedicalResearch.com Interview with: Ahmad M. Khalil, PhD Department of Genetics School of Medicine Case Western Reserve University Cleveland, Ohio 44106-4955 Medical Research: What is the background for this study? What are the main findings? Dr. Khalil: DNA in human cells is modified chemically by methylation. The process of DNA methylation plays important roles in protecting human DNA and ensures proper gene expression.  In cancer cells, the process of DNA methylation becomes deregulated, however, the mechanisms of how this occurs are not known.  In our study, we have uncovered a novel mechanism on how colon cancer cells change their DNA methylation, and consequently, become more tumorigenic. We specifically identified a long non-coding RNA that interacts with and regulates the enzyme that modifies DNA with methylation - the enzyme is called DNMT1. This lncRNA become suppressed in colon tumors, which we believe is a key step in loss of DNA methylation in colon cancer cells. (more…)
Author Interviews, Dermatology, Genetic Research / 12.09.2015

Thomas N. Darling, MD, PhD Department of Dermatology Uniformed Services University of the Health Sciences Bethesda, MD 20814 MedicalResearch.com Interview with: Thomas N. Darling, MD, PhD Department of Dermatology Uniformed Services University of the Health Sciences Bethesda, MD 20814 Medical Research: What is the background for this study? What are the main findings? Dr. Darling: Many people with tuberous sclerosis complex (TSC) have skin tumors that can bleed or cause distress. Only surgical approaches were useful for treating these skin tumors in the past. Recently, drugs called mTOR inhibitors, including sirolimus, were shown to shrink internal tumors in those affected by tuberous sclerosis complex. We wanted to document what happens to the skin tumors in those being treated with oral sirolimus. We found that most patients taking oral sirolimus showed improvement in their skin tumors, and that these effects were maintained during a couple years of treatment. We did not observe any evidence for the skin tumors becoming resistant to the drug. (more…)
Author Interviews, Genetic Research, Sexual Health / 12.09.2015

MedicalResearch.com Interview with: Binbin Wang, PhD Center for Genetics, National Research Institute for Family Planning Beijing China Medical Research: What is the background for this study? What are the main findings? Dr.Wang:Homosexuality has become an important issue all around the world, as well as in China. Beside of the human right problems it poses, the reality that more and more HIV cases are infected through homosexual activity,especially men who have sex with men (MSM), should be concerned. People are wondering how homosexuality develops. As a genetic researcher, I'd like to find the answers in the field of genetics. This study is based on previous evidence that genes may have impact on homosexuality. Besides, animal models have provided clues that abnormality in some neurotransmitters, such as dopamine, may alter the sex behavior of animals. Therefore, we choose COMT (the gene catechol-O-methyltransferase) as the target, which is important for the synthesis of dopamine. We find that an amino acid residue change in COMT could increase the risk of developing male homosexuality. Our results provide some evidence that male homosexuality is connected with genes. (more…)
Aging, Author Interviews, Genetic Research, Smoking, UCLA / 11.09.2015

Dr. Morgan Elyse Levine PhD Postdoctoral Fellow Department of Human Genetics University of California, Los Angeles MedicalResearch.com Interview with: Dr. Morgan Elyse Levine PhD Postdoctoral Fellow Department of Human Genetics University of California, Los Angeles Medical Research: What is the background for this study? What are the main findings? Dr. Levine: Studies using mice, worms, and flies have suggested that longevity may be linked to stress resistance. All of us are constantly encountering things that damage our cells and tissue and disrupt physiological functioning. Therefore, people who are genetically predisposed to better prevent or repair this damage may age slower. Smoking is one of the most damaging things someone can do to their health, yet some smokers are able to survive to extreme ages. This study looked at long-lived smokers to see if we could identify a "genetic signature". We generated a genetic risk score that was found to be associated with longevity both in smokers and non-smokers, and also appeared to be associated with cancer risk. (more…)
Author Interviews, Breast Cancer, Genetic Research, UCSF / 04.09.2015

Dr. Elisa Long PhD Assistant professor UCLA Anderson School of ManagementMedicalResearch.com Interview with: Dr. Elisa Long PhD Assistant professor UCLA Anderson School of Management Medical Research: What is the background for this study? What are the main findings? Dr. Long: The study was motivated by my own diagnosis of triple-negative breast cancer last year, at the age of 33. I also learned that I carried a BRCA1 mutation, despite no family history. As a patient, I would have benefitted tremendously from a universal BRCA screening program, but as a health services researcher, I had to ask if indiscriminate screening of all women in the U.S.—where only 1 in 400 carry a mutation—is a good use of resources. Using a previously published decision analytic model, we calculated the cost-effectiveness of universal BRCA screening. We find that compared to screening based on family history, it is not cost-effective, assuming a test price of $2,000 to $4,000. However, as the price of genetic testing continues to fall, as indicated by the $249 test now offered by Color Genomics, universal BRCA screening becomes much more affordable. Additionally, population screening of Ashkenazi Jewish women—among whom 1 in 50 carry a BRCA mutation—is very cost-effective, because the chances of finding a carrier are much higher. (more…)
Author Interviews, Chemotherapy, Genetic Research, Melanoma / 04.09.2015

Rutao Cui M. D., Ph. D. Vice Chair, Professor, Department of Pharmacology and Experimental Therapeutic Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center Director The Laboratory of Skin Cancer Therapeutics (LSCT) Boston UniversityMedicalResearch.com Interview with: Rutao Cui M. D., Ph. D.  Vice Chair, Professor Department of Pharmacology and Experimental Therapeutic Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center Director The Laboratory of Skin Cancer Therapeutics (LSCT) Boston University Medical Research: What is the background for this study? What are the main findings? Dr. Cui: Recent studies have revealed that the APC/CCdh1 E3 ubiquitin ligase may function as a tumor suppressor. However, the tumor suppressor role of APC/CCdh1 in melanoma remains largely unclear. Here, we report sporadic mutations occurring in APC components, including Cdh1 in human melanoma samples and that loss of APC/CCdh1 may predispose human melanomagenesis. (more…)
Author Interviews, Genetic Research, Pediatrics, Psychological Science / 02.09.2015

Beate W. Hygen PhD Student Department of Psychology Norwegian University of Science and Technology Social ScienceMedicalResearch.com Interview with: Beate W. Hygen PhD Student Department of Psychology Norwegian University of Science and Technology Social Science Medical Research: What is the background for this study? Response: The study is part of the Trondheim Early Secure Study (TESS) conducted at the  Department of Psychology, Norwegian University of Science and Technology (NTNU) and NTNU Social Science. The main aim of TESS is to detect risk and protective factors with regards to children’s mental health and well-being.  TESS examines multiple factors which may play a role in children`s development. There is substantial research, based on diathesis-stress theorizing, indicating that some individuals, including children, are more susceptible to the negative effects of contextual adversity than are others. However, according to differential susceptibility theory, such "vulnerable" individuals may also be the ones that benefit the most from positive environmental conditions. Thus, some individuals are more malleable for "better and for worse" to environmental exposures. The article Child exposure to serious life events, COMT, and aggression: Testing differential susceptibility theory was designed to examine if the COMT polymorphism moderated the effect of early-life adversity on aggressive behavior. Thus, we sought to competitively evaluate which model of person X environment interaction best accounted for the anticipated differential effects of life event stress on children's aggressive behavior. (more…)
Author Interviews, Cancer Research, Genetic Research / 02.09.2015

Sameek Roychowdhury, MD, PhD Assistant Professor, Internal Medicine, College of Medicine Assistant Professor, Department of Pharmacology, College of Pharmacy Department of Internal Medicine Division of Medical Oncology Wexner Medical Center The Ohio State UniversityMedicalResearch.com Interview with: Sameek Roychowdhury, MD, PhD Assistant Professor, Internal Medicine, College of Medicine Assistant Professor, Department of Pharmacology College of Pharmacy Department of Internal Medicine Division of Medical Oncology Wexner Medical Center The Ohio State University Medical Research: What is the background for this study? What are the main findings? Dr. Roychowdhury: Precision cancer medicine is a new paradigm to match patients to therapies based on the molecular alterations in their cancer. Novel genomic testing of cancer using next generation sequencing can reveal numerous mutations for each patient across many genes and types of cancer, and this requires detailed time-intensive interpretation. Driver mutations can confer a selective growth or survival advantage to cancer cells, while passenger mutations do not. Cancer Driver Log, or CanDL, is meant to aid interpretation of mutations by providing the latest literature evidence for individual driver mutations, and thereby aiding pathologists, lab directors, and oncologists in interpreting mutations found in their patient’s cancer. (more…)
Author Interviews, Brain Cancer - Brain Tumors, Genetic Research / 02.09.2015

Roger Packer MD Senior Vice President Center for Neuroscience & Behavioral Health Children's National Medical Center Washington, D.C. Medicalresearch.com Interview with: Roger Packer MD Senior Vice President Center for Neuroscience & Behavioral Health Children's National Medical Center Washington, D.C.   MedicalResearch: What is the background for this study? What are the main findings? Dr. Packer: The background is that medulloblastoma is the most common childhood malignant brain tumor. It carries with it a variable prognosis. For some subsets of patients, with current available treatment which includes surgery, radiation and chemotherapy, we see survival rates as high as 90% (and often cures) 5 years following diagnosis and treatment. However, for some subsets of patients, survival rates are much poorer, in those with higher risk characteristics as low as 40% at 5 years. Current treatment also carries with it a significant risk for long term sequelae, including intellectual loss secondary to radiation therapy and persistent, at times devastating neurologic complications such as unsteadiness. To try to improve our understanding and ultimately our therapy for medulloblastoma, an international working group has shared patient specimens and patient information to attempt to determine what the molecular predictors of outcome are for children with medulloblastoma and if such molecular genetic findings can be used to develop better, safer therapies. Children’s National is part of this international collective of institutions, which published this and other studies. The main findings of this study are that complex, integrated genetic analysis of tumor specimens can be used to better understand and set the scene for better treatment of medulloblastoma.  Medulloblastoma can be broken into relatively distinct, molecular subtypes each with its own prognosis and potential therapy. A major finding of this study was that within a given tumor, different areas showed the same molecular genetic pattern. The importance of this is that since the tumors are relatively the same in different areas, molecularly-targeted therapies have an excellent chance of working on the entire tumor, resulting in better tumor control and safer treatments. (more…)