Author Interviews, Genetic Research, NYU, PLoS / 08.08.2015

Dr. Arthur Caplan Ph.D. Drs. William F and Virginia Connolly Mitty Professor Head of the Division of Medical Ethics New York University, Langone Medical Center, NYMedicalResearch.com Interview with: Dr. Arthur Caplan Ph.D. Drs. William F and Virginia Connolly Mitty Professor Head of the Division of Medical Ethics New York University, Langone Medical Center, NY Medical Research: What is the background of the Down Syndrome Prenatal Education Act? Dr. Caplan: For many years women who  receive a positive prenatal test for Down syndrome have been aborting their pregnancies.  Rates of pregnancy termination, while somewhat disputed, are very high.  In the USA, UK and Denmark they have consistently been over 80% for many years.   This has led some parents of children with Down to wonder if the counseling that women receive is biased negatively against a life with Down. They working with pro life legislators in many states have promoted legislation to insure that mothers carrying an infant with a diagnosis of Down Syndrome have access to positive information and helpful resources about life with a child with Down.  This legislation has been enacted in many states and there is a Federal law as well. Medical Research: How does Chloe's Law impact genetic testing? Dr. Caplan: These laws represent a seismic shift in counseling about genetic disorders and diseases.  Historically counselors aspired to be value-free—simply trying to provide objective information to their patients/clients.  With laws like Chloe’s the public is saying they do not trust the neutrality of counselors and counseling and want more positive messages sent about Down.  This is quite simply an ethical revolution in how counseling for Down will be done in the future.  It is also a direct Challenge to the legitimacy of value-neutrality as a counseling norm that certainly will be extended to other conditions and disabilities where abortion rates are high and where there is the belief that there is unjustified prejudice or bias against disabilities among those working in clinical genetics. (more…)
Author Interviews, Cancer Research, Genetic Research / 02.08.2015

Christos Nikolaidis Ph.D. Laboratory of Pharmacology Medical School, Democritus University of Thrace Dragana, Alexandroupolis GreeceMedicalResearch.com Interview with: Christos Nikolaidis Ph.D. Laboratory of Pharmacology Medical School, Democritus University of Thrace Dragana, Alexandroupolis Greece Medical Research: What is the background for this study? Response: Epigenetic changes are part of the natural history of cervical neoplasia. Tracking these changes at the molecular level is necessary for understanding disease progression, response to treatment and prognosis. Epigenetic biomarkers can potentially assess the stage of cervical intraepithelial neoplasia (CIN). This information can be used for screening purposes, to improve the overall quality of cervical cancer diagnostics. Medical Research: What are the main findings? Response: Paired boxed 1 (PAX1) gene methylation status has been widely used as a biomarker for cervical cancer screening.  We have conducted a meta-analysis of the diagnostic test accuracy of PAX1 methylation, on moderate cervical dysplasia or worse (CIN2+) versus normal epithelium, and severe cervical dysplasia or worse (CIN3+) versus normal epithelium, for a total population of 1385 women. The results of this assay were generally satisfactory for CIN2+ vs normal, and extremely satisfactory for CIN3+ vs normal (Sensitivity=0.77, Specificity=0.92, AUC=0.931). This raises the possibility of utilizing this biomarker to improve current diagnostic protocols. (more…)
Author Interviews, Genetic Research / 01.08.2015

Dr. Rosalind Arden Centre for Philosophy of Natural & Social Science London School of Economics LondonMedicalResearch.com Interview with: Dr. Rosalind Arden Centre for Philosophy of Natural & Social Science London School of Economics London MedicalResearch: What is the background for this study? What are the main findings? Dr. Arden: We've known for a while that people who score higher on IQ-type tests tend to live longer. A study published in the British Medical Journal (Whalley & Deary, 2001) examined intelligence in childhood and later survival. People born in Scotland in 1921 took an IQ-type test at age 11 in 1932. Those with higher test scores were more likely to survive to age 76. What we haven't known is 'why?' One possibility is that advantages from being raised in a wealthier family may enhance intelligence and health - leading to brighter people living longer. Another possibility is that many genes that influence brains also influence bodies. If well-built brains co-occur with well-built bodies, that could also explain the link. These are only two of several possible explanations. We aimed to test whether genes caused the link between intelligence and life-expectancy. We found 1) the link between intelligence and life expectancy is positive but small. 2) The cause of the link is almost all genetic. We found this by examining differences within twin pairs. Twins offer a quasi-natural experiment because they share many features of the environment that are often thought (mistakenly) to cause differences between people. And marvelously, for science there are two kinds of twins, with known genetic relatedness (100 % or 50%). This give us a means to test questions about the cause of differences in a population, as well as the causes of correlations among traits within a population. (more…)
Author Interviews, Genetic Research, Heart Disease, PNAS, Rheumatology / 27.07.2015

MedicalResearch.com Interview with: Philippe Bouillet, PhD Walter and Eliza Hall Institute Parkville, Vic Australia Medical Research: What is the background for this study? What are the main findings? Dr. Bouillet: This study was initiated when we discovered mice that developed rheumatoid arthritis as a result of what was obviously a spontaneous dominant genetic mutation. Using several approaches, we identified the mutation as the insertion of a mobile genetic element called retrotransposon into the regulatory sequences of the gene encoding tumor necrosis factor (TNF). The mutation caused excessive amounts of TNF to be produced, a known cause of rheumatoid arthritis. The surprise came when some mice with the mutation died prematurely and suddenly with from heart disease. We showed that excess TNF also led to inflammation of the aortic and mitral valves, causing aortic regurgitation. Depending on the genetic background of the mice, the disease could also culminate in aortic aneurysm and death. We also investigated the regulatory region of the TNF gene and identified novel regulators and a new genetic element that normally make sure that levels of serum TNF are kept within reasonable limits, high enough to ensure its numerous physiological functions, low enough to prevent its harmful effects such as those described here. (more…)
Author Interviews, Cancer Research, Genetic Research, MD Anderson / 24.07.2015

Eduardo Vilar-Sanchez, MD, PhD Assistant Professor, Department of Clinical Cancer Prevention Division of OVP, Cancer Prevention and Population Science The University of Texas MD Anderson Cancer Center Houston, TX 77030MedicalResearch.com Interview with: Eduardo Vilar-Sanchez, MD, PhD Assistant Professor, Department of Clinical Cancer Prevention Division of OVP, Cancer Prevention and Population Science The University of Texas MD Anderson Cancer Center Houston, TX 77030 Medical Research: What is the background for this study? What are the main findings? Dr. Vilar-Sanchez: I am a physician scientist at The University of Texas MD Anderson Cancer Center (MDA), a medical oncologist specializing in cancer genetics, especially colorectal cancer (CRC) syndromes. At MD Anderson, I have medical practice consisting primarily of colorectal cancer, as part of the clinical cancer arm of MD Anderson. I became interested in this topic because it is now well recognized that colorectal cancer is increasing in prevalence in young individuals. CRC is the third most common cancer in the US with 90% diagnosed in patients older than 50. While most CRC patients develop cancer in their 60s or 70s, the incidence is now rising in individuals younger than 50. Over the next two decades, it is projected that the incidence of CRC in young adults under 35 will double. Only 5% of all CRC patients have a known hereditary predisposition cancer syndrome. Patients diagnosed at or under age 35 represent an extreme phenotypic presentation, constituting only 1.5% of all CRC cases. We retrospectively reviewed all patients with CRC patients age 35 or under, who were evaluated by the Genetic Services group at MD Anderson. In this group, a surprising 30% had a recognized hereditary cancer syndrome, a marked increase compared to the general CRC population. (more…)
Author Interviews, Genetic Research, Heart Disease / 24.07.2015

MedicalResearch.com Interview with: Dr. Paraskevi Christofidou Department of Cardiovascular Sciences, University of Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester UK MedicalResearch: What is the background for this study? Dr. Christofidou: Homozygosity arises when identical alleles are present on both chromosomes. Runs of homozygosity (ROHs) are very long segments of uninterrupted sequences of homozygous variants across the human genome. Runs of homozygosity represent "re-union" of pieces from DNA from parents in their children. The two DNA copies are identical because have been inherited from a common ancestor somewhere in the distant past. Runs of homozygosity are recognized signature of recessive inheritance, because they allow unmasking of recessive variants. Recessive variants only show their effect when present on both chromosomes of an individual's genome. Some of these ROHs may potentially harbor variants that exert their pathological effects in the homozygous recessive state. This is important because it helps us better understand the consequences of the recessive model of inheritance in relation to complex diseases. Coronary artery disease (CAD) is a terminal clinical manifestation of cardiovascular disease and is the leading cause of death worldwide and is the UK's single biggest killer. Nearly one in six men and one in ten women die from CAD. Coronary artery disease is a complex, multifactorial disorder originating from a complicated interplay of multiple genetic and environmental factors. Contributions of ROHs to the genetic architecture of CAD are not known. The primary goal of this project was a comprehensive analysis of association between genome-wide homozygosity measures and CAD in individuals of white European ancestry. A secondary aim was to explore the association of ROHs and gene expression in human monocytes and macrophages. MedicalResearch: What are the main findings? Dr. Christofidou: Our analysis of 24,320 individuals from 11 populations of white European ethnicity revealed statistically significant differences in homozygosity levels between individuals with Coronary artery disease and control subjects. On average, individuals with CAD had 0.63 ROHs more than control subjects. The average total length of ROHs was approximately 1046.92 kb greater in individuals with CAD than control subjects. We were able to qualify a measure of genome-wide homozygosity levels in relation to CAD - an estimated 13% increase in CAD per 1 standard deviation increase in the proportion of the autosomal genome covered by ROHs. Individual ROHs showed significant associations with monocyte and macrophage expression of genes located nearby. These associations suggest that many ROHs might be signatures of biologically active recessive variants with a potential to regulate transcription. (more…)
Author Interviews, Connective Tissue Disease, Genetic Research, Rheumatology / 20.07.2015

MedicalResearch.com Interview with: Dr. Changfu Kuo MD PhD Division of Rheumatology, Orthopaedics, and Dermatology School of Medicine, University of Nottingham, Nottingham, England Division of Rheumatology, Allergy, and Immunology Chang Gung Memorial Hospital, Taoyuan, Taiwan Medical Research: What is the background for this study? What are the main findings? Dr. Kuo: Systemic lupus erythematosus (SLE) is a prototype of autoimmune disease with features like autoantibody production and multiple target organ damage. SLE can affect any part of the body and the course of the disease is highly diverse and unpredictable. SLE can occur at any age and affect both females and males with a sex ratio of 9 to 1. Familial predisposition has been recognised as a risk factor previously and heritability of SLE has been estimated to be 66%. However, previous reports are often based on less robust sampling strategies and case ascertainment which generally depend on hospital records, self-reported diagnosis and disease registries, therefore limiting generalisability. The previous estimates of heritability are overestimated, due to a lack of consideration of shared environmental contribution. This study utilised a unique health insurance database that provides information on the whole population of Taiwan and permits determination of spouse and first-degree relatives. Over 23 million people were included in this study. Furthermore, through inclusion of SLE status of the spouse in our analyses the study is also able to examine how much of familial clustering results from genetic versus shared environmental factors. Overall the familial relative risk is 16.92. The genetic contribution to SLE susceptibility is estimated to be 44%. In addition to SLE, other autoimmune diseases are also more prevalent in individuals with a family history of SLE. (more…)
Author Interviews, Genetic Research, Heart Disease, McGill / 20.07.2015

Christopher Labos MD CM, MSc FRCPC Division of Epidemiology, Biostatistics and Occupational Health McGill University Montreal, Quebec CanadaMedicalResearch.com Interview with: Christopher Labos MD CM, MSc FRCPC Division of Epidemiology, Biostatistics and Occupational Health McGill University Montreal, Quebec Canada Medical Research: What is the background for this study? What are the main findings? Response: There have been great advances in the field of genetics in recent years. Especially in cardiology, a number of genetic variants have been identified that are associated with cardiovascular disease. But it is not clear how useful these variants are in terms of predicting future evens in patients that have already suffered a myocardial infarction. What we found in our study is that a genetic risk score composed of the 30 most common genetic variants associated with cardiovascular diseases was not useful in predicting recurrent events in the first year after a patient suffered a myocardial infarction. (more…)
Author Interviews, Genetic Research, Ophthalmology / 17.07.2015

Professor Robert E MacLaren MB ChB DPhil FRCOphth FRCS Nuffield Laboratory of Ophthalmology Nuffield Department of Clinical Neurosciences, University of Oxford Oxford Biomedical Research Centre, University of Oxford, Oxford, UK Moorfields Eye Hospital & UCL NIHR Biomedical Research Centre for Ophthalmology London, UK.MedicalResearch.com Interview with: Professor Robert E MacLaren MB ChB DPhil FRCOphth FRCS Nuffield Laboratory of Ophthalmology Nuffield Department of Clinical Neurosciences Oxford Biomedical Research Centre, University of Oxford, Moorfields Eye Hospital & UCL NIHR Biomedical Research Centre for Ophthalmology London, UK.
Medical Research: What is the background for this study? What are the main findings? Prof. MacLaren: The study shows that gene therapy can be used to release a protein in the eye that arrests the development of retinitis pigmentosa, a blinding disease caused by degeneration of the retina. The study was performed in mice which had a similar genetic defect to that found in humans with the disease. The mice also had fluorescent green “glow in the dark” light sensing cells known as cones, which we could see and count by looking into the eye – like counting stars in the night sky. By counting the green fluorescent cones we were able to work out the exact dose of gene therapy needed to keep these cells alive indefinitely. The study was funded by Fight for Sight, a UK charity that supports finding cures for eye diseases. (more…)
Author Interviews, Fertility, Genetic Research, Science / 17.07.2015

Stephen A. Krawetz, Ph.D. Associate Director C.S. Mott Center for Human Growth and Development, Charlotte B. Failing Professor of Fetal Therapy and Diagnosis, Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201MedicalResearch.com Interview with: Stephen A. Krawetz, Ph.D. Associate Director C.S. Mott Center for Human Growth and Development, Charlotte B. Failing Professor of Fetal Therapy and Diagnosis, Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201 Medical Research: What is the background for this study? What are the main findings? Dr. Krawetz: The current study developed over approximately the past 20 years of work in my laboratory.  In the mid 1990s, along with David Miller, we independently discovered that sperm contain RNA.  This was followed by our joint publication in The Lancet that began to describe the RNAs in normal fertile males along with our paper in Nature that showed that RNA was delivered to the oocyte at fertilization.  Following these studies we assessed the ability of RNAs to be used as markers of morphologically abnormal sperm (teratozoospermia).  My laboratory then had the opportunity to explore the complexity of the population of sperm RNAs using Next Generation Sequencing.   We recently began the translation of this work from the bench to bedside which takes us to the current paper in Science Translational Medicine that was a multi-institutional collaborative effort.  Members of the team include Dr. Meritxell Jodar, Edward Sendler, Robert Goodrich, from my laboratory, along with Dr. Clifford L. Librach, Dr. Sergey I. Moskovtsev, and Sonja Swanson - CReATe Fertility Center, University of Toronto; Dr. Russ Hauser -Harvard University and Dr. Michael P. Diamond, Georgia Regents University. Here we tackled the issue of idiopathic infertility, that is, unknown infertility, since the couple appears normal in all respects.  We specifically framed our study as the contribution of the male and female as a couple towards the birth of a healthy child focusing on male idiopathic infertility within the setting of a Reproductive Clinic.  Representative publications from my laboratory that outline this part of my research program appear below. 1)            Jodar, M., Sendler, E., Moskovtsev, S. Librach, C., Goodrich, R., Swanson, S., Hauser, R., Diamond, M. and Krawetz, S.A. (2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Science Translational Medicine, 7(295):295re6. 2)            Sendler, E., Johnson, G.D., Mao, S., Goodrich, R.J., Diamond, M.P., Hauser, R., and Krawetz, S.A. (2013) Stability, Delivery and Functions of Human Sperm RNAs at Fertilization.  Nucleic Acids Research 41:4104-4117. PMID: 23471003 3)            Platts, A.E., Dix, D. J., Chemes, H.E., Thompson, K.E., Goodrich, R., Rockett, J. C., Rawe, V.Y., Quintana, S., Diamond, M.P., Strader, L.F. and Krawetz, S.A. (2007)  Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs.  Human Molecular Genetics. 16:763-773.  PMID: 17327269 4)            Ostermeier, G.C., Miller, D., Huntriss, J.D., Diamond, M.P. and Krawetz, S.A. (2004) Delivering spermatozoan RNA to the oocyte.  Nature 429:154.  PMID: 15141202 5)            Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. and Krawetz, S.A. (2002) Spermatozoal RNA profiles of normal fertile men. The Lancet. 360:773-777.  PMID: 12241836 (more…)
Author Interviews, Genetic Research, Surgical Research, Yale / 17.07.2015

John A. Elefteriades, MD William W.L. Glenn Professor of Surgery Chief of Cardiothoracic Surgery Director, Aortic Institute at Yale-New Haven Yale University School of MedicineMedicalResearch.com Interview with: John A. Elefteriades, MD William W.L. Glenn Professor of Surgery Chief of Cardiothoracic Surgery Director, Aortic Institute at Yale-New Haven Yale University School of Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Elefteriades: The race to map the human genome was declared completed in 2003, at a cost of 3 billion dollars for the international collaborative university group and 300 million dollars for Craig Venter at Celera. Whole exome sequencing can now be performed at a cost of only several thousand dollars per individual. So, whole exome sequencing (also called Next Generation Sequencing) can now be applied to understand and treat diseases of many organ systems. In this study, we applied whole exome sequencing to study over 100 patients with thoracic aneurysm. In the late 1990s, both Dr. Diana Milewicz in Texas and our group at Yale had determined that many thoracic aortic aneurysms were genetically transmitted. Dr. Milewicz went on to identify many of the causative mutations. In this study, we were able to look, by whole exome sequencing performed on saliva, for all 21 mutations known to cause thoracic aortic aneurysm--all at one time in one comprehensive genetic test. We were able to protect patients with the most serious discovered mutations by early surgery, the need for which could not otherwise have been apparent.  (more…)
Author Interviews, Genetic Research / 13.07.2015

MedicalResearch.com Interview with: Chun Chieh Fan Ph.D student USCD Cognitive Science and Professor Anders M. Dale Ph.D Department of Cognitive Science, Multimodal Imaging Laboratory, Department of Radiology University of California, San Diego School of Medicine La Jolla, CA 92037 Medical Research: What is the background for this study? What are the main findings? Response: The shape of human skull is closely associated with the ancestral background. Forensics uses it for determining ethnicity. Anthropologists use it to infer neuroanatomical change in human evolution. Yet it is unclear the inner content of skull, human brain, contains how much information about individual’s ancestry. Our study found that different continental ancestries are associated with unique cortical folding patterns. Even for contemporary populations in modern day USA, a melting pot of ethnicities, cortical folding patterns are highly predictive of the percentage of each continental ancestry, as determined based on the person’s genotype. These shape differences between ancestral heritages are not necessarily related to brain function. It is highly possible that the shape differences are resulting from a random process accumulated along human history, without significant functional consequences. (more…)
Author Interviews, Cancer Research, Genetic Research, JAMA / 08.07.2015

Aung Ko Win, MBBS MPH PhD Research Fellow NHMRC Early Career Clinical Research Fellow Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne VIC 3010 AustraliaMedicalResearch.com Interview with: Aung Ko Win, MBBS MPH PhD Research Fellow NHMRC Early Career Clinical Research Fellow Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne VIC 3010 Australia Medical Research: What is the background for this study? What are the main findings? Response: About 2-5% of uterine cancer are associated with an underlying genetic condition mainly Lynch syndrome. Lynch syndrome is caused by a mutation in one of the mismatch repair genes. At least 1 in 1000 people in the population have a mutation that causes Lynch syndrome and these people have a very high risk of cancers mainly bowel and uterine cancers. One in three women with a mutation in one of the mismatch repair genes are likely to develop a uterine cancer in their lifetime. The only way to reduce the risk of uterine cancer for these women is to remove the uterus. There is no current recommendation for screening method to detect uterine cancer early. Almost nothing is known about if and how lifestyle factors and hormonal factors can modify their risk of uterine cancer. By studying 1128 women with a mutation that causes Lynch syndrome who were recruited from Australia, New Zealand, Canada and the USA, we found that later age at first menstrual cycle, having one or more live births, and using hormonal contraceptive use for one year or longer were associated with a lower risk of uterine cancer. (more…)
Author Interviews, Breast Cancer, Duke, Genetic Research, JAMA / 11.06.2015

Michaela Dinan, Ph.D. Duke Clinical Research Institute and Duke Cancer Institute Department of Medicine Duke University School of Medicine Durham, North CarolinaMedicalResearch.com Interview with: Michaela Dinan, Ph.D. Duke Clinical Research Institute and Duke Cancer Institute Department of Medicine Duke University School of Medicine Durham, North Carolina Medical Research: What is the background for this study? What are the main findings? Response: I think it will be critical to further explore the implications of Oncotype DX breast cancer assay (ODX testing) in women with breast cancer.  The ODX test helps predict which cancers will be more aggressive as well as guide recommendations as to which patients would most likely benefit from chemotherapy. I think we should look to see what impact this test is really having on the use of chemotherapy and its associated costs and outcomes for real-world breast cancer patients. (more…)
Author Interviews, Colon Cancer, Genetic Research, JAMA, Johns Hopkins / 05.06.2015

MedicalResearch.com Interview with: Timothy Michael Pawlik, M.D., M.P.H., Ph.D. Chief, Division of Surgical Oncology Professor of Surgery John HopkinsMedicalResearch.com Interview with: Timothy Michael Pawlik, M.D., M.P.H., Ph.D. Chief, Division of Surgical Oncology Professor of Surgery John Hopkins Medical Research: What is the background for this study? Dr. Pawlik: The prognosis of patients operated on for colorectal liver metastasis (CRLM) is currently defined by various “traditional” clinicopathologic factors. However the insight that they provide is incomplete. KRAS is the most common oncogene of the RAS family and is reported in up to 30 to 40% of patients with colorectal liver metastasis. As a result, KRAS mutational status  recently attracted a lot of attention as a potential prognostic factor in colorectal liver metastasis. However, overall mutant KRAS status (compared to wild type) correlated with worse survival only in some studies. We hypothesized that the specific KRAS activating mutations (codon 12 and codon 13) confer different biologic behaviors to the tumor and in turn, account for different (if any) prognostic values. The different proportions of each KRAS specific mutation could determine whether the overall mutational status would be associated with worse survival. In our view, the different proportions of specific mutations in various cohorts could account for the variability of the outcomes in different studies. Medical Research: What are the main findings? Dr. Pawlik: Our results showed that only codon 12 KRAS mutations conferred a worse prognosis whereas codon 13 ones did not. Furthermore, we examined the different point mutations that constitute codon 12 mutations and we found that among G12A, G12D, G12V, G12C and G12S KRAS point mutations, only G12V and G12S were independent prognostic factors of worse survival. That confirmed our hypothesis that only some of the point mutations do have a significant prognostic role and that the relative incidence of those mutations could determine if overall KRAS mutational status would be associated with worse survival in a certain cohort. (more…)
Author Interviews, Fertility, Genetic Research, NEJM, University of Pittsburgh / 04.06.2015

Alexander N Yatsenko, MD, PhD Assistant Professor, Department of OBGYN and Reproductive Science, Magee-Womens Research Institute, University of Pittsburgh, PA  Pittsburgh, PA 15213MedicalResearch.com Interview with: Alexander N Yatsenko, MD, PhD Assistant Professor, Department of OBGYN and Reproductive Science, Magee-Womens Research Institute, University of Pittsburgh, PA Pittsburgh, PA 15213 Medical Research: What is the background for this study? What are the main findings? Dr. Yatsenko: The known causes of male infertility not due to physical obstruction are usually because of sex-chromosome defects, such as deletions of the Y chromosome or duplication of the entire X chromosome in Klinefelter syndrome. Eight times out of 10, conventional genetic testing doesn’t reveal a chromosomal problem and infertility is considered idiopathic. We wanted to try to find other genetic reasons for the problem. We found a deletion in part of the DNA coding of the testis-expressed gene 11 (TEX11) on the X-chromosome, which men inherit from their mothers. The alteration caused meiotic arrest, meaning the precursor cells could not properly undergo meiosis. We also found similar TEX11 gene mutations and meiotic arrest in two out of 49 men diagnosed with idiopathic azoospermia in Pittsburgh or at a Poland infertility clinic, and in five out of 240 infertile men assessed at a collaborating Andrology clinic in Muenster, Germany. These genetic findings were confirmed on protein level using patients’ testis biopsies. (more…)
ASCO, Author Interviews, Cancer Research, Chemotherapy, Genetic Research / 03.06.2015

MedicalResearch.com spoke with Dr. Jonathan Lancaster, MD, Ph.D. at the 2015 ASCO meeting in Chicago.  Dr. Lancaster is the new Vice President of Medical Affairs for Oncology, Myriad Genetic Laboratories, at Myriad. Dr. Lancaster jointed Myriad in February 2015 after twelve years at the Moffitt Cancer Center. Prior to Moffitt, Dr. Lancaster was medical director of the Gynecologic Dysplasia Clinic at Duke University Medical Center in Durham, NC, where he also completed his residency and fellowship training.MedicalResearch.com spoke with Dr. Johnathan Lancaster, MD, Ph.D. at the 2015 ASCO meeting in Chicago. Dr. Lancaster is the new Vice President of Medical Affairs for Oncology, Myriad Genetic Laboratories, at Myriad. Dr. Lancaster jointed Myriad in February 2015 after twelve years at the Moffitt Cancer Center. Prior to Moffitt, Dr. Lancaster was medical director of the Gynecologic Dysplasia Clinic at Duke University Medical Center in Durham, NC, where he also completed his residency and fellowship training. MedicalResearch.com: Can you tell us a little more about your background? How did you come to work at Myriad? Dr. Lancaster: My background and interests lie at the intersection of patient care and the molecular and genetic understanding of cancer. I completed my MD and Ph.D. in molecular genetics at the University of Wales, and then came to Duke for a research fellowship and residency training in Obstetrics & Gynecology. I spent twelve years as a gynecology-oncology surgeon. At the Moffitt Cancer Center, I ran a research lab attempting to understand the molecular and genetic underpinnings of ovarian cancer development and progression. Our translation research attempted to identify markers, or microRNAs, that help predict ovarian tumors’ response to chemotherapeutic agents. I also have experience in the management and financial issues facing medicine and health care. While at Moffitt, I was president of the 350-member Moffitt Medical Group, deputy physician-in-chief and director of the Center for Women's Oncology. The opportunity at Myriad Genetics allows me to utilize my experience in all three interests, clinical care, research and management, to contribute to a broader mission of cancer treatment and prevention. MedicalResearch.com: What studies are being presented at ASCO this year by Myriad associated researchers? Dr. Lancaster: There are 19 abstracts presented by Myriad at ASCO 2015, which is a testament to the emphasis Myriad places on basic and translational research (Myriad reinvests $300-400 of the proceeds from every clinical test performed into research). The studies center around two main themes: 1: An enhanced panel of genes, called MyRisk, to test for increased risk of hereditary cancers. 2: The use of Homologous Recombination Deficiency (HRD) testing and score, called MyChoice, which helps clinicians determine which patients may respond best to some chemotherapeutic agents. MedicalResearch.com: What does the MyRisk panel offer over and above the information learned from BRAC1/2 testing? Why should a patient or clinician want this testing performed? Dr. Lancaster: The MyRisk panel tests for 25 state-of-the-art genes with the goal of determining who may be at increased risk for certain malignancies even if they are BRAC1/2 negative. The typical patient is one who has a family history of cancer but may have been told she doesn’t have the ‘breast cancer gene’ because she is BRAC1/2 negative. We now know that up to 50% of these patients may carry other genes that make them more susceptible to cancer. Panel testing allows clinicians to identify many more patients at risk for cancer who would have been missed with more traditional BRAC1/2 testing alone. (more…)
Author Interviews, Diabetes, Genetic Research, Lipids, PLoS / 31.05.2015

Dr. Yann C Klimentidis, PhD Assistant professor of Epidemiology and Biostatistics Mel and Enid Zuckerman College of Public Health University of Arizona Medical CenterMedicalResearch.com Interview with: Yann Klimentidis Ph.D. Assistant Professor Mel and Enid Zuckerman College of Public Health University of Arizona Medical Research: What is the background for this study? What are the main findings? Dr. Klimentidis: Previous studies have hinted at the possibility that genes which are associated with higher triglyceride levels may also be associated with lower type-2 diabetes. We set out  to test this hypothesis in multiple prospective cohort studies, in European-Americans and in African-Americans. We found that on a collective basis, the alleles which are associated with higher triglycerides are also associated with reduced type-2 diabetes risk. We also identified some individual genetic variants which are driving this trend. (more…)
Author Interviews, Genetic Research, JAMA / 26.05.2015

Prof. Alexandre Reymond Director, Center for Integrative Genomics University of Lausanne Lausanne SwitzerlandMedicalResearch.com Interview with : Prof. Alexandre Reymond Director, Center for Integrative Genomics University of Lausanne Lausanne Switzerland MedicalResearch : What is the background for this study? Prof. Reymond: Though a subset of recurrent DNA copy number variants (differing numbers of copies of genetic sequence at locations in the genome; CNVs) with rare population prevalence are known to have strong impact on carrier’s health, up to now their association with phenotypes such as intellectual disability has been almost exclusively evaluated in clinical context using individuals ascertained for diagnostics of developmental disorders. Thus the contribution of these genetic variants to health, cognition and life quality in the general population remains unclear. We used a population biobank, that of Estonia (Estonian Genome Center, University of Tartu), which contains samples from 52,000 adult participants (representative 5% of the country’s adult population), a British birth cohort (The Avon Longitudinal Study of Parents and Children; ALSPAC) and two more population-based cohorts from the USA and Italy to explore the consequences of CNVs in presumptively healthy populations. MedicalResearch : What are the main findings? Prof. Reymond: Rare recurrent CNVs known to be causative for specific syndromes (termed genomic disorders) have a global population prevalence of around 1%. Contrary to popular assumption that carriers of these syndromic CNVs identified in unselected, but assumed to be healthy, adult population cohorts are asymptomatic, we found that they are associated with unrecognized, but serious clinical sequelae. Additionally our results showed that individually rare (less than 1 in 2000 individuals) but collectively common (around 10% of population) intermediate-size CNVs are negatively associated with carriers’ educational attainment. Altogether our results suggest that the life quality of at least 1 of 40 people might be negatively affected by rare CNVs. (more…)
Author Interviews, Diabetes, Genetic Research, Weight Research / 22.05.2015

MedicalResearch.com interview Dorota Kaminska, MSc Department of Clinical Nutrition University of Eastern Finland MedicalResearch: What is the background for this study? What are the main findings? Response: The prevalence of obesity is increasing worldwide, making it one of the biggest health problems currently facing both developed and developing countries. Obesity is considered a primary risk factor for developing type 2 diabetes. While the majority of people with type 2 diabetes are obese, most of obese people do not develop diabetes, indicating that obesity is not the only risk factor for type 2 diabetes. Both obesity and type 2 diabetes are multifactorial complex diseases that are caused by a combination of genetic, environmental, and lifestyle factors. Results from twin studies suggest that genetic factors explain 50% to 90% of the variance in body mass index (BMI) and from 45% to 85% of the diabetes risk. However genetic variations identified by genome wide association studies (GWAS) explain only 2-4% of the obesity risk and 5-10% of the type 2 diabetes risk. Several options have been debated to be a source of so called “missing heritability”, including, among others, structural DNA variations, gene-gene and gene-environment interactions, epigenetic modifications and RNA splicing. We used adipose tissue samples from Kuopio Obesity Surgery (KOBS), very low calorie diet (VLCD), Metabolic Syndrome in Men (METSIM) and European Network on Functional Genomics of Type 2 Diabetes (EUGENE2) studies to determine alternative splicing pattern of selected genes. The study focused on determining the effects of obesity and weight loss on alternative splicing of metabolically active genes (TCF7L2 and INSR). We showed that alternative splicing of both genes is dysregulated in obesity and type 2 diabetes, resulting in impaired insulin action in adipose tissue. Additionally we demonstrated, that obesity induced changes in splicing can be reversed by weight loss induced by gastric bypass surgery or very low calorie diet. Furthermore, the study identified alternatively spliced genes in the genomic regions associated with obesity risk, demonstrating that splicing of the MSH5 gene in subcutaneous fat is regulated by weight loss. The study also found that body mass index is a main determinant of TRA2B, BAG6 and MSH5 splicing in subcutaneous fat; however, the functional consequences of this finding require further investigation. These findings imply that the obesity-associated gene variants might act through regulation of splicing which in turn might underlie the pathogenesis of obesity in individuals carrying the risk variants. (more…)
Author Interviews, Genetic Research, Psychological Science / 20.05.2015

Wendong Li, Ph.D. Assistant professor of psychological sciences Department of Psychological Sciences Kansas State University Manhattan, KSMedicalResearch.com Interview with: Wendong Li, Ph.D. Assistant professor of psychological sciences Department of Psychological Sciences Kansas State University Manhattan, KS Medical Research: What is the background for this study? What are the main findings? Dr. Wen-Dong Li: There has been a "nature versus nurture" debate in leadership: Are leaders born or made? In academia, research on trait theories of leadership has shown that important individual characteristics such as personality traits are predictive of whether one is a leader or not (leadership role occupancy or emergence). One author of this paper, Dr. Arvey conducted twin studies showing that about 30% of the individual differences in leadership is attributable to individual differences in their genetic makeup. But so far, little research has examined whether specific genes are involved and no research has examined the pathways linking genes to leadership. This is where this research came in. We found that a dopamine transporter gene, DAT1 was involved in genetic influences on leadership role occupancy, but through two opposing pathways. One pathway is through proactive personality: DAT1 10-repeat allele was negatively related to proactive personality, which in turn was positively associated with leadership role occupancy. The negative indirect effect was significant. On the other hand, DAT1 was positively related to (moderate) rule breaking, which was positively associated with leadership role occupancy. The overall relationship between DAT1 and leadership was not significant. Thus we call it a mixed blessing because the two opposing mechanisms offset each other. (more…)
Author Interviews, Genetic Research, Infections, Inflammation, Stanford / 15.05.2015

MedicalResearch.com Interview with: Timothy E Sweeney, MD PhD Resident, General Surgery Postdoc, Khatri Lab, Bioinformatics Stanford University Medical Research: What is the background for this study? What are the main findings? Dr. Sweeney: Sepsis is defined as the presence of systemic inflammation due to infection. Systemic inflammation can be caused from many things, such as trauma, surgery, thrombosis, autoimmunity, etc. It can also be caused by infection. On the other hand, infection does not necessarily cause systemic inflammation, either:  a person can get a minor infection, like strep throat, and not have a systemic response. It's the intersection of severe inflammation (a syndrome called SIRS) with infection that defines sepsis. In general surgery, we frequently see patients after traumatic injury or surgery who are having an inflammatory response (ie, fevers, fast heart rate, high white blood cell count, etc). But it's not clear whether this inflammatory response is a reaction to the trauma or surgery, or whether there might be an infection brewing that is causing the reaction. Identifying the inflammatory response doesn't require many special tests-- it's easy to spot. So we know which patients have inflammation and which do not. What is difficult is determining the root cause of the inflammation, and, in particular, whether there is an infection present that needs treatment with antibiotics. Current diagnostics for infection (not sepsis) are either slow (like blood cultures, which can take 24-72 hours to return) or not highly accurate (like procalcitonin). We sought to define a better test that could specifically differentiate between people with sterile inflammation, and people with inflammation due to infection (sepsis). By integrating gene expression data from multiple publicly available cohorts, we were able to find a set of 82 genes that are significantly differently expressed between these two groups. We then used an algorithm called a greedy forward search to find a subset of 11 genes that were most diagnostic for sepsis. (more…)
Author Interviews, Genetic Research, Karolinski Institute, Nature, Neurological Disorders / 11.05.2015

MedicalResearch.com Interview with: Kristina Bečanovič Ph.D. Department of Clinical Neuroscience Karolinska Institutet, Stockholm, Sweden Medical Research: What is the background for this study? Dr. Bečanović: While the symptoms normally debut in middle-age, there is wide individual variation in how Huntington disease manifests itself, and even though two people carry the exact same genetic mutation that codes for the huntingtin protein, there can be up to a 20-year difference in onset of motor symptoms. This suggests that genetic variants, transcription factors and environmental factors could contribute to the observed differences in disease expressivity. As the identification of regulatory factors of the huntingtin gene would be targets for therapeutic intervention, we set out to study the regulation of the huntingtin gene as it has not been well-known which factors regulate the expression levels. We were interested in identifying both genetic variants and transcription factors that are of importance for gene regulation. We therefore used DNA from Huntington disease patients to study the regulation of the huntingtin gene promoter in cells. (more…)
Author Interviews, Genetic Research / 09.05.2015

Rebecca Todd Ph.D. Assistant Professor University of British Columbia Department of Psychology Centre for Interactive Research on Sustainability Vancouver, BCMedicalResearch.com Interview with: Rebecca Todd Ph.D. Assistant Professor University of British Columbia Department of Psychology Centre for Interactive Research on Sustainability Vancouver, BC Medical Research: What is the background for this study? What are the main findings? Dr. Todd: This study brings together two lines of research. First, a couple of years ago my colleagues and I reported that in general people literally see emotional aspects of the world as more vivid - as if they burn more brightly on the eye - than mundane things. We call this effect emotionally enhanced vividness, or EEV. Here we wanted to look at how this phenomenon of emotionally enhanced vividness might differ between individuals. Second, in another previous study we found that people who carry a very common variation in the ADRA2b gene, which influences levels of norepinephrine (a neuromodulator in the brain that is important to the stress response and for emotional influences on memory) were more likely to have their attention captured by emotionally relevant aspects of the world. We also found that how arousing they perceived an event to be at the time it happened predicted how well they remembered it better than for people who did not carry this variation. Here we continued to examine what is unique to this group of people by testing to see if they showed higher levels of the other phenomenon we had found, emotionally enhanced vividness, and what patterns of brain activation would play a role. (more…)
Author Interviews, Genetic Research, Infections, Inflammation, NYU / 07.05.2015

Dr. Ludovic Desvignes. PhD. Assistant Professor, Departments of Medicine and Pathology NYU Langone Medical CenterMedicalResearch.com Interview Dr. Ludovic Desvignes PhD. Assistant Professor, Departments of Medicine and Pathology NYU Langone Medical Center MedicalResearch: What is the background for this study? Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center, between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and colleagues had developed a mouse model of rare, inherited mutations he had identified in infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for calcium flux in cells of the immune system. The young patients affected by these mutations suffer from severe, recurrent and chronic infections that often cause death before their first birthday. In particular, some of these patients cannot control infection with BCG, which is a normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB). TB is a chronic infection and one of the leading causes of infection-related death worldwide. Going into this study, Dr. Feske and colleagues knew that without functional calcium channels, immune cells do not function properly. However, they did not fully understand how these channels contribute to immune responses to infectious pathogens in a living organism and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst and I collaborated with Dr. Feske and provided him with our clinical and research expertise in TB. MedicalResearch: What are the main findings? Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of immune cells, known as T cells or T lymphocytes. We infected these mice with Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes chronic infection by manipulating the immune system even in healthy people. The first very surprising result of our study was that mice lacking calcium flux in T cells handled acute TB fairly well. Only during the chronic phase of infection did they become unable to control mycobacterial growth and developed a strong inflammation in their lungs, which was due to an infiltration by different types of immune cells, including T cells. We discovered that the accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die, which is a normal mechanism to limit an immune response and prevent excessive inflammation. Another immune control mechanism that failed in the absence of STIM1 is mediated by a subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to prevent normal immune responses from going “overboard” by suppressing the functions of other immune cells, including T cells. We found that calcium signals are required for the development of iTreg cells and that their numbers were strongly reduced in the lungs of infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence of STIM1 contributes to the severe lung inflammation in chronic TB. The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-deficient mice produced large amounts of a protein called interferon gamma. While interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and colleagues had previously observed that calcium fluxes promote the production of interferon gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective in the production of that protein. During chronic TB, however, calcium signaling turned out to be not only dispensable for the production of interferon gamma by T cells but it was actually required to limit its production and thus, to control inflammation. (more…)
Author Interviews, Breast Cancer, Case Western, Genetic Research / 07.05.2015

Ahmad M. Khalil, PhD Assistant professor, Department of Genetics and Genome Sciences Case Western Reserve University School of MedicineMedicalResearch.com Interview with: Ahmad M. Khalil, PhD Assistant professor, Department of Genetics and Genome Sciences Case Western Reserve University School of Medicine MedicalResearch: What is the background for this study? What are the main findings? Dr. Khalil: This study aimed to identify other genes that work synergistically with the oncogene HER2 in HER2positive (HER+) breast cancer. The gene HER2 is amplified in those patients, which results in excess activities that promote uncontrolled cell growth. There are drugs that target HER2 and diminish its activity. However, these drugs can work initially, but patients relapse; or sometimes, the drugs don't work at all in some patients. Thus, by identifying other genes that work synergistically with the HER2 gene, we now have more genes to target by various drugs or compounds to destroy the tumor. The challenge was how to identify the key genes that work synergistically with HER2, especially in human subjects. To that end, we used clinical samples from a clinical trial of a drug that is known to inhibit HER2 activity to identify those genes. To further refine our list, we used cell culture models of the disease to also inhibit HER2. By combining those data sets, we identified 44 protein-coding genes. Next, we wanted to make sure that those genes stand a third independent filter. For that part, we interrogated those 44 genes in HER2+ tumors vs matched normal tissues from The Cancer Genome Atlas database — a collection of hundreds of tumors and normal tissues. Of the 44 genes, 35 genes passed this third filter. By examining the known functions of those genes, we can deduce that those genes work cooperatively with HER2 to promote carcinogenesis. There are currently known drugs that target some of those genes. We will use these drugs in combination with a drug that target HER2 to determine if the combination works better at destroying the tumor entirely. Lastly, we found that a special type of genes that we previously discovered, called lincRNAs, could also affect the oncogenic activity of HER2. These lincRNAs can also be targeted with HER2 to eliminate the tumor. (more…)
Author Interviews, Genetic Research, NEJM, Ophthalmology / 05.05.2015

Professor James Bainbridge, MA, PhD, FRCOphthProfessor of Retinal Studies, UCL Institute of Ophthalmology NIHR Research Professor, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of OphthalmologyMedicalResearch.com Interview with: Professor James Bainbridge, MA, PhD, FRCOphth Professor of Retinal Studies, UCL Institute of Ophthalmology NIHR Research Professor, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of OphthalmologyConsultant Ophthalmologist, Moorfields Eye Hospital NHS Foundation Trust Medical Research: What is the background for this study? What are the main findings? Prof. Bainbridge : Leber Congenital Amaurosis (LCA) is one of the most common causes of inherited, untreatable blindness in children. There are at least 14 different types of Leber Congenital Amaurosis of which LCA Type 2 (LCA2), caused by defects in the gene RPE65, affects around one in 100,000 people worldwide. Evidence from animal studies support that LCA2 may be amenable to treatment with RPE65 gene replacement therapy. The main findings of this phase I/II clinical trial confirm our preliminary findings (published in NEJM, 2008) that gene therapy can improve night vision. Improvements peak within the first 12 months after treatment but then decline during the three-year follow-up period which is consistent with the published results and interim findings from other studies of RPE65 gene therapy. (more…)
Author Interviews, Genetic Research, PLoS / 02.05.2015

G. Mandela Fernández-Grandon PhDNatural Resources Institute,University of Greenwich,Chatham, United KingdomMedicalResearch.com Interview with: G. Mandela Fernández-Grandon PhD Natural Resources Institute, University of Greenwich, Chatham, United Kingdom Medical Research: What is the background for this study? Response: People often wonder why, when they are out with their friends or family, one person seems to get ravaged by mosquitoes but others come away relatively bite free. Mosquito bites can be a nuisance to many of us but they are no trivial matter. Mosquitoes are one of the most serious threats to public health through the transmission of diseases such as malaria, dengue fever, yellow fever, chikungunya and others. We knew that mosquitoes rely on odour to find their hosts but until now the link between our body odour and genes had only been shown using human sniffers1. In a strictly controlled laboratory environment, we were able to present the odours of individuals in identical and non-identical twin pairs to mosquitoes allowing them following the odour stream of whichever they found to be more attractive. Medical Research: What are the main findings? Response: Mosquitoes are equally attracted to identical twins in a pair but with non-identical twins they display a preference for one individual. The ability of mosquitoes to distinguish non-identical twins but not identical twins suggests a genetic basis for our odour profile, a genetic difference which plays a role in whether we get bitten more or less than others. (more…)