Author Interviews, Biomarkers, Breast Cancer, Genetic Research, Yale / 29.03.2017

MedicalResearch.com Interview with: Tara Sanft, MD Assistant Professor of Medicine (Medical Oncology) Medical Director of Adult Survivorship Yale Cancer Center Survivorship Clinic  MedicalResearch.com: What is the background for this study? Response: Previous studies have demonstrated the benefit of extended endocrine therapy (EET) for hormone receptor-positive (HR+) breast cancer in preventing late relapse, however that benefit is limited to 3-5% of women where late recurrence was prevented or staved off. However, EET has become common practice and as a result we are exposing many patients to risks of side effects and toxicities associated with anti-estrogen therapies when they may not be benefitting, and, conversely may not be treating the patients that might actually benefit. There is a real need to better identify the patients who are both at most risk of late distant recurrence, and most likely to benefit from EET. This prospective study included 141 patients with a mean age of 62. In the study, 83% of patients were postmenopausal, 73% were stage I. Breast Cancer Index (BCI) is a gene expression-based test and is the only currently available validated biomarker that is both prognostic for late distant recurrence and predictive for likelihood of benefit from EET. The purpose of this prospective study was to assess the impact of BCI on: physician EET recommendations; physician confidence; patient satisfaction, anxiety, and decision-conflict; and the cost impact of BCI. (more…)
Author Interviews, Breast Cancer, Genetic Research, University Texas / 24.03.2017

MedicalResearch.com Interview with: Fangjian Guo, MD, PhD Department of Obstetrics and Gynecology Center for Interdisciplinary Research in Women’s Health University of Texas Medical Branch Galveston TX MedicalResearch.com: What is the background for this study? What are the main findings? Response: BRCA testing in patients diagnosed with early-onset breast or ovarian cancer can identify women with high-risk mutations, which can guide treatment. Women who learn they have a high-risk mutation may also want to inform family members that they may also carry a high-risk mutation. Additionally, BRCA testing can be used to identify high-risk mutation carriers before they develop breast or ovarian cancer. Carriers can then manage their cancer risks with screening (MRI/mammogram), chemoprevention, or prophylactic surgery. Current guidelines recommend BRCA testing for individuals who are considered high-risk for breast or ovarian cancer based on personal or family history.  However, this practice fails to identify most BRCA mutation carriers. It is estimated that more than 90% of mutation carriers have not been identified. One of the issues is that many women who do get tested are actually low-risk and do not have any personal or family history of breast or ovarian cancer. This study assessed how BRCA testing was used in the US health care system during the past decade. We found that in 2004 most of the tests (75.7%) were performed in patients who had been diagnosed with breast or ovarian cancer. Only 24.3% of tests were performed in unaffected women. However, since 2006, the proportion of BRCA tests performed in unaffected women has increased sharply, with over 60% of the tests performed in unaffected women in 2014. (more…)
Author Interviews, Cancer Research, Genetic Research, JAMA / 24.03.2017

MedicalResearch.com Interview with: Heikki Joensuu, MD Department of Oncology Helsinki University Hospital University of Helsinki Helsinki, Finland  MedicalResearch.com: What is the background for this study? Response: The randomized Scandinavian Sarcoma Group (SSG) XVIII trial compared three years of adjuvant imatinib to one year of adjuvant imatinib as adjuvant treatments of patients who had undergone macroscopically complete surgery for a GIST with a high risk for tumor recurrence. In this trial, patients treated with 3 years of imatinib had improved overall survival as compared to those who were allocated to one year of adjuvant imatinib. In 2 other randomized trials that compared either 1 year of adjuvant imatinib to one year or placebo, or 2 years of adjuvant imatinib to observation, no improvement in overall survival was found, although in all three trials adjuvant imatinib improved recurrence-free survival (RFS). The reasons for the discrepant findings with respect of overall survival in the 3 trials have been unclear. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease / 21.03.2017

MedicalResearch.com Interview with: Lia Crotti, MD, PhD Department of Cardiovascular, Neural and Metabolic Sciences San Luca Hospital IRCCS Istituto Auxologico Italiano MedicalResearch.com: What is the background for this study? Response: Sudden cardiac death in one of the major cause of death in Western Countries and among the causes of these deaths in young people under the age of 35, inherited forms of cardiomyopathy have a prominent role. Among these cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) plays a major role. In ARVC, the heart tissue is replaced by fatty and fibrous tissue. This process encourages the development of life-threatening arrhythmias, such as ventricular fibrillation, that causes a cardiac arrest and sudden death in few minutes without a ready device to shock the heart. Intense physical activity favors the progression of the disease and arrhythmias are frequently triggered by adrenergic activation: those are the reason why young athletes with this disease are at high risk. (more…)
Author Interviews, Biomarkers, Breast Cancer, Genetic Research, Journal Clinical Oncology / 21.03.2017

MedicalResearch.com Interview with: Anne Kuijer, MD Departments of Surgery and Radiology University Medical Center Utrecht and Thijs van Dalen, PhD Department of Surgery Netherlands Cancer Institute, Amsterdam MedicalResearch.com: What is the background for this study? What are the main findings? Response: In recent years it has become evident that clinicopathological factors fail to accurately determine prognosis in hormone receptor positive early stage breast cancer patients at intermediate risk of developing metastases. Gene-expression profiles, such as the 70-gene signature (MammaPrint) are therefore increasingly used for chemotherapy decision-making. In the current multicentre study we assessed the impact of 70-gene signature use on chemotherapy decisions in these patients. We demonstrated that, without the use of the 70-gene signature, half of patients was advised chemotherapy, which reflects the current controversy regarding chemotherapy benefit. Use of the 70-gene signature changed the chemotherapy advice in half of all patients and adherence to the 70-gene signature result was high. (more…)
Author Interviews, Exercise - Fitness, Genetic Research, Heart Disease, JAMA, University of Michigan / 19.03.2017

MedicalResearch.com Interview with: Sara Saberi, MD Assistant Professor Inherited Cardiomyopathy Program Frankel Cardiovascular Center University of Michigan Hospital and Health Systems  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Patients with hypertrophic cardiomyopathy are often told not to exercise or to significantly curb their exercise due to concern over the potential risk of increased ventricular arrhythmias and sudden cardiac death. There is no data regarding risks/benefits of exercise in HCM though. There is, however, data that shows that patients with HCM are less active and more obese than the general population AND a majority feel that exercise restrictions negatively impact their emotional well-being. So, we devised a randomized clinical trial of a 16-week moderate-intensity aerobic exercise program versus usual activity with the primary outcome being change in peak VO2 (oxygen consumption). This exercise intervention resulted in a 1.27 mL/kg/min improvement in peak VO2 over the usual activity group, a statistically significant finding. There were no major adverse events (no death, aborted sudden cardiac death, appropriate ICD therapies, or sustained ventricular tachycardia). There was also a 10% improvement in quality of life as measured by the Physical Functioning scale of the SF-36v2. (more…)
Author Interviews, Breast Cancer, Cancer Research, Genetic Research, Race/Ethnic Diversity, Yale / 16.03.2017

MedicalResearch.com Interview with: Cary P. Gross, MD Section of General Internal Medicine Yale University School of Medicine New Haven, CT MedicalResearch.com: What is the background for this study? What are the main findings? Response: Prior work has demonstrated racial and socioeconomic disparities in breast cancer diagnosis, treatment, and outcomes.  As the oncology field has progressed over the past decade, the use of genetic testing to guide treatment decisions is one of the most exciting new developments. Our team was concerned that these new gene tests, which can offer important benefits, may have the potential to exacerbate disparities further.  That is, if there is unequal access to gene testing among patients for whom it is recommended, then our progress against cancer will not be equitably shared among people of all races and ethnicities. (more…)
Author Interviews, Genetic Research, Social Issues / 15.03.2017

MedicalResearch.com Interview with: Emily Rauscher PhD Assistant Professor Department of Sociology University of Kansas   MedicalResearch.com: What is the background for this study? Response: A lot of previous research has identified genotypes that increase sensitivity to context.  Much of this research, however, looks at particular aspects of health and is not able to address the methodological challenges of investigating gene-environment interactions.  To gain a better sense of the potential outcomes that may be susceptible to gene-environment interactions, I examine financial standing in young adulthood.  Testing this type of interaction is challenging because genotype and social environment are not randomly distributed throughout the population. Given this non-random distribution, unobserved confounders (such as parental behaviors, education, ethnicity, or social capital) could influence both parent and child financial standing. (more…)
Author Interviews, Genetic Research, Social Issues, Weight Research / 08.03.2017

MedicalResearch.com Interview with: Professor Don Haider-Markel Chair, Department of Political Science University of Kansas Lawrence, KS 66045 MedicalResearch.com: What is the background for this study? Response: We have studied causal attributions for conditions and problems in society for some time. We noticed that public debate over obesity had increased and new policy proposals were being proposed to address what was deemed as a growing public health problem. As the salience of the issue increased so too did partisan views on the topic. Based on these observations, we wanted to explore individual beliefs about the causes, or attributions for, obesity. Existing research and theory suggested that Republicans following a conservative philosophy would be more likely to attribute obesity to personal choices, such as eating habits and lack of exercise—in short, putting the locus of control on individuals. Meanwhile liberal leaning Democrats, with a known predisposition to suggest conditions or problems are outside of the control of the individual, would be more likely to attribute obesity to either genetic or other biological factors, or the broader context of widely available low-cost high-fat food sources. Additionally, we know that individuals tend to make attributions that are self-serving. In other words, people tend to make attributions that put themselves in a positive light. Thus, personal weight should factor into obesity attributions. Here we expected that overweight people would be more likely to make attributions that removed personal blame, such as pointing to a genetic cause. People closer to an ideal weight would, on the other hand, be more likely to attribute weight-level to personal choices. (more…)
Author Interviews, Biomarkers, Cancer Research, Genetic Research, Nature, UCSD / 07.03.2017

MedicalResearch.com Interview with: Kun Zhang, PhD Professor UCSD Department of Bioengineering La Jolla, CA 92093-0412 MedicalResearch.com: What is the background for this study? What are the main findings? Response: We have been interested in a type of chemical modification on the DNA, called CpG methylation, for years. This is like a decoration of DNA molecules that is specific to the cell type or tissue type. We were particularly interested in studying how such decoration spread along the DNA molecules. In this study, we did a very comprehensive search of the entire human genome for various human cell types and tissue types, and found close to 150,000 regions (called MHB in this study) in which adjacent CpG share the same decoration. We then went on to find out how many of such regions are unique to each normal cell/tissue type, and how many are specific to cancers. Then we took some of these highly informative regions as “biomarkers”, and showed that we can detect the absence or presence of cancer, and, in the latter case, where the tumor grow, in a patient’s blood. (more…)
Author Interviews, Blood Pressure - Hypertension, Genetic Research, Kidney Disease, Nature, Race/Ethnic Diversity, University of Pennsylvania / 07.03.2017

MedicalResearch.com Interview with: Katalin Susztak MD, PhD Associate Professor of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Response: Previous studies showed an association between genetic variants in the APOL1 gene and kidney disease development, but it has not been confidently shown that this genetic variant is actually causal for kidney disease. For this reason we developed a mouse model that recapitulates the human phenotype. (more…)
AACR, Author Interviews, Diabetes, Genetic Research, Melanoma / 01.03.2017

MedicalResearch.com Interview with: Reeti Behera, Ph.D. Postdoctoral fellow in the Weeraratna lab The Wistar Institute Philadelphia PA MedicalResearch.com: What is the background for this study? What are the main findings? Response: Malignant melanoma is an aggressive disease and is the cause of the majority of skin cancer deaths. In particular, older individuals have a much poorer prognosis for melanoma and are more resistant to targeted therapy than compared to young individuals. A recently published study from our lab has shown that age-related changes in secreted factors in the microenvironment can drive melanoma progression and therapy resistance. Klotho is a protein whose expression levels decreases with aging. In this study, we have shown that a decrease in klotho levels in the aged microenvironment drives melanoma aggression and therapy resistance by promoting the oncogenic signaling pathway Wnt5A. We also have shown that reconstituting klotho levels in the aged microenvironment by using rosiglitazone, an FDA-approved drug used to treat diabetes, can reduce tumor burden in aged mice. We also show that Klotho expression is decreased in therapy-resistant melanoma tumors. Reconstituting klotho levels in therapy-resistant melanoma cells by treating with rosiglitazone can inhibit Wnt5A levels and MAPK pathway. We also show that rosiglitazone can significantly decrease therapy-resistant tumor burden in the aged mice, but not in the young. (more…)
Author Interviews, Biomarkers, Breast Cancer, Genetic Research, Race/Ethnic Diversity, Wistar / 28.02.2017

MedicalResearch.com Interview with: Maureen E. Murphy, Ph.D. Professor and Program Leader, Molecular and Cellular Oncogenesis Program Associate Vice President for Faculty Affairs Associate Director for Education and Career Development The Wistar Institute Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Response: The Murphy group discovered a coding-region variant of the p53 tumor suppressor gene, called Pro47Ser, that exists in individuals of African descent. In previous studies this group reported that this amino acid change reduces the ability of p53 to function as a tumor suppressor. In this study, African American women from two different large cohorts were assessed for the incidence of the Pro47Ser variant in pre-menopausal breast cancer. A modest but statistically significant association was found between Pro47Ser and pre-menopausal breast cancer. (more…)
Author Interviews, Genetic Research / 26.02.2017

MedicalResearch.com Interview with: Dr Chiara Manzini PhD Assistant Professor of Pharmacology and Physiology, and Integrative Systems Biology George Washington University MedicalResearch.com: What is the background for this study? What are the main findings? Response: I have been working on finding genes that are mutated in rare forms of muscular dystrophy associated with brain and eye deficits for many years. In the current study, which was a large collaborative effort, we found that mutations in the INPP5K gene cause a new type of muscular dystrophy with short stature, intellectual disability and cataracts. INPP5K is critical for processing a chemical called inositol phosphate which has multiple functions within the cell. We found that the mutations in the patients severely disrupt INPP5K function and when we removed the gene during zebrafish development, the fish showed the same findings observed in the patients: small size, disrupted muscle structure and eye deficits. We are very excited because this is a new disease gene for muscular dystrophy and a novel disease mechanisms, which can open up multiple new lines of investigation. (more…)
Author Interviews, Biomarkers, Genetic Research, PLoS, Prostate Cancer / 23.02.2017

MedicalResearch.com Interview with: G. Andrés Cisneros, Ph.D. Associate Professor Department of Chemistry Center for Advanced Scientific Computing and Modeling, University of North Texas MedicalResearch.com: What is the background for this study? What are the main findings? Response: The accurate maintenance of DNA is crucial, if DNA damage is not addressed it can lead to various diseases including cancer. Therefore, the question arises about what happens if enzymes in charge of DNA repair are themselves mutated. We previously developed a method to perform targeted searches for cancer-related SNPs on genes of interest called HyDn-SNP-S. This method was applied to find prostate-cancer SNPs on DNA dealkylases in the ALKB family of enzymes. Our results uncovered a particular mutation on ALKBH7, R191Q, that is significantly associated with prostate cancer. Subsequent computer simulations and experiments indicate that this cancer mutation results in a decreased ability of ALKBH7 to bind its co-factor, thus impeding its ability to perform its native function. (more…)
Author Interviews, Biomarkers, Genetic Research, Personalized Medicine, Prostate Cancer / 17.02.2017

MedicalResearch.com Interview with: Dr. John L. Gore, MD Associate Professor Adjunct Associate Professor-Surgery Department of Urology University of Washington MedicalResearch.com: What is the background for this study? What are the main findings? Response: The rationale for our study derives from the uncertainty that both patients and clinicians confront when trying to make decisions about adjuvant therapy for prostate cancers found to have aggressive pathologic features at the time of radical prostatectomy. There is level 1 evidence in support of adjuvant radiation therapy in this setting, but several factors restrain providers from recommending adjuvant radiation. We found that interjecting a genomic test that predicts the risk of clinical metastases 5 years after surgery impacts the treatment recommended and helps men and clinicians feel more confident in the decision they are making or recommending. (more…)
Author Interviews, Biomarkers, Breast Cancer, Genetic Research / 17.02.2017

MedicalResearch.com Interview with: Carlos H. Barcenas M.D., M.Sc. Assistant Professor Department of Breast Medical Oncology MD Anderson Cancer Center MedicalResearch.com: What is the background for this study? What are the main findings? Response: Over the last decade we have realized that we were over-treating many early stage breast cancer patients. In addition to the chemotherapy’s obvious side effects, there are also long term complications for breast cancer survivors. Since 2005, we are using a 21-gene-expression assay that predicts the risk of distant recurrence among early stage breast cancer patients. In 2015, initial results from the international clinical trial, TAILORx, found that women with hormone receptor positive, HER2 and lymph node negative early stage disease that had a low recurrence score (RS) of 0-10 from this assay could have chemotherapy omitted altogether. While these findings changed care for women with a low RS, questions remain regarding the management of women with an intermediate RS, defined by this trial as a RS of 11-25. For our retrospective, single-institution study we identified 1,424 stage I and II breast cancer patients with hormone receptor positive, HER2 and lymph node negative treated between 2005 and 2011 who underwent the 21-gene expression assay. The RS distribution was: 297 (21 percent) scored 0–10; 894 (63 percent) scored 11-25; and 233 (16 percent) scored >25. Of those groups, 1.7, 15 and 73.4 percent received chemotherapy, respectively. With a median follow up of 58 months, those with a RS of 11-25 had an invasive disease-free survival (IDFS) rate at five years of 92.6 percent, regardless if patients received chemotherapy or not. Among those patients who did not receive chemotherapy, the estimated rates of IDFS and overall survival was 93 percent and 98 percent, respectively, which was comparable to those who did receive chemotherapy. (more…)
Author Interviews, Breast Cancer, Genetic Research / 16.02.2017

MedicalResearch.com Interview with: Dr. med. Rachel Würstlein Senior Specialist Clinic and Polyclinic for Obstetrics and Gynecology Klinikum der Ludwig-Maximilians-Universität München • Campus Innenstadt Munich MedicalResearch.com: What is the background for this study? Response: Gene expression profiles provide important information on the risk of recurrence, and subtyping in HR+ HER2- early breast cancer, in addition to conventional clinicopathological factors. The PRIMe study was performed by the West German Study Group (WSG) and prospectively investigated the impact of the gene expression tests MammaPrint, a 70-Gene Breast Cancer Recurrence Assay, and the corresponding 80-Gene Molecular Subtyping Assay, BluePrint, on adjuvant chemotherapy decisions for early-stage breast cancer patients. To do this, a risk assessment (chemotherapy followed by endocrine therapy, versus endocrine therapy alone) for distant metastasis was performed in 452 patients from 27 study centers using conventional clinicopathological factors such as tumour size and grade first, then compared to the results of the gene expression tests MammaPrint and BluePrint. Doctors and patients then reviewed the results and made a decision on the optimal treatment plan, namely in deciding whether or not patients would benefit from, and should therefore be treated with adjuvant chemotherapy. (more…)
ALS, Author Interviews, Genetic Research, JAMA / 15.02.2017

MedicalResearch.com Interview with: Prof. Dr. Christine Van Broeckhoven PhD DSc Professor in Molecular Biology and GeneticsUniversity of Antwerp Science Director, VIB Center for Molecular Neurology Research Director, Laboratory for Neurogenetics, Institute Born-Bunge Senior Group Leader, Neurodegenerative Brain Diseases University of Antwerp and Dr. Sara Van Mossevelde, MD Center for Molecular Neurology, VIB Institute Born-Bunge, University of Antwerp Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp, Belgium MedicalResearch.com: What is the background for this study? What are the main findings? Response: Patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) and a C9orf72 repeat expansion present with highly variable onset ages of disease. In the Belgian patient cohort the onset ages ranged from 29 to 82 years of age. This high variability suggested the influence of modifying factors on disease expression. As in other repeat expansion diseases, repeat length is the prime candidate as genetic modifier. In a molecular study (Gijselinck et al., Molecular psychiatry 2016), we were able to provide evidence for an inverse correlation of repeat length with onset age in affected parent – affected children in a C0orf72 families. Also, the degree of methylation of the C9orf72 repeat correlated with repeat size. In this clinical study of affected parent – affected children pairs we provided additional evidence for the occurrence of disease anticipation in C9orf72 pedigrees by analyzing age at onset, disease duration and age at death in successive generations. Within 36 C9orf72 pedigrees with available age data of patients in two to four generations, we observed a significant decrease in age at onset across successive generation while no generational effect was seen on disease burden, disease duration or age at death. (more…)
Author Interviews, Brigham & Women's - Harvard, Genetic Research, Hearing Loss, Nature / 09.02.2017

MedicalResearch.com Interview with: Gwenaelle Geleoc, PhD Assistant Professor Department of Otolaryngology F.M. Kirby Neurobiology Center Children's Hospital and Harvard Medical School Boston, MA MedicalResearch.com: What is the background for this study? What are the main findings? Response: We seek to develop gene therapy to restore auditory and balance function in a mouse model of Usher syndrome. Usher syndrome is a rare genetic disorder which causes deafness, progressive blindness and in some cases balance deficits. We used a novel viral vector developed by Luk Vandenberghe and package gene sequences encoding for Ush1c and applied it to young mice suffering from Usher syndrome. These mice mimic a mutation found in patients of Acadian descent. We assessed recovery of hearing and balance function in young adult mice which had received the treatment. Otherwise deaf and dizzy, we found that the treated mice had recovered hearing down to soft sounds equivalent to a whisper and normal balance function. (more…)
Author Interviews, Diabetes, Genetic Research, JAMA, Race/Ethnic Diversity / 07.02.2017

MedicalResearch.com Interview with: Mary E. Lacy, MPH Department of Epidemiology Brown University School of Public Health Providence, RI MedicalResearch.com: What is the background for this study? What are the main findings? Response: Hemoglobin A1c (A1C) is a blood test that is used to screen for and monitor diabetes. It measures average blood sugar control over the past 2-3 months. A person with sickle cell trait is a carrier for sickle cell disease but often doesn’t have any clinical symptoms. African Americans are more likely than Whites to have diabetes and are more likely to have sickle cell trait. In this article we examined if A1C can be interpreted in the same way in people with and without sickle cell trait. We found that, despite similar results on other measures of blood sugar control, people with sickle cell trait had lower A1C results than people without sickle cell trait. This means that A1C may underestimate diabetes risk in people with sickle cell trait. We also found that, when using standard A1C cutoffs to screen for disease prevalence, we identified 40% fewer cases of prediabetes and 48% fewer cases of diabetes in individuals with sickle cell trait than in those without sickle cell trait. To me, this finding really underscores the potential clinical impact that the observed underestimation of A1C in those with sickle cell trait could have. (more…)
ASCO, Author Interviews, Cancer Research, Colon Cancer, Genetic Research, Journal Clinical Oncology / 01.02.2017

MedicalResearch.com Interview with: Matthew B Yurgelun, M.D Instructor in Medicine, Harvard Medical School Dana-Farber Cancer Institute MedicalResearch.com: What is the background for this study? What are the main findings? Response: It has long been known that hereditary factors play a key role in colorectal cancer risk. It is currently well-established that approximately 3% of all colorectal cancers arise in the setting of Lynch syndrome, a relatively common inherited syndrome that markedly increases one’s lifetime risk of colorectal cancer, as well as cancers of the uterus, ovaries, stomach, small intestine, urinary tract, pancreas, and other malignancies. Current standard-of-care in the field is to test all colorectal cancer specimens for mismatch repair deficiency, which is a very reliable means of screening for Lynch syndrome. The prevalence of other hereditary syndromes among patients with colorectal cancer has not been known, though other such factors have been presumed to be quite rare. (more…)
Author Interviews, Blood Pressure - Hypertension, Genetic Research / 01.02.2017

MedicalResearch.com Interview with: Helen R Warren PhD Analysis, Statistics, Genetic Epidemiology Queen Mary, University of London MedicalResearch.com: What is the background for this study? What are the main findings? Response: This study analysed data from UK Biobank, which is a large cohort including over 500,000 male and female participants from across the UK, aged 40-69 years. We performed a genetic association study for blood pressure, which analysed ~140,000 individuals of European ancestry (as currently interim genetic data is only available for ~150,000 participants). Our study identified 107 genetic regions associated with blood pressure, which had not been previously reported at the time of our analysis. All our new findings were robustly validated within independent replication data resources, comprising a large, total sample size of up to 420,000 individuals. (more…)
Author Interviews, Genetic Research, Nature, Neurological Disorders / 31.01.2017

MedicalResearch.com Interview with: Keerthi Krishnan PhD Cold Spring Harbor Laboratory Cold Spring Harbor, New York 11724 MedicalResearch.com: What is the background for this study? What are the main findings? Response: Rett Syndrome is diagnosed as a neurodevelopmental disorder in girls, caused mainly by mutations in the gene MECP2. Many previous studies, including mine, have shown that mutations in MECP2 result in improper communication between nerve cells in the brain during sensitive periods of development. However, it was unclear if the same mechanisms were responsible for cognitive and behavioral problems found in adulthood. In this paper, we have utilized a natural, learned response called pup retrieval behavior to study adult neural plasticity in a female mouse model of Rett Syndrome. With some learning, adult female mice will gather scattered pups to the nest, in response to distress calls from the pups. We found that the Rett Syndrome model mice with reduced MECP2 protein do not gather pups efficiently. This is due to the abnormal formation of structures called perineuronal nets on a specific type of neurons (called parvalbumin+ GABAergic neurons) that block plasticity and prevent learning of the appropriate response. Furthermore, the same neural and molecular mechanisms found earlier in development were also found to mediate learning in adulthood. (more…)
Author Interviews, Genetic Research, Infections, Pediatrics / 19.01.2017

MedicalResearch.com Interview with: Prof. Adrian Liston (VIB-KU Leuven) MedicalResearch.com: What is the background for this study? Response: With vaccinations, sanitation, antibiotics and general improvements in living standards, infectious disease is no longer a major killer of children. Death or hospitalisation of children from infection is rare in countries with modern health care systems. Those rare events were once thought to be chance outcomes on the roulette of bad luck, but increasingly we are recognising that genetic mutations underlie severe pediatric infections. In our study we are seeking to identify the mutations and immunological changes that occur in children, causing them to have severe reactions to infectious disease. (more…)
Author Interviews, Genetic Research, Nature / 17.01.2017

MedicalResearch.com Interview with: Natalie Shaw, MD, MMSc National Institute of Environmental Health Sciences Research Triangle Park, North Carolina and Harrison Brand, PhD Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research Massachusetts General Hospital, Boston Massachusetts, USA. MedicalResearch.com: What is the background for this study? What are the main findings? Response: Congenital arhinia, or absence of the nose and olfactory system, is an extremely rare malformation, often accompanied by defects in the eyes and reproductive system. Arhinia has been reported in only 80 patients in the past century and though a genetic cause had been suspected, no previous study had identified a plausible genetic candidate. Through an international collaboration among clinicians and investigators spanning 10 different countries, we were able to assemble a cohort of 40 arhinia patients. Using whole-exome sequencing, we found that 84% of the patients had rare mutations in the same gene – SMCHD1. Further, modeling studies based on patient cells and SMCHD1 knockdown in zebrafish strongly support a role for the gene in arhinia. We were surprised by this discovery because mutations that impair SMCHD1 function are known to interact with other regions of the genome to cause a type of muscular dystrophy (FSHD2) that does not affect the bones or cartilage of the face. Deep phenotyping of our cohort revealed that individuals with arhinia can in fact develop FSHD2, but it is still unclear why individuals with FSHD2 do not have arhinia. (more…)
Author Interviews, Baylor College of Medicine Houston, Genetic Research, NEJM / 09.01.2017

MedicalResearch.com Interview with: Jennifer E Posey MD, PhD Assistant Professor Department of Molecular and Human Genetics Baylor College of Medicine Tamar Harel MD, PhD Clinical Genetics Academic Research Fellow Department of Molecular and Human Genetics Baylor College of Medicine Current affiliation: Department of Genetic and Metabolic Diseases Hadassah-Hebrew University Medical Center Jerusalem, Israel MedicalResearch.com: What is the background for this study? What are the main findings? Response: As physician scientists and geneticists, our goal is to understand how genetic variation in each of us can impact health and disease. Physicians are often taught that the simplest explanation for a medical condition is the most correct explanation, and have historically searched for a single unifying diagnosis. However, in our own practice, we have met – and learned from – individuals who have more than one genetic condition affecting their health. In the past, it was difficult for physicians to diagnose such individuals. Genetic testing required a physician to recognize the potential for more than one genetic diagnosis in an individual. Single-gene and gene panel testing provided an additional barrier to accurate diagnoses, as they are more narrow in scope, and more than one molecular test was often needed to identify all conditions. Targeted testing also required a physician to accurately pre-suppose which combination of genetic conditions was most likely, and choose the correct targeted tests. The clinical availability of whole exome sequencing (WES) has removed these barriers: WES is a broad-based, unbiased analysis of an individual’s genetic variation that does not pre-suppose a specific genetic cause. If analysis is pursued systematically, WES can identify more than one genetic diagnosis in an individual, even when not suspected. In our study, we have been able to assess the frequency with which individuals can have more than one genetic diagnosis, and have begun to understand how genetic variation at more than one place in the genome can affect how a condition may present. We found that among 7,374 individuals referred for WES, 2,076 (28%) had a molecular diagnosis. Of these 2,076, 5% had two, three, or four molecular diagnoses. In our analyses of the clinical features that may be observed in an individual with two genetic conditions, we found that pairs of diagnoses with overlapping clinical features may be incompletely diagnosed as having one or the other condition, and pairs of diagnoses with very distinct clinical features may be erroneously diagnosed in the clinic as having an entirely new condition. (more…)
Abuse and Neglect, Genetic Research, Schizophrenia, UCSD / 06.01.2017

MedicalResearch.com Interview with: Brian P. Head, MS, PhD Associate Professor, UCSD Research Scientist, VASDHS Department of Anesthesiology VA San Diego Healthcare System San Diego, CA 92161-9125 MedicalResearch.com: What is the background for this study? What are the main findings? Response: DISC1 is a schizophrenia associated gene originally identified in a Scottish family. DISC1 protein is highly expressed in the developing brain and in the dentate gyrus of the adult hippocampus, and is involved in neuritogenesis and neuronal signaling. DISC1 is located in multiple intracellular locations including axons and synapses, and loss of DISC1 function causes deficits in neural development, neuronal proliferation, axonal growth, and cytoskeleton modulation, which are consistent with abnormal neural development in schizophrenia. SynCav1 means synapsin-driven caveolin construct. Synapsin promoter is neuronal specific which allows us to increase caveolin expression-specifically in neurons. We have previously shown that SynCav1 increases neuronal signaling and dendritic growth and arborization in vitro (Head BP JBC 2011), and when delivered in vivo augments functional neuroplasticity and improves learning and memory in adult and aged mice (Mandyam CD Biol Psych 2015). Since loss of DISC1 function equates to schizophrenic-like symptoms, then decreased DISC1 expression in Cav-1 KO mice agrees with this premise. Thus, loss of Cav-1 increases their likelihood of developing schizophrenia-like symptoms. Because re-espression of Cav-1 restored DISC1 expression as well as expression of key synaptic proteins, this proof-of-concept findings not only builds upon our previously results demonstrating that Cav-1 is critical for neuronal signaling and functional synaptic plasticity but also strongly links Cav-1 with maintaining normal DISC1 expression levels and potentially attenuating schizophrenia-like symptoms. (more…)