Author Interviews, Dermatology, Nature / 23.02.2015

Chwee Teck (C.T.) LIM PhD Provost’s Chair Professor, Deputy Head, Department of Biomedical Engineering & Department of Mechanical Engineering Principal Investigator, Mechanobiology Institute Faculty Fellow, Singapore-MIT Alliance for Research & Technology (SMART) National University of Singapore Faculty of Engineering, SingaporeMedicalResearch.com Interview with: Chwee Teck (C.T.) LIM PhD Provost’s Chair Professor, Deputy Head, Department of Biomedical Engineering & Department of Mechanical Engineering Principal Investigator, Mechanobiology Institute Faculty Fellow, Singapore-MIT Alliance for Research & Technology (SMART) National University of Singapore   Medical Research: What is the background for this study? What are the main findings? Professor Chwee Teck Lim: Epithelial cells have a natural tendency to close gaps and this feature plays a crucial role in many biological processes such as embryological development and wound healing. For example, skin does consist of epithelial cells that when wounded, will elicit closure to initiate healing.  How epithelial cells close such gaps has always fascinated researchers from across many disciplines. It is generally accepted that two major mechanisms exist that underlie such a closure. The first is a "cell-crawling" mechanism wherein cells at the edge of the gap actively send protrusions or lamellipodia and use them as footholds to migrate over the gap. However, such a migration requires that the gap is conducive for cells to attach and form adhesions or footholds. The second mechanism is based on a coordinated contraction of multiple bundles of cellular cytoskeletal components (bundles of actin) in a manner similar to that of a "purse-string". Despite many studies, it has always been difficult to understand and characterize these processes separately since most often they co-exist. In this study, we show that keratinocyte monolayers have a tendency to close circular non-adhesive gaps (gaps that have been coated with a polymer that does not allow cells to adhere or form foot-holds) through contraction of bundles of actin within cells at the edge of the gap. We find that such as closure is strongly affected by the size of the gap (gaps more than 150 um in diameter have a tendency to close only partially), curvature of the gap (gaps with high curvature show better closure), and strength of intercellular adhesion (poor intercellular adhesion completely inhibits closure of non-adhesive gaps).
Aging, Author Interviews, Memory, Nature, Nutrition / 09.02.2015

Ashok K. Shetty, Ph.D. Professor and Director of Neurosciences Institute for Regenerative Medicine and Department of Molecular and Cellular Medicine
Texas A&M Health Science Center College of Medicine, Temple, TX
Research Career Scientist, Central Texas Veterans Health Care System (CTVHCS), Temple, TXMedicalResearch.com Interview with: Ashok K. Shetty, Ph.D. Professor and Director of Neurosciences Institute for Regenerative Medicine and Department of Molecular and Cellular Medicine
Texas A&M Health Science Center College of Medicine, Temple, TX
Research Career Scientist, Central Texas Veterans Health Care System (CTVHCS), Temple, TX Medical Research: What is the background for this study? Prof. Shetty: Hippocampus is a region in the brain important for maintaining functions such as learning, memory and mood. However, this region is highly vulnerable to aging and brain insults. Previous research has shown that diminished function in the dentate gyrus region of the hippocampus is one of the key reasons for memory impairments seen in old age. Dentate gyrus is also one of the few regions in the brain where neural stem cells generate new neurons on a daily basis, also referred to as "adult neurogenesis". Studies have suggested that a significant fraction of newly born neurons mature, get incorporated into the existing hippocampus circuitry and contribute to learning, formation of new memories, and normal mood. However, with aging, the dentate gyrus shows decreased function with some conspicuous structural changes, which include reduced production of new neurons, diminished microvasculature implying reduced blood flow, and occurrence of hypertrophy of astrocytes and activated microglia, signs of chronic low-level inflammation. Because alterations such as reduced neurogenesis, decreased blood flow and brain inflammation can contribute to memory and mood impairments, the idea that drugs that are efficacious for mitigating these changes may preserve memory and mood function in old age has emerged. Such drugs may be prescribed to the aging population if they are efficacious for maintaining normal cognitive and mood function in old age with no or minimal side effects. Medical Research: What is the rationale for choosing resveratrol for preventing age-related memory dysfunction in this study? Prof. Shetty:  Administration of resveratrol, a naturally occurring polyphenol found in the skin of red grapes, red wine, peanuts and some berries, appeared suitable for counteracting age-related detrimental changes in the hippocampus. This is because, previous studies have shown that resveratrol has ability to promote the formation of new capillaries (through pro-angiogenic effects) and to suppress oxidative stress and inflammation (via antioxidant and antiinflammatory effects) with no adverse side effects. Other studies have also reported that resveratrol can mediate extension of the life span and delayed onset of age related diseases. More importantly, a recent human study suggested that a reasonably lower dose of resveratrol intake for 26 weeks is good enough to improve memory performance as well as hippocampus functional connectivity in 23 healthy overweight older individuals (Witte et al., J. Neurosci., 34: 7862-7870, 2014).
Author Interviews, Genetic Research, Nature, Rheumatology / 06.02.2015

psoriasis_kneesMedicalResearch.com Interview with: Professor Anne Barton FRCP PhD and Dr John Bowes PhD Centre for Musculoskeletal Research and Centre for Genetics and Genomics, The University of Manchester, Manchester UK Medical Research: What is the background for this study? Response: Psoriatic arthritis (PsA) is an inflammatory condition causing pain and stiffness in joints and tendons. Approximately one third of patients with psoriasis will go on to develop PsA resulting in a reduction in their quality of life caused by increasing disability and additional health complications. A key area of research within the Arthritis Research UK Centre for Genetics and Genomics in the Centre for Musculoskeletal Research is the identification of risk factors for the development of Psoriatic arthritis; this will allow us to understand the underlying cause of disease and ultimately help identify psoriasis patients at high risk of PsA, allowing early treatment to be introduced to reduce the impact of PsA. Our study focuses on the identification of genetic risk factors for Psoriatic arthritis; we compared the frequency of genetic variants, referred to as single nucleotide polymorphisms (SNPs), between large numbers of DNA samples from patients with PsA and healthy control samples. When the frequency of the SNP is significantly different between cases and controls, the SNP is said to be associated with risk of developing Psoriatic arthritis and this association is interpreted as being important in the disease process. Medical Research: What are the main findings? Response: When we analysed the data from the study we found a new association to SNPs on chromosome 5, and when we investigated these SNPs for association with skin-only psoriasis, we did not find any evidence for association. In addition, we also found SNPs that were specifically associated with Psoriatic arthritis at a gene on chromosome 1. This gene is known to be associated with psoriasis, but our results show that there are different SNPs associated with PsA and psoriasis at this gene. Hence, our results identify new SNPs that are specifically associated with PsA. In addition, identifying which cells are the key drivers of inflammation in Psoriatic arthritis will help us to focus on how the genetic changes act in those cells to cause disease. Our results show that many of the PsA associated SNPs occur in regions of the genome that are important in the function of CD8+ cells,  an important cell type in the immune system.
Author Interviews, Nature, Ovarian Cancer / 29.01.2015

Dr. Terry Magnuson PhD Vice Dean for Research Department of Genetics, School of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599MedicalResearch.com Interview with: Dr. Terry Magnuson PhD Vice Dean for Research Department of Genetics, School of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599 Medical Research: What is the background for this study? What are the main findings? Response: Ovarian clear-cell carcinoma is a lethal form of ovarian cancer with limited therapeutic options. Recent patient-derived tumor sequencing studies support a strong genetic basis for the disease, but the roles of gene mutations in cancer causation are still unclear. We observed rapid induction of ovarian clear-cell carcinoma in mice that were genetically engineered to carry mutations in ARID1A and PIK3CA−the two most frequently mutated genes. Comparisons between human and mouse tumors uncovered a downstream role for the Interleukin-6 (IL-6) cytokine-signaling pathway in tumor progression. Thus, ARID1A and PIK3CA mutations cause ovarian clear-cell carcinoma and promote tumor cell growth by acting upon the IL-6 signaling pathway.
Author Interviews, Genetic Research, Melanoma, Nature / 25.01.2015

MedicalResearch.com Interview with: Prof Lukas Sommer. Ph.D. Cell and Developmental Biology University of Zurich Institute of Anatomy Zurich Switzerland MedicalResearch: What is the background for this study? What are the main findings? Prof. Lukas Sommer:   Melanoma, the most aggressive of all skin cancers, is often fatal for patients due to the pronounced formation of metastases. Up to date, a melanoma’s rampant growth was mainly attributed to genetic causes, such as mutations in certain genes. However, we now reveal that so-called epigenetic factors also play a crucial role in the formation of metastases in malignant skin cancer. Epigenetic factors do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. In our study we identified “EZH2” as an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells. In these cells, “EZH2” controls genes that govern both tumor growth and genes that are important for the formation of metastases. We exploited this central position of EZH2 to combat the cancer by using a pharmacological inhibitor to suppress the activity of EZH2. As a result, we were able to prevent the growth and malignant spread of the cancer in an animal model and in human melanoma cells.
Author Interviews, Diabetes, Nature, University of Michigan / 23.01.2015

MedicalResearch.com Interview with: Martin G. Myers, Jr., M.D., M.P.H. Director, Michigan Diabetes Research & Training Center Associate Professor of Internal Medicine - MEND Division Professor of Molecular & Integrative Physiology Marilyn H. Vincent Professor of Diabetes Research and Department of Pharmacology, University of Cambridge, Cambridge, UK.MedicalResearch.com Interview with: Martin G. Myers, Jr., M.D., M.P.H. Director, Michigan Diabetes Research & Training Center Associate Professor of Internal Medicine - MEND Division Professor of Molecular & Integrative Physiology Marilyn H. Vincent Professor of Diabetes Research and Department of Pharmacology, University of Cambridge, Cambridge Medical Research: What is the background for this study? What are the main findings? Dr. Myers: Diabetic people who take insulin to treat their diabetes are at risk of low blood sugar, which can cause serious consequences (including death).  This risk increases as blood sugar control improves, and so this risk limits the ability to control blood sugar.  The body has a system (the counter-regulatory response) that acts to prevent blood sugar from going too low, but this is often impaired in diabetic patients. We identified a brain circuit that senses and responds to falling blood sugar, and which acts to increase blood sugar.  Furthermore, we showed that the hormone leptin modulates the sensitivity of this circuit, and identified the neurotransmitter (CCK) that acts in this circuit to increase blood sugar.  Thus, we have identified several potential drug targets that could be used to prevent or treat low blood sugar in insulin-treated diabetics.  If we are able to pharmacologically modulate the activity of this brain circuit, it could improve the treatment of these patients.
Author Interviews, Breast Cancer, Genetic Research, Nature / 11.01.2015

MedicalResearch.com Interview with: Dr. Pentao Liu PhD and Dr. Walid Khaled PhD Wellcome Trust Sanger Institute Cambridgeshire United Kingdom Medical Research: What is the background for this study? What are the main findings? Dr. Pentao Liu: The significance of this research is that it aims to tackle the worst type of breast cancer. Triple Negative Breast Cancer (TNBC) has the poorest patient survival rate compared to other forms of breast cancer.  At present there are no targeted therapies available for TNBC, leaving the non-specific chemotherapy as the only treatment option. In this study we identify a new key gene in  Triple Negative Breast Cancer which could potentially be inhibited for the targeted treatment of TNBC. In this study we report the identification of a novel gene for Triple Negative Breast Cancer. By analyzing genomics data from 3,000 patients we find BCL11A to be highly expressed in TNBC. We then demonstrate experimentally that upregulation of BCL11A drives tumour development while its downregulation leads to reduction in tumour size. In the experimental mouse model, inactivation of this gene completely abolishes breast tumour development.
Author Interviews, Nature, Neurological Disorders / 30.12.2014

György Buzsáki, M.D., Ph.D. Biggs Professor of Neural Sciences NYU Neuroscience Institute New York University Langone Medical Center New York, NY 10016MedicalResearch.com Interview with: György Buzsáki, M.D., Ph.D. Biggs Professor of Neural Sciences NYU Neuroscience Institute New York University Langone Medical Center New York, NY 10016 Medical Research: What is the background for the NeuroGrid device? Dr. Buzsaki: The main form of communication among neurons in the brain occurs through action potentials (‘spikes’). Understanding the mechanisms that translate spikes of individual neurons into perceptions, thoughts, and actions requires the ability to monitor large populations of neurons at the spatial and temporal resolution of their interactions. We developed a novel, organic material-based, ultra-conformable, biocompatible and scalable neural interface array (the ‘NeuroGrid’) with neuron-size density electrodes capable of acquiring action potential of individual neurons from the surface of the brain. The NeuroGrid has several innovative characteristics that overcome limitations in current methods of surface recording: (i) light-weight and conformable architecture to establish stable electrical and mechanical contacts, thereby ensuring minimal damage to underlying tissue; (ii) efficient abiotic/biotic interface resulting in a high signal to noise ratio and the ability to resolve spikes. This is achieved by using conducting polymers as the interfacing material. Conducting polymers are mix conductors, they can conduct electronics and ionic currents hence they can efficiently transduce ion based neural activity into electronic signals (iii) scalable neuron-size density electrodes to allow isolation and characterization of multiple individual neurons’ action potential across the cortical surface.
Aging, Author Interviews, Nature, Scripps / 27.12.2014

Paul Schimmel, Ph.D. Professor The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, California MedicalResearch.com Interview with: Paul Schimmel, Ph.D. Professor The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, California Medical Research: What is the background for this study? What are the main findings? Dr. Schimmel: Resveratrol (RSV) is thought to provide health benefits by activating a protective stress response. In the paper we described a new, previously missed mechanism for its action. This mechanism is activated at much lower concentrations of resveratrol than previously described or imagined. Consequently, other mechanisms, which appear to act at higher concentrations of resveratrol, are layered over a preexisting foundation set by the newly revealed mechanism.
Author Interviews, Case Western, Nature, Neurological Disorders / 26.12.2014

Bradley T. Lang, PhD Researcher, Jerry Silver Lab Department of Neurosciences Case Western Reserve University School of MedicineMedicalResearch.com Interview with: Bradley T. Lang, PhD Researcher, Jerry Silver Lab Department of Neurosciences Case Western Reserve University School of Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Lang: In the late 1980’s, Jerry Silver, PhD, discovered the presence of chondroitin sulfate proteoglycans in the developing nervous system, which form barriers to prevent aberrant growth. He has been building on this finding for more than 30 years, attempting to understand why the adult spinal cord is incapable of regenerating, or why axons don’t grow where they don’t. He has found that the glial scar, which surrounds the site of neural trauma, is incredibly rich in proteoglycans, which prevent regeneration in the spinal cord. In 2009 we collaborated with a group at Harvard to discover the very first receptor for chondroitin sulfate proteoglycans, protein tyrosine phosphatase-sigma, or PTPsigma. Medical Research: What are the main findings? Dr. Lang: The findings in this paper are twofold. We first describe a novel mechanism of regeneration failure, where regenerating axons become stabilized within a gradient of chondroitin sulfate proteoglycan, completely preventing motility. This finding helps explain why axons persist in the vicinity of the glial scar after injury indefinitely, with little to no regeneration potential—they are simply embedded within the scar. We were able to model this interaction in a petri dish to screen for drugs that were capable of promoting motility. The second finding in the manuscript is the discovery and characterization of a novel peptide therapeutic that binds to the receptor for chondroitin sulfate proteoglycans and releases inhibition. Most importantly, this drug was given systemically, similar to a daily insulin injection, avoiding complications due to direct nervous system infusion/injection. After several weeks of treatment (which began 1 day after injury), rats with severe spinal cord injury regained coordinated locomotion, bladder control, and/or balance. In total, 21/26 treated animals regained some function.
Author Interviews, HIV, Nature, UCLA / 22.12.2014

David Gerberry PhD Center for Biomedical Modeling, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CaliforniaMedicalResearch.com Interview with: David Gerberry PhD Assistant Professor Department of Mathematics and Computer Science Xavier University, Cincinnati, Ohio   Medical Research: What is the background for this study? What are the main findings? Response: In an attempt to control the spread of HIV, governments in sub-Saharan Africa are considering providing antiretroviral drugs to people who do not have the virus but are at risk for becoming infected. Such drugs are known as pre-exposure prophylaxis, or PrEP.  Given the cost of PrEP, an important question is how to maximize the impact of interventions given a fixed level of prevention resources. A common strategy is to target resources to the individuals that are at the highest risk for infection.  This group of people is often referred to as the "core group" and can be thought of as sex workers, clients of sex workers and other individuals that are at very high risk for infection.  While targeting this core group is ideal and would result in the most cost-effectiveness interventions, being able to identify these individuals is difficult in practice and they are often unwilling to participate in the intervention; take pre-exposure prophylaxis or change their behavior for example.  From a mathematical perspective it is also very difficult to quantify their increased level of risk.  For example, is a sex worker at 5 times, 25 times, 100 times or 1000 times the risk for HIV infection?  Without this quantification, it is impossible to estimate the cost-effectiveness of a targeted strategy. In our work, we build an intervention strategy based on geographical targeting.  This takes advantage of the fact that HIV incidence is much higher in certain geographical locations than others.  Therefore, individuals in these areas are at increased risk for HIV infection.  Most importantly, such an intervention is feasible because reliable data exists across much of sub-Saharan Africa for the severity of the HIV epidemic in different regions.  To illustrate our ideas we used mathematical modeling to consider resource allocation in South Africa and found that targeting the provinces with highest HIV incidence would prevent 40% more infections than a plan that ignored geographic variation while using the same amount of resources.
Author Interviews, Cancer Research, Nature / 19.12.2014

Dr Catherine Olsen | Senior Research Officer QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, QLD 4029MedicalResearch.com Interview with: Dr Catherine Olsen  |  Senior Research Officer QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, QLD 4029 Medical Research: What is the background for this study? What are the main findings? Response: Squamous cell carcinomas (SCCs)are the second most common skin cancer occurring in white skinned populations. They cause significant morbidity as they can invade local structures (often the nose or ears) and they also have the potential to metastasize although most are successfully treated before any spread occurs. They are also very expensive cancers to treat because they are so common, posing a significant burden on health care budgets. NSAIDS have been shown to be protective for other cancers (e.g. colorectal and oesophageal cancer). This prompted use to evaluate all of the available evidence on NSAIDs use and SCC by conducting a systematic review and meta-analysis of the association.
Author Interviews, Dermatology, Nature, Sleep Disorders / 14.12.2014

Dr. Jonathan L. Silverberg MD PhD MPH Assistant Professor in Dermatology, Medical Social Sciences and Preventive Medicine Northwestern University, Chicago, IllinoisMedicalResearch.com Interview with: Dr. Jonathan L. Silverberg MD PhD MPH Assistant Professor in Dermatology, Medical Social Sciences and Preventive Medicine Northwestern University, Chicago, Illinois Medical Research: What is the background for this study? What are the main findings? Dr. Silverberg: Chronic itch related to childhood eczema has been shown to cause worsened sleep quality with shorter sleep duration, more frequent and prolonged awakening, and overall lower sleep efficiency. However, little is known about the sleep disturbances that occur in adults with eczema.
Author Interviews, Diabetes, Nature, Weight Research / 12.12.2014

MedicalResearch.com Interview with: Prof. Dr. Patrice D. Cani PhD, Research Associate FRS-FNRS Louvain Drug Research Instiute, Metabolism and Nutrition WELBIO, Walloon Excellence in Life sciences and BIOtechnology NeuroMicrobiota lab, European Associated Laboratory (INSERM/UCL) and Dr Amandine Everard Université Catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, Brussels, Belgium Medical Research: What is the background for this study? What are the main findings? Response: Our intestine harbors more than 100 trillions of bacteria. This huge number of bacteria permanently interacts with our own human cells. Among the systems involved in this crosstalk, the immune system plays a key role in these interactions. We previously showed that specific gut bacteria are able to control energy metabolism, harmful inflammation associated with obesity, body weight gain and type-2 diabetes. However mechanisms involved these effects of gut bacteria on the host during obesity and type-2 diabetes were poorly understood. We identify the essential role of the intestinal immune system in the onset of obesity and type-2 diabetes both induced by a high dose of fat in the diet. This discovery highlights an unexpected mechanism for the control of energy metabolism during obesity and type-2 diabetes. We demonstrate for the first time that the inactivation of a part of the intestine immune system (more specifically the protein MyD88), which is overstimulated by a diet rich in fat, allows to induce weight-loss and to reduce type-2 diabetes associated with obesity. When we tune the immune system by disabling the protein MyD88 specifically in cells covering the intestine, we are able to limit the adipose tissue development induced by the diet rich in fat, to slow down diabetes, to reduce harmful inflammation associated with obesity, to reinforce gut barrier function assumed by our intestine to avoid the inappropriate translocations of bacteria compounds from our intestine in our body. We reveal various mechanisms explaining the partial protection against obesity induced by the inactivation of this protein of the immune system. Among them, we point out that mice that do not have this protein of the immune system (i.e. MyD88) in their intestine are partially protected against obesity because they spend more energy than other obese mice. Moreover, our study shows that this protein of the immune system is able to shape the composition of the gut microbiota residing in our intestine under a high-fat diet. These changes observed in mice deleted for this protein also explain their protection against obesity because when we transfer intestinal bacteria of these mice into other mice that are axenic (without flora), these latest mice are also partially protected against obesity. In conclusions, our studies published in the scientific journal Nature Communications, demonstrated that during consumption of fat food, the intestinal immune system plays an important role in fat storage regulation in the body and is capable to modify the composition of intestinal bacteria (including some which are still unidentified), confirm the implication of intestinal bacteria in the onset of obesity.
Alcohol, Author Interviews, Nature, University Texas / 05.12.2014

MedicalResearch.com Interview with: R. Dayne Mayfield PhD and Sean Farris Post Doc Fellow Harris Lab Waggoner Center for Alcohol and Addiction Research University of Texas at Austin MedicalResearch: What is the background for this study? Response: Alcoholism is psychiatric disorder adversely affecting the health of millions of individuals worldwide. Despite considerable research efforts, alcoholism cannot be attributed to any individual gene. We sought out to identify coordinately regulated gene networks, rather than a single candidate gene, that may be collectively driving the consumption of alcohol.
Author Interviews, General Medicine, Genetic Research, Nature / 03.12.2014

MedicalResearch Interview with: Prof Dr Isabelle Mansuy Lab of Neuroepigenetics University/ETH Zürich Brain Research Institute Zürich, Switzerland   MedicalResearch: What is the background for this study? What are the main findings? Prof. Mansuy: It is recognised that being exposed to traumatic stress in early life increases the susceptibility to psychiatric and metabolic diseases later in life. This is true for people directly exposed but also for their progeny across generations. It is also known that sometimes, stress exposure in early life can help an individual develop response strategies and be better prepared for later stressful experiences. The mechanisms of such beneficial effects and the question of whether they can be transmitted or not are not known. This study in mice was designed to answer these questions. The main findings are that exposure to traumatic stress of mouse newborns makes the animals and their progeny more efficient in challenging tasks when adult. For instance, they are more able to adapt to rules that change in a complex task to get a water ration when they are thirsty. This suggests more adaptive behaviours in challenging situations that are transmitted across generation. The study identifies the mineralocorticoid receptor, a stress hormone receptor in the brain, as an important molecular mediator of this effect and demonstrates that its expression is altered in the brain by epigenetic mechanisms.
Author Interviews, Memory, Nature / 23.11.2014

Vijay Ramanan, PhD Indiana University Center for Neuroimaging (CfN) Department of Radiology Indianapolis, IN 46202MedicalResearch.com Interview with: Vijay Ramanan, PhD Indiana University Center for Neuroimaging (CfN) Department of Radiology Indianapolis, IN 46202 Medical Research: What is the background for this study? What are the main findings? Dr. Ramanan: Impairment in episodic memory is one of the first clinical deficits in early Alzheimer’s disease, the most common cause of dementia.  Among other examples, this might be reflected as an inability to recall an article recently read or as difficulty remembering what one had for dinner last night.  Unfortunately, the genetic and environmental mechanisms underlying these deficits are not fully understood.  Our goal was to discover new genes and pathways underlying memory performance to help identify potential drug targets for protecting against and ultimately reversing memory loss in dementia and normal aging. Through studying a large representative sample of older Americans, we discovered a variant (single nucleotide polymorphism or SNP) in the FASTKD2 gene associated with better memory performance and replicated this finding in independent samples.  We then integrated additional data to extend our understanding of the effect of this SNP.  For example, we know that the hippocampus is a vital brain structure for encoding and retrieving memories and it is well-understood that decreased hippocampal volume is a key early marker of Alzheimer’s disease and one that can be measured noninvasively through magnetic resonance imaging (MRI).  We predicted that this new memory-protective SNP would be associated with increased hippocampal volume and this turned out to be true.  We also discovered that carriers of this memory-protective SNP exhibited lower levels of proteins involved in cell death in the cerebrospinal fluid bathing the brain and spinal cord, a striking finding given that FASTKD2 encodes a protein that appears to promote apoptosis (i.e., programmed cell death).  Together, these convergent findings are consistent with a neuroprotective effect of this novel SNP discovery.  More broadly, our results nominate FASTKD2 and its functional pathways as potential targets for modulating neurodegeneration to combat memory loss in older adults.
Author Interviews, Biomarkers, Infections, Nature, UCLA / 19.11.2014

Weian Zhao PhD Assistant Professor at the Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center, Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology and Department of Pharmaceutical Sciences at University of California, Irvine. Founder of Velox BiosystemsMedicalResearch.com Interview with: Weian Zhao PhD Assistant Professor at the Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center, Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology and Department of Pharmaceutical Sciences at University of California, Irvine. Medical Research: What is the background for this study? Dr. Zhao: Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The extremely high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages. The present gold standard to detect a blood infections, is a blood culture and it takes 2-5 days for the detection and the identification of the bacteria. Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with blood infections.  Therefore, less expensive and less technically demanding methods are urgently needed for the rapid and sensitive identification of blood infections.
Author Interviews, Eating Disorders, Nature / 17.11.2014

Pietro Cottone, Ph.D. Associate Professor Departments of Pharmacology and Psychiatry Laboratory of Addictive Disorders Boston University School of Medicine Boston, MA 02118MedicalResearch.com Interview with: Pietro Cottone, Ph.D. Associate Professor Departments of Pharmacology and Psychiatry Laboratory of Addictive Disorders Boston University School of Medicine Boston, MA 02118 Medical Research: What is the background for this study? What are the main findings? Dr. Cottone: Binge-eating disorder affects over ten million people in the USA and it is characterized by excessive consumption of junk food within brief periods of time, accompanied by loss of control, uncomfortable fullness and intense feelings of disgust and embarrassment. Increasing evidence suggests that binge-eating disorder can be regarded as an addiction behavior. Memantine, a neuroprotective drug which blocks the glutamatergic system in the brain, is an Alzheimer's disease medication, and it has been shown potential to treat a variety of addictive disorders. We first developed a rodent model of binge eating by providing a sugary, chocolate diet only for one hour a day, while the control group was given the standard laboratory diet. Rats exposed to the sugary diet rapidly develop binge eating behavior, observed as a 4 fold increase in food intake compared to controls. Furthermore, binge eating rats are willing to work to a much greater extent to obtain just the cue associated with the sugary food (not the actual food), as compared to controls. In addition, binge eating subjects exhibit compulsive behavior by putting themselves in a potentially risky situation in order to get to the sugary food, while the control group obviously avoids that risk. We then tested whether administering memantine could reduce binge eating of the sugary diet, the strength of cues associated with junk food as well as the compulsiveness associated with binge eating. In addition, we studied which area of the brain was mediating the effects of memantine, by injecting the drug directly into the brain of binge eating rats. Our data show that memantine was able to block binge eating of the sugary diet, the willingness to work to obtain a cue associated with junk food, as well as the risky behavior of rats when the sugary diet was provided in a potentially unsafe environment. When we injected the drug directly into the nucleus accumbens of rats, they stopped binge eating. Importantly, the drug had no effects in control rats eating a standard laboratory diet.
Author Interviews, Genetic Research, Nature, NYU/NYMC / 06.11.2014

Leslie Mitchell, PhD New York University Langone Medical Center Boeke Lab, Institute for Systems Genetics NY NY, 10016MedicalResearch.com Interview with: Leslie Mitchell, PhD New York University Langone Medical Center Boeke Lab, Institute for Systems Genetics NY NY, 10016 Medical Research: What is the background for this study? What are the main findings? Dr. Mitchell: One of our major interests is building synthetic chromosomes. Typically we construct synthetic chromosomes using a bottom-up approach, first designing the sequence in silico and then synthesizing and piecing together the DNA to build the designer molecule. While eukaryotic chromosomes are usually linear in structure, oftentimes we build our designer synthetic chromosomes as circular molecules to take advantage of cloning technologies available in E. coli, an organism that tolerates only circular chromosomes. We developed the telomerator as a means by which to convert circular synthetic chromosomes into linear molecules, which more closely resemble the native chromosomes found in eukaryotic cells. We discovered that the telomerator is an extremely effective tool for generating linear derivatives of circular synthetic chromosomes. There are two main reasons for this.
  • First, the action of the telomerator can be assessed using a simple phenotypic assay so it is easy to differentiate cells that encode linear synthetic chromosomes from those with the circular format.
  • Second, the telomerator encodes ‘telomere seed sequences’ that are exposed and recognized by the cell upon linearization, thus the ends of a newly linearized chromosome are protected, which ensures its stability over generations. We put the telomerator to the test by integrating it in 54 different positions on a circular synthetic yeast chromosome called synIXR (Dymond et al. 2011). In 51 of the 54 positions we could successfully linearize the synIXR chromosome and recover viable cells, however many of the different linear derivatives conferred growth defects. We determined the mechanism underlying both the growth defects and lethality associated with linearization to be telomere position effect. In other words, when essential genes were re-positioned near telomeres their reduction in expression due to subtelomeric silencing was detrimental to the cell.
Author Interviews, Biomarkers, Nature, Pancreatic / 03.11.2014

Dr. Murray Korc MD, Professor Department of Medicine, Division of Endocrinology, Biochemistry and Molecular Biology, and the Pancreatic Cancer Signature Center IU Simon Cancer Center, Indiana University School of Medicine Indianapolis, IndianaMedicalResearch.com Interview with Dr. Murray Korc MD, Professor Department of Medicine, Division of Endocrinology, Biochemistry and Molecular Biology, and the Pancreatic Cancer Signature Center IU Simon Cancer Center, Indiana University School of Medicine Indianapolis, Indiana Medical Research: What is the background for this study? What are the main findings? Dr. Korc: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate of 6%. Currently, there are no highly specific and sensitive biomarkers in the blood that can be used for definitively diagnosing the presence of this cancer. In addition, in spite of the usefulness of CA19-9 in differentiating between patients with pancreatic cancer and chronic pancreatitis, this test may yield a significant number of false positive and false negative results, and it may be influenced by the presence of jaundice. These difficulties are compounded by the fact that patients with pancreatitis are at-risk for developing Pancreatic ductal adenocarcinoma. We decided to carry out a study of microRNAs using plasma from treatment-naïve PDAC patients, chronic pancreatitis patients, and controls without pancreatic disease. We focused on microRNAs because they are known to be present in the blood and to be very stable. We chose to conduct these assays in plasma because we reasoned that there would be fewer confounding factors by comparison with either whole blood or serum. We determined that five microRNAs were elevated in plasma from PDAC patients by comparison with either chronic pancreatitis or controls. Importantly, among these five microRNAs, high levels of miR-10b, miR-155, and miR-106b in the plasma were highly accurate in diagnosing Pancreatic ductal adenocarcinoma with ~95% sensitivity and ~100% specificity.
Author Interviews, Bipolar Disorder, Genetic Research, Nature / 21.10.2014

Edward I. Ginns, MD, PhD, Director Program in Medical Genetics and Lysosomal Disorders Treatment and Research Program University of Massachusetts Medical School Reed Rose Gordon Building, Room 137 Shrewsbury, MA 01545MedicalResearch.com: Interview with: Edward I. Ginns, MD, PhD, Director Program in Medical Genetics and Lysosomal Disorders Treatment and Research Program University of Massachusetts Medical School Reed Rose Gordon Building, Room 137 Shrewsbury, MA 01545 Medical Research: What are the main findings of the study? Dr. Ginns: Our study identified that sonic hedgehog signaling, an important brain pathway, is involved in bipolar affective disorder. This finding shows a mechanism and provides new targets for drug development. It suggests that sonic hedgehog signaling can be modulated to help manage bipolar symptoms in adults by using drugs already being studied in clinical trials for other medical conditions. The new findings were uncovered by decades of translational research in the Old Order Amish families of Pennsylvania, where in a few special families in the Amish Study there is a high incidence of both bipolar disorder and a rare genetic dwarfism, Ellis van‐Creveld (EvC) syndrome. No person with EvC had bipolar disorder despite forty years of documented research across multiple generations, suggesting that the genetic cause of this rare dwarfism was protective of bipolar affective disorder.
Author Interviews, Diabetes, Imperial College, Nature / 15.10.2014

Dr. David Hodson PhD Faculty of Medicine, Department of Medicine Imperial College LondonMedicalResearch.com: Interview with: Dr. David Hodson PhD Faculty of Medicine, Department of Medicine Imperial College London Medical Research: What is the background for this research? Dr. Hodson: Type 2 diabetes represents a huge socioeconomic challenge. As well as causing significant morbidity due to chronically elevated glucose levels, this disease is also a drain on healthcare budgets (~$20billion in the UK per year). While current treatments are effective, they are sometimes associated with side effects, usually due to off-target actions on organs such as the heart and brain. In addition, the ability to regulate blood glucose levels more tightly may decrease complications stemming from type diabetes (e.g. nerve, kidney and retina damage). As a proof-of-principle that the spatiotemporal precision of light can be harnessed to finely guide and control drug activity, we therefore decided to produce a light-activated anti-diabetic.
Author Interviews, Genetic Research, Nature, Prostate Cancer / 18.09.2014

Dr. Jyotsna Batra QUT Institute of Health and Biomedical Innovation's Queensland University of Technology Queensland, AustraliaMedicalResearch.com Interview with: Dr. Jyotsna Batra QUT Institute of Health and Biomedical Innovation's Queensland University of Technology Queensland, Australia   Medical Research: What are the main findings of the study? Dr Batra: Prostate cancer is a disease with upto 40% genetic component. Previous Genome-wide association studies have identified 77 risk loci associated with prostate cancer. This study is further extension of previous GWASs and also involved meta-analysis of multi-ethnic populations. Through this large study involving approximately 90,0000 individuals, 23 new susceptibility loci were identified to be associated with prostate cancer, 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer.
Author Interviews, Brigham & Women's - Harvard, Nature / 15.09.2014

MedicalResearch.com Interview with: MichDr. Michael Super, Ph.D.ael Super M.Sc., PhD Senior Staff Scientist Advanced Technology Team Wyss Institute at Harvard Center for Life Science, 2nd Floor Boston MA 02115 Medical Research: What is the background for this study? How big a problem is sepsis? Dr. Super:
  • Sepsis is a major problem and is the primary cause of death from infection. The incidence of sepsis is rising.
  • Sepsis affects more than 18 M people each year and at least 1/3 ( 6 million) die every year of sepsis.
  • Sepsis is a disease that affects the very young and old and it is estimated that 60-80% of childhood deaths in the developing world are due to sepsis.
Author Interviews, Cancer Research, Dartmouth, Melanoma, Nature / 12.09.2014

Dr. Constance Brinckerhoff Professor of Medicine Professor of Biochemistry Geisel School of Medicine at DartmouthMedicalResearch.com Interview with: Dr. Constance Brinckerhoff Professor of Medicine Professor of Biochemistry Geisel School of Medicine at Dartmouth Medical Research: What are the main findings of the study? Dr. Brinckerhoff: The genetic mutation BRAFV600E , frequently found in metastatic melanoma, not only secretes a protein that promotes the growth of melanoma tumor cells, but can also modify the network of normal cells around the tumor to support the disease’s progression. Targeting this mutation with Vemurafenib reduces this interaction, and suggests possible new treatment options for melanoma therapy.
Author Interviews, Duke, General Medicine, Mental Health Research, Nature / 31.07.2014

Rainbo Hultman, PhD Postdoctoral Research Associate Laboratory for Psychiatric Neuroengineering, Principal Investigator Affective Cognitive and Addiction Disorders (ACAD) Research Group Department of Psychiatry and Behavioral Sciences Center for Neuroengineering Duke University Medical Center Durham, NC 27710MedicalResearch.com Interview with: Rainbo Hultman, PhD Postdoctoral Research Associate Laboratory for Psychiatric Neuroengineering, Principal Investigator Affective Cognitive and Addiction Disorders (ACAD) Research Group Department of Psychiatry and Behavioral Sciences Center for Neuroengineering Duke University Medical Center Durham, NC 27710 Medical Research: What are the main findings of the study? Dr. Hultman: Using a mouse model of stress-induced psychiatric dysfunction, we found that the brainwave patterns in two key brain regions (prefrontal cortex, PFC and amygdala, AMY) encode for susceptibility to such dysfunction. Furthermore, such susceptibility can be predicted from the brainwave patterns in these regions before the onset of stress.
Author Interviews, Breast Cancer, Diabetes, Genetic Research, Nature, Vanderbilt / 23.07.2014

[caption id="attachment_6606" align="alignleft" width="125"]Qiuyin Cai, M.D., Ph.D. Associate Professor of Medicine Vanderbilt University Dr. Qiuyin Cai, M.D., Ph.D. Courtesy: Vanderbilt University[/caption] MedicalResearch.com Interview with: Qiuyin Cai, M.D., Ph.D. Associate Professor of Medicine Vanderbilt University Medical Research: What are the main findings of the study? Dr. Cai: We conducted a genome-wide association study in East Asians to search for additional genetic changes that are linked to breast cancer development. The study was conducted as part of the Asia Breast Cancer Consortium, which includes 22,780 women with breast cancer and 24,181 control subjects. We found DNA sequence changes in two genes, PRC1 and ZC3H11A, and a change near the ARRDC3 gene were associated with breast cancer risk. These results were also replicated in a large consortium, including 16,003 breast cancer cases and 41,335 control subjects of European ancestry.
Author Interviews, Breast Cancer, Genetic Research, Nature / 23.07.2014

MedicalResearch.com Interview with Dr Lim Weng Khong Research Fellow, National Cancer Centre Singapore. Medical Research: What are the main findings of the study? Dr Lim Weng Khong: This study uncovered the genetic cause fibroadenomas, which are very common benign breast tumours in women. The team from National Cancer Centre Singapore, Singapore General Hospital and Duke-NUS Graduate Medical School identified a critical gene called MED12 that has frequent durations in a remarkable 60 per cent of fibroadenomas studied. Their findings have been published in the top-ranked journal Nature Genetics.
Author Interviews, Diabetes, Genetic Research, Nature / 30.06.2014

Dr. Domenico Accili MD Professor of Medicine Department of Medicine Columbia University College of Physicians and Surgeons New York, New York 10032MedicalResearch.com: Interview with Dr. Domenico Accili MD Professor of Medicine Department of Medicine Columbia University College of Physicians and Surgeons New York, New York 10032 MedicalResearch: What are the main findings of the study? Dr. Accili: By switching off a single gene (foxo1), scientists at Columbia University’s Naomi Berrie Diabetes Center have converted human gastrointestinal cells into insulin-producing cells, demonstrating in principle that a drug could retrain cells inside a person’s GI tract to produce insulin.