Author Interviews, Nature, OBGYNE / 08.07.2015

Shawn L. Chavez, Ph.D Assistant Scientist/Professor Oregon National Primate Research Center OHSU | Oregon Health & Science UniversityMedicalResearch.com Interview with: Shawn L. Chavez, Ph.D Assistant Scientist/Professor Oregon National Primate Research Center OHSU | Oregon Health & Science University Medical Research: What is the background for this study? Dr. Chavez: This study builds upon a previous study also published in Nature Communications in 2012, which demonstrated that chromosomally normal and abnormal 4-cell human embryos can be largely distinguished by combining the timing intervals of the first three cell divisions with the presence or absence of a dynamic process called cellular fragmentation. The current study further combines time-lapse imaging of embryo development and full chromosome analysis with high throughout single-cell gene expression profiling to assess the chromosomal status of human embryos up to the 8-cell stage. Medical Research: What are the main findings? Dr. Chavez: The key findings of this research were that by measuring the duration of the first cell division, one can identify which embryos are chromosomally normal versus abnormal even earlier in development. By examining gene expression at a single-cell level, we were able to correlate the chromosomal make-up of an embryo to a subset of 12 genes that are activated prior to the first cell division. These genes likely came from either the egg or sperm and can be used to predict whether an embryo will be chromosomally normal or abnormal within the first 30 hours of development. (more…)
Author Interviews, Heart Disease, Nature / 07.07.2015

Dr. Gary K OwensRobert M. Berne Cardiovascular Research Center University of Virginia, Charlottesville, VirginiaMedicalResearch.com Interview with: Dr. Gary K Owens Ph.D Robert M. Berne Cardiovascular Research Center University of Virginia, Charlottesville, Virginia Medical Research: What is the background for this study? Dr. Owens: The leading cause of death in the USA and worldwide is cardiovascular disease with many of the clinical consequences including heart attacks (myocardial infarctions) and strokes being secondary consequences of atherosclerosis, commonly referred to as hardening of the arteries. Importantly, a heart attack is not caused by gradual narrowing of a large coronary artery by the atherosclerotic plaque, but rather is caused by acute rupture of a plaque that results in a catastrophic thrombotic event that can completely occlude a major coronary artery shutting off blood supply to a major heart region. Similarly, rupture of a plaque can result in formation of a thrombus that breaks off and circulates to a cerebral vessel where it can occlude blood flow to a brain region leading to a stroke. As such, it is critical to understand the mechanisms that regulate the stability of plaques, and the likelihood of plaque rupture. The general dogma among clinicians and cardiovascular researchers has been that atherosclerotic plaques that have an abundance of macrophages and macrophage-derived foam cells relative to smooth muscle cells (SMC), the cells that normally line all of your blood vessels, are less stable and more prone to rupture with subsequent clinical consequences. However, the evidence for this is based on use of methods that are unreliable in identifying which cells within the plaque are truly derived from macrophages versus SMC, and even more importantly, what mechanisms regulate phenotypic transitions of these cells that are critical in the pathogenesis of this disease. Indeed, results of studies in cultured smooth muscle cells and macrophages have shown that each cell can express markers of the other cell type in response to stimuli likely to be present within advanced atherosclerotic lesions while down-regulating expression of their typical cell selective markers. As such, previous studies in the field have likely mis-identified which cell is which in many cases. The goals of our studies were to clearly identify which cells within advanced atherosclerotic lesions are derived from SMC, to determine the various phenotypes exhibited by these cells and their functional role in lesion pathogenesis,  and to determine what regulates these phenotypic transitions. (more…)
Author Interviews, Biomarkers, Chemotherapy, Nature, Pancreatic / 01.07.2015

Dr. Janaiah Kota Assistant Professor, Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, IN,MedicalResearch.com Interview with: Dr. Janaiah Kota Assistant Professor, Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, IN, Medical Research: What is the background for this study? Dr. Kota: Pancreatic cancer tumors are surrounded by a thick fibrotic shell known as “stroma” which protects the cancer cells from anticancer drugs such as chemotherapy. However, complete depletion of tumor stroma leads to more aggressive disease and decreases survival. The stromal abundance needs to be appropriately moderated (i.e. not too much nor too little) in pancreatic tumors. None of the current anti-stromal therapies have been effective enough to resolve this problem. Unless we understand the molecular signatures associated with tumor stroma, it will be challenging to develop an effective therapeutic strategy. There is a desperate need to develop new therapies for pancreatic cancer as only 7 percent of people with the disease survive more than 5 years after diagnosis. According to the National Cancer Institute, there will be an estimated 48,960 new cases of pancreatic cancer and 40,560 deaths from the disease in 2015. Medical Research: What are the main findings? Dr. Kota: We found that the loss of microRNA-29 (miR-29) is a common phenomenon of pancreatic cancer stromal cells, and that by restoring it, the viability and growth of the cancerous cells and stromal accumulation was reduced. The use of miR-29 as a therapeutic agent may be more effective in targeting reactive stroma, as a single miRNA regulates the expression of several genes associated with disease mechanisms. We expect that this novel approach has the potential to overcome the problems associated with current anti-stromal drugs and could lead to improved therapeutic strategies, enhanced drug delivery to the tumor bed, and, in the future, improved patient survival. (more…)
Asthma, Author Interviews, Nature, Nutrition / 01.07.2015

Dr. Alison Thorburn Ph.D. School of Medical and Applied Sciences, Central Queensland University Rockhampton, Queensland 4702, AustraliaMedicalResearch.com Interview with: Dr. Alison Thorburn Ph.D. Department of Immunology Monash University Victoria, Australia Medical Research: What is the background for this study? Dr. Thorburn: Asthma is a highly prevalent disease in the Western World. The prevailing explanation for this has been the hygiene hypothesis, which proposes that a decline in family size and improved hygiene has decreased exposure to infectious agents and therefore resulted in dysregulated immune responses that lead to asthma. However, recently there has been more attention on the role of diet and the gut microbiota in explaining the prevalence of inflammatory diseases in Western World. Indeed, many studies implicate obesity, as well as a high fat, low fruit and vegetable diet with higher prevalence of asthma. On the other hand, a Mediterranean diet, which is high in fruit and vegetables, is associated with lower prevelance of asthma. Interestingly, the consumption of dietary fiber is reduced in severe asthmatics. These and other data suggest that the diet (particularly dietary fibre) and the gut microbiota may play an important role in the development of asthma. Medical Research: What are the main findings? Dr. Thorburn: The main findings of this study are that: -        In mice: A high-fiber diet promotes a gut microbiota that produces high levels of anti-inflammatory short-chain fatty acids (SCFAs), particularly acetate. Acetate (alkaline form of vinegar) suppressed the development of allergic airways disease (AAD, a model for human asthma) in adult mice and the offspring of pregnant mice. -        In humans: High dietary fiber intake during late pregnancy is associated with higher acetate levels in the serum and a decrease in the percentage of infants showing predictors for asthma development in later life. -        The mechanism underlying these findings involves increasing T regulatory cell number and function through epigenetic mechanisms, which enhance immune regulation to prevent inflammation. (more…)
Author Interviews, Heart Disease, Nature, Nutrition / 23.06.2015

MedicalResearch.com Interview with: Prof. Wilhelm Krek Institute of Molecular Health Sciences Zürich, Switzerland MedicalResearch: What is the background for this study? What are the main findings? Prof. Krek: Fructose and glucose are major components of dietary sugars consumed in the western world. A current prevailing view holds that glucose is used directly by various tissues as an energy source while fructose is first and foremost metabolized to fat by the liver arguing that these dietary sugars are metabolized differently despite having identical caloric values. Accordingly, overconsumption of fructose causes fatty liver disease and through dissemination of fat to peripheral organs such that adipose tissue contributes to obesity. The key enzyme in fructose metabolism is ketohexokinase (KHK). KHK-A and KHK-C are two isoforms of KHK that are produced through mutually exclusive alternative splicing of the KHK pre-mRNA. KHK-C displays a much higher affinity for fructose than KHK-A. Unlike other tissues that normally express KHK-A, the liver produces predominantly KHK-C providing a possible explanation of the above-noted pathologies upon overconsumption of fructose. Whether fructose metabolism is subject to signal-induced changes in alternative splicing of KHK isoform expression as a mechanism to mediate context-dependent changes in cell metabolism is not known. In this work, we identify the splicing factor SF3B1 as a key mediator of ketohexokinase alternative splicing and thus activator of fructose metabolism and further show that the SF3B1-KHK system is a direct target of regulation by hypoxia and promoter of heart disease. From the analysis of a series of genetic mouse models of pathologic cardiac hypertrophy and human samples of heart disease, we conclude that activation of the newly identified HIF1α-SF3B1-KHK-C axis and the ensuing promotion of fructose metabolism is essential for pathologic stress-induced anabolic growth and the development of heart disease. (more…)
Author Interviews, Brigham & Women's - Harvard, Dermatology, Nature, Surgical Research / 23.06.2015

MedicalResearch.com Interview with: Dr. Alexander Golberg Ph.D. Center for Engineering in Medicine Department of Surgery, Massachusetts General Hospital Harvard Medical School, and Shriners Burns Hospital Boston, MA, 02114 Porter School of Environmental Studies Tel Aviv University, Israel MedicalResearch: What is the background for this study? What are the main findings? Dr. Golberg: Well, the population grows and becomes older. Degenerative skin diseases affect one third of individuals over the age of sixty. Current therapies use various physical and chemical methods to rejuvenate skin; but since the therapies affect many tissue components including cells and extracellular matrix, they may also induce significant side effects, such as scarring. We report on a new, non-invasive, non-thermal technique to rejuvenate skin with pulsed electric fields. The fields destroy cells while simultaneously completely preserving the extracellular matrix architecture and releasing multiple growth factors locally that induce new cells and tissue growth. We have identified the specific pulsed electric field parameters in rats that lead to prominent proliferation of the epidermis, formation of microvasculature, and secretion of new collagen at treated areas without scarring. Our results suggest that pulsed electric fields can improve skin function and thus can potentially serve as a novel non-invasive skin therapy for multiple degenerative skin diseases. (more…)
Author Interviews, Immunotherapy, Melanoma, Nature / 19.06.2015

MedicalResearch.com Interview with: Chiara Martinoli, PhD Medical Oncology of Melanoma European Institute of Oncology Milan, Italy MedicalResearch: What is the background for this study? What are the main findings? Dr. Martinoli: The recent advent of new immunomodulatory drugs and targeted therapies is changing the therapeutic algorithm for metastatic melanoma patients. Immunomodulation with the anti-CTLA-4 antibody ipilimumab improves survival but is not devoid of potential risks. There is an urgent need for biomarkers to identify patients best suited to receive this therapy, in order to maximize treatment benefit and spare toxicities. In this study, by analyzing pre-therapy hematological parameters of a large group of metastatic melanoma patients treated with ipilimumab, we showed that neutrophil-to-lymphocyte ratio is strongly and independently associated to patient outcome. Patients with a low baseline neutrophil-to-lymphocyte ratio had a double-reduced risk of disease progression and a two-to-four-fold reduced risk of death, regardless of age, sex and LDH. (more…)
Author Interviews, Biomarkers, Cancer Research, Mayo Clinic, MD Anderson, Nature / 18.06.2015

Eric Jonasch, MD Associate Professor Department of Genitourinary Medical Oncology University of Texas MD Anderson Cancer Center Houston, TXMedicalResearch.com Interview with: Eric Jonasch, MD Associate Professor Department of Genitourinary Medical Oncology University of Texas MD Anderson Cancer Center Houston, TX and Dr. Thai H. Ho, MD Ph.D. Department of Oncology Mayo Clinic Scottsdale ArizonaDr. Thai H. Ho, MD Ph.D. Department of Oncology Mayo Clinic Scottsdale Arizona Medical Research: What is the background for this study? What are the main findings? Response: The blueprints of a cell are encoded in DNA strands (its genome) which are highly compressed in order to fit into a tiny cell. The reading (called the epigenome) of these DNA ‘blueprints’ determines whether that cell will develop into a kidney cell or another type of cell. However, in cancer, errors occur either in the blueprints themselves or the cell makes mistakes in reading the blueprints. Cancers of the kidney affect more than 61,000 patients annually and over 13,000 patients die annually, making it one of the top 10 leading causes of cancer deaths. Studies have revealed that mutations occur in genes that regulate how our DNA ‘blueprints’ are compacted in greater than >50% of kidney cancers, making these genes as a group the most frequently mutated. In our study, we identified that these errors that initially arise in an early kidney cancer lead to propagation of these same errors in metastases, a phenomenon in which the cancer has spread to another organ and is a major cause of death. Furthermore, we generated a detailed map of these epigenomic changes in patient-derived tumors. (more…)
Author Interviews, Biomarkers, Nature, Prostate Cancer, Technology / 27.05.2015

Gabriel Popescu PhD Associate Professor Department of Electrical and Computer Engineering & Bioengineering University of Illinois at Urbana-Champaign Beckman Institute for Advanced Science and Technology Urbana, IL 61801MedicalResearch.com Interview with: Gabriel Popescu PhD Associate Professor and Shamira Sridharan, Ph.D. candidate Quantitative Light Imaging Laboratory, Department of Bioengineering, Beckman Institute for Advanced Science and Technology University of Illinois at Urbana Champaign Urbana, IL Medical Research: What is the background for this study? What are the main findings? Dr. Popescu: We developed a new optical tool that can identify patients at high risk for recurrence of prostate cancer after undergoing radical prostatectomy as treatment.  Early identification of risk for recurrence can allow early treatment of disease. Our main finding was that among individuals with worse disease outcomes, the tissue is more disorganized.  This manifests as a decrease in anisotropy, or light scattering angle, which reports on nano-scale differences in tissue architecture. (more…)
Author Interviews, Diabetes, Nature, Neurological Disorders, Vegetarians / 26.05.2015

Ulka Agarwal, M.D. California State University, East Bay Student Health and Counseling Services, Hayward, MedicalResearch.com Interview with: Ulka Agarwal, M.D. California State University, East Bay Student Health and Counseling Services Hayward, CA MedicalResearch: What is the background for this study? What are the main findings? Dr. Agarwal: Diabetic peripheral neuropathy affects 60 percent of patients with type 2 diabetes and can come with painful symptoms but limited treatment options. We thought a dietary intervention may help alleviate these symptoms since glycemic control plays a role in diabetes complications. To get started with the pilot, we put 17 adults on a low-fat vegan diet for 20 weeks and prescribed weekly nutrition classes. We found significant improvements in pain, measured by the Short Form McGill Pain questionnaire, the Michigan Neuropathy Screening Instrument physical assessment, and through electrochemical skin conductance in the foot. The participants also lost an average of 14 pounds. (more…)
Author Interviews, Nature, NIH / 13.05.2015

Humphrey Yao, Ph.D. Lead Researcher Reproductive and Developmental Biology Laboratory National Institute of Environmental Health Sciences (NIEHS) National Institutes of Health (NIH) Research Triangle Park, North CarolinaMedicalResearch.com Interview with: Humphrey Yao, Ph.D. Lead Researcher Reproductive and Developmental Biology Laboratory National Institute of Environmental Health Sciences (NIEHS) National Institutes of Health (NIH) Research Triangle Park, North Carolina Medical Research: What is the background for this study? What are the main findings? Dr. Yao: We wanted to understand how an organ forms, and what basic cell types were needed to form an organ. So, we used a mouse ovary model system to understand the process. The functional unit of the ovary is called the follicle, and it is made up of three types of cells — the maturing egg, granulosa cells, and theca cells. Scientists knew where the egg and the granulosa cells came from, but no one knew where theca cells came from. Theca cells are important, because they allow females to produce the hormones that sustain follicle growth. Researchers also lacked information about how the egg, granulosa cells, and theca cells talked to each other to promote growth and maintain a healthy ovary. We made two discoveries. First, we answered the long-standing question of theca cell origin by determining that they have two sources, both inside and outside of the ovary. We don’t yet know why theca cells have two sources. Second, we uncovered the molecular signaling system that the egg, granulosa cells, and theca cells use to communicate. We didn’t expect to find this three-way cellular crosstalk, but now that we know how they signal each other, I believe we are closer to understanding how an ovary develops and what happens when something goes wrong. Ovarian disorders, such as premature ovarian failure and polycystic ovarian syndrome, may start when cellular communication is altered or if the various cells fail to develop properly. (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, Cancer Research, Nature, UT Southwestern / 03.05.2015

Dr. Alec (Chengcheng) Zhang Michael L. Rosenberg Scholar in Medical Research Associate Professor of Physiology and Developmental Biology Member of the Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical CenterMedicalResearch.com Interview with: Dr. Alec (Chengcheng) Zhang Michael L. Rosenberg Scholar in Medical Research Associate Professor of Physiology and Developmental Biology, Member of the Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical Center Medical Research: What is the background for this study? What are the main findings? Response: Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. Treatments for AML yield poor outcomes, especially for the typical senior patients. The medical need for new therapies for AML is underscored by the fact that no new therapies for AML have been approved in over 30 years. There are over 50 experimental agents in clinical trials for the treatment of AML today, although only a few agents have promising data to date. New molecular targets and therapeutic strategies are needed for AML treatment. In 2012, we published a paper showing that we cloned the human leukocyte immunoglobulin-like receptor B2 (LILRB2) as a receptor for several angiopoietin-like proteins (Angptls) (Zheng et al 2012 Nature 485:656-660). The LILRB family receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and are classified as inhibitory receptors because ITIM motifs can recruit phosphatases SHP-1, SHP-2, or SHIP to negatively regulate immune cell activation. Surprisingly, in that work, we showed that PirB, the mouse ortholog of LILRB2, is expressed by AML stem cells (AML-SCs) and supports AML development. Although counterintuitive, this result is consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. In the current paper, we continued the research and report that a number of receptors containing the ITIMs are crucial for the development of AML. We mainly focus on studying the function and downstream signaling of LAIR1 as a representative ITIM-containing receptor. We found that the deletion of LAIR1 does not affect normal hematopoiesis but abolishes leukemia development in several different mouse leukemia models. We also identified a mechanism by which LAIR1 supports AML development, showing that the LAIR1/SHP-1/CAMK1/CREB pathway sustains the survival and self-renewal of AML cells. Importantly, our findings are well supported by bioinformatics analysis of AML patient databases and experimental results of human leukemia cells. Since certain ITIM-containing receptors are essential for AML cells but not critical for normal hematopoiesis, and blocking their signaling can boost immunity, these ITIM-containing receptors including LAIR1 represent ideal targets for treating AML. (more…)
Aging, Author Interviews, Nature / 03.05.2015

Juan Carlos Izpisua Belmonte PhD Professor, Gene Expression Laboratory Roger Guillemin Chair Salk Institute For Biological ScienceMedicalResearch.com Interview with: Juan Carlos Izpisua Belmonte PhD Professor, Gene Expression Laboratory Roger Guillemin Chair Salk Institute For Biological Science MedicalResearch: What is the background for this study? What are the main findings? Response: Werner protein (WRN) plays roles in DNA replication, transcription, repair as well as telomere maintenance. Mutations in WRN are associated with Werner syndrome. In the current study we discovered that WRN was interacting with proteins implicated in heterochromatin maintenance. We observed that mutations in the WRN protein led to alterations in heterochromatin and those alterations are drivers of the aging process. (more…)
Author Interviews, Endocrinology, Nature, NYU, Social Issues / 16.04.2015

Bianca Jones Marlin, PhD Froemke Laboratory New York University Langone School of MedicineMedicalResearch.com Interview with: Bianca Jones Marlin, PhD Froemke Laboratory New York University Langone School of Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Marlin: Oxytocin is a hormone that plays an important role in the expression of social and parental behaviors, but little is know about how it works in the brain to produce these behaviors. Virgin mice will usually ignore, and sometimes cannibalize newborn mouse pups. Our study has shown that oxytocin works in the auditory cortex of virgin mice to change both their neural responses, and eventually their behaviors, to mirror the maternal response. (more…)
Author Interviews, Genetic Research, Nature, Pancreatic, UT Southwestern / 10.04.2015

Dr. Agnieszka Witkiewicz MD Associate Professor of Pathology Harold C. Simmons Comprehensive Cancer Center UT SouthwesternMedicalResearch.com Interview with: Dr. Agnieszka Witkiewicz MD Associate Professor of Pathology Harold C. Simmons Comprehensive Cancer Center UT Southwestern MedicalResearch: What is the background for this study? Dr. Witkiewicz: Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis, with a five year survival rate of approximately 6%. This poor outcome is related to multiple factors, including the relatively late stage of diagnosis, many patients presenting with unresectable disease, and therapy recalcitrance resulting in disease recurrence in spite of operable disease and systemic therapy. Thus far, insights into how to target the treatment of Pancreatic ductal adenocarcinoma have remained unclear in spite of prior sequencing efforts. MedicalResearch: What are the main findings? Dr. Witkiewicz: The underlying critical finding of the study was that Pancreatic ductal adenocarcinoma is genetically diverse and that, in principle, this diversity could be exploited for the treatment of disease.   Specifically, many cases harbored deregulation in pathways that are the target for drug development.   For example, we identified cases that were driven by BRAF V600E and that were sensitive to the FDA approved drug Vemurafenib.   Similarly, multiple cases harbored defects in DNA repair processes that impart sensitivity to select chemotherapeutic agents and PARP inhibitors.  Common pathway deregulation was observed in reference to beta-catenin, notch, hedgehog, chromatin remodeling, and cell cycle regulatory pathways that are all targets for therapeutic intervention. (more…)
Author Interviews, Cancer Research, Nature, NYU / 03.04.2015

MedicalResearch.com Interview with: Alka Mansukhani Ph.D. Associate Professor Department of Microbiology NYU Langone Medical CenterMedicalResearch.com Interview with: Alka Mansukhani Ph.D. Associate Professor Department of Microbiology Member of the Laura and Isaac Perlmutter Cancer Center NYU Langone Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Mansukhani: Osteosarcoma is a highly aggressive pediatric bone cancer that is almost always advanced at diagnosis. Treatment outcomes have not improved in three decades and 40% of patients eventually succumb to the disease. A few years ago we identified that normal bone stem cells relied on the function of a gene called Sox2 to remain immature an self-renew. We went on to find that osteosarcoma cancer stem cells, that arise from immature bone cells, express high levels of Sox2. Like their normal counterparts, these cancer cells also need Sox2. Sox2 maintains the stemness properties of the cancer cells as well as their ability to form tumors in mice. Depleting Sox2 resulted in cells that had reduced tumor-forming potential and instead, were able to become mature bone cells. http://www.stbaldricks.org/blog/post/new-discovery-may-hold-the-key-to-destroying-osteosarcoma/ In this new study we have identified the mechanism by which Sox2 maintains the properties of osteosarcoma cancer stem cells. Sox2 inactivates the growth restraining function of the well-known tumor suppressive hippo pathway. Hippo signaling restrains the activity of a potent oncogene, YAP. In the osteosarcoma stem cells, Sox2 directly represses two genes (Nf2 and WWC1) in the hippo pathway and thereby unleashes the growth promoting activity of YAP. Like Sox2, YAP is required to maintain the tumorigenic properties of osteosarcoma cells. Consistently, we found high YAP and low NF2 and WWC1 expression in human osteosarcoma tissues. Our study makes a direct connection between Sox2 and repression of hippo signaling to enable YAP activity in osteosarcomas. This mechanism also operates in glioblastoma, an aggressive brain tumor. (more…)
Author Interviews, Nature / 18.03.2015

MedicalResearch.com Interview with: Dr. Pak Kin Wong Ph.D. Aerospace& Mechanical Engineering Department Biomedical Engineering and Bio5 Institute The University of Arizona Medical Research: What is the background for this study? What are the main findings? Response: Collective cell migration is central to various (patho)physiological processes, such as tissue development, regeneration, and cancer metastasis. At the onset of the process, a subset of cells acquires distinct leader cell phenotypes in the initially homogeneous population and leads the migration. However, how leader cells are initiated among the initial homogeneous population and how leader cell density is regulated during collective migration remain unknown. In this study, we demonstrate the formation of leader cells is regulated dynamically by Dll4 signaling through Notch1 and cellular stress near the leading edge. Our finding provides a molecular basis for the stochastic emergence of leader cells, a process originally considered random. (more…)
Author Interviews, Genetic Research, McGill, Nature / 12.03.2015

Prof. Moshe Szyf Ph.D. James McGill Professor of Pharmacology and Therapeutics McGill UniversityMedicalResearch.com Interview with: Prof. Moshe Szyf Ph.D. James McGill Professor of Pharmacology and Therapeutics McGill University Medical Research: What is the background for this study? What are the main findings? Dr. Szyf: Humans exhibit a marked variation in traits both physical and behavioral and different susceptibilities  for developing disease. What causes this inter-individual variation? The prevailing dogma has been that changes in the sequences of genes or heritable genetic differences are responsible for these  differences. We tested here an alternative hypothesis that perhaps some of the reason for this natural variation in traits is not caused by differences in inherited genes but by “epigenetic” changes that alter the way genes work without changing the genes.  The main difference between genetic and epigenetic changes is that epigenetic changes could be introduced by experience and exposure to environment. The experiences that can cause epigenetic changes include physical as well as social environments. Although we had known that epigenetic differences occur in humans and animals we didn’t have evidence that these changes are behind the natural variation in traits that is observed in humans and animals. Ants are an exciting biological paradigm that exhibits quantitative variations in size and therefore provided a unique opportunity to test this hypothesis. (more…)
Author Interviews, Gastrointestinal Disease, Nature, Nutrition / 08.03.2015

Benoit Chassaing, Ph.D. Post-Doctoral Fellow Dr. Gewirtz's lab. Institute for Biomedical Sciences Center for Inflammation, Immunity, & Infection Georgia State University Atlanta GA 30303MedicalResearch.com Interview with: Benoit Chassaing, Ph.D. Post-Doctoral Fellow Dr.  Gewirtz's lab. Institute for Biomedical Sciences Center for Inflammation, Immunity, & Infection Georgia State University Atlanta GA 30303 Medical Research: What is the background for this study? What are the main findings? Dr. Chassaing: A key feature of inflammatory bowel diseases and metabolic syndrome is alteration of the gut microbiota in a manner that promotes inflammation. Importantly, incidence of IBD and metabolic syndrome has been markedly increasing since about the mid-20th century, and this dramatic increase has occurred amidst constant human genetics, suggesting a pivotal role for an environmental factor. We considered that any modern additions to the food supply might play an important role, and addition of emulsifiers to food seems to fit the time frame of increased incidence in these diseases. We found that emulsifiers, which are added to most processed foods to aid texture and extend shelf life, can alter the gut microbiota composition and localization to induce intestinal inflammation that promotes development of inflammatory bowel disease and metabolic syndrome. (more…)
Author Interviews, Genetic Research, Nature / 04.03.2015

Fernando Pardo-Manuel De Villena, PhD Professor and Associate Chair for Research Department of Genetics School of Medicine University of North Carolina at Chapel HMedicalResearch.com Interview with: Fernando Pardo-Manuel De Villena, PhD Professor and Associate Chair for Research Department of Genetics School of Medicine University of North Carolina at Chapel Hill Medical Research: What is the background for this study? What are the main findings? Response: We set out to identify mutations that affect diseases through changes in gene expression. Our first major finding is that some mouse populations such as the Collabaorative Cross are exceptionally good models to achieve this goal. We also wanted to sort out an ongoing controversy about the number, location and type of genes that are differentially expressed when you inherit them from your mom or your dad (so called imprinted genes).  We conclude that to some extent both sides were right; there are only a limited number of imprinted genes in the classical sense but there are also hundreds or thousands of genes that are preferentially expressed from the father. (more…)
Author Interviews, HIV, Nature, Scripps / 04.03.2015

Dr. Michael Farzan PhD Vice Chairman Department of Immunology and Microbial Science Florida Campus The Scripps Research InstituteMedicalResearch.com Interview with: Dr. Michael Farzan PhD Vice Chairman Department of Immunology and Microbial Science Florida Campus The Scripps Research Institute Medical Research: What is the background for this study? Dr. Farzan: The key points are that HIV-1 needs two receptors – CD4 and CCR5 – to infect cells.  CD4’s primary job is to initially bind the viral entry protein, which upon CD4 binding, uncloaks its CCR5 binding site.   A number of years ago we observed that CCR5 had an unusual modification that was really important to HIV-1.  We later showed that antibodies – protein your body makes to protect from pathogens – mimics CCR5 by incorporating this modification.  We develop a peptide from one of these antibodies that mimics CCR5. Medical Research: What are the main findings? Dr. Farzan: By combined a soluble form of CD4 with this CCR5-mimicking peptide, we created a protein that neutralizes all HIV-1 isolates tested, including the hardest-to-stop viruses, as well as distantly related viruses found in monkeys.  It does so better than the best HIV-1 antibodies.  We expressed this protein using a commonly used gene-therapy vector, and showed that after a one-time inoculation we could protect from doses much higher than most humans are likely to see, and we did so 34 weeks after the inoculation. (more…)
Author Interviews, Cancer Research, MD Anderson, Nature, Personalized Medicine / 28.02.2015

Dr. Anil Sood MD Professor of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer CenterMedicalResearch.com Interview with: Dr. Anil Sood MD Professor of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer Center Medical Research: What is the background for this study? What are the main findings? MedicalResearch: What is the background for this approach? What are the main findings? Dr. Sood: The background involves several different issues: management approaches have varied quite a bit across the US; definition of “optimal” surgery and rates of complete surgical removal of tumor (R0) have also varied. It is quite apparent that patients who benefit the most from surgery upfront are those who have removal of tumor resection. To address these issues, we have implanted a much more personalized approach whereby patients with suspected advanced ovarian cancer undergo laparoscopic assessment using a validated scoring system (based on the pattern and extent of disease noted during laparoscopic assessment); patients with a score <8 undergo upfront debulking surgery and those with a score ≥8 receive neoadjuvant chemotherapy followed by surgery after 3-4 cycles. To date, this program has been fully implemented as part of the Moonshot Program at M.D. Anderson. This program has already resulted in several benefits – for example, prior to this algorithm being put into place among all patients with suspected advanced ovarian cancer, around 20% would have removal of tumor resection; after the implementation of the algorithm, of those going to upfront debulking surgery (after laparoscopic assessment), almost 85% of times removal of tumor resection can be achieved. Also, this method of treatment is allowing for new and innovative clinical trial designs. (more…)
Author Interviews, Mayo Clinic, Nature, Pancreatic / 24.02.2015

Peter Storz, Ph.D. Associate Professor & Consultant Department of Cancer Biology Mayo Clinic Jacksonville, FL 32224MedicalResearch.com Interview with: Peter Storz, Ph.D. Associate Professor & Consultant Department of Cancer Biology Mayo Clinic Jacksonville, FL 32224   Medical Research: What is the background for this study? What are the main findings? Dr. Storz:   Our study focuses on cellular signaling mechanisms that lead to the initiation of pancreatic cancer. After acquisition of an oncogenic mutation of Kras, pancreatic acinar cells can undergo a transdifferentiation process to a phenotype that gives rise to pancreatic intraepithelial lesions (PanINs). These lesions then can further progress to pancreatic cancer. (more…)
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). (more…)
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). (more…)
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. (more…)