Author Interviews, Heart Disease, Johns Hopkins, Nature, Technology / 11.05.2016

MedicalResearch.com Interview with: Natalia Trayanova PhD, FHRS, FAHA Murray B. Sachs Endowed Chair Professor of Biomedical Engineering Joint Appointment, Medicine Johns Hopkins University Institute for Computational Medicine Johns Hopkins University Baltimore, MD MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Trayanova: The methodology for modeling cardiac electrical function has matured sufficiently that we can now create computational models of the electrical functioning of the entire heart. My research is focused on translating this methodology into the clinic. The goal is to create, if you will, "a virtual heart for every patient", that will enable the physician to play our scenarios that manifest the heart dysfunction in the given patient, and to enable physicians to make personalized decisions about patient treatment. The present paper is the first application of this overall vision. The motivation for this particular paper was that determining which patients are at risk for sudden cardiac death represents a major unmet clinical need. Patients at risk receive life-saving implantable defibrillators (ICDs), but because of the low sensitivity and specificity of current approach (based on low ejection fraction), risk assessment is inaccurate. Thus, many patients receive ICDs without needing them, while others die of sudden cardiac death because they are not targeted for ICD therapy under the current clinical recommendations. Our goal was to develop a non-invasive personalized virtual-heart risk assessment tool that has the potential to ultimately prevent sudden cardiac death and avoid unnecessary ICD implantations. (more…)
Author Interviews, Genetic Research, Nature / 10.05.2016

MedicalResearch.com Interview with: Serena Nik-Zainal MD PhD Wellcome Beit Fellow & Honorary Consultant in Clinical Genetics CDF Group Leader Wellcome Trust Sanger Institute United Kingdom  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Nik-Zainal: We have used the massive improvement in speed of "sequencing" (reading the human genetic material) in order to obtain comprehensive whole genome maps of 560 human breast cancer patients. This is the largest whole genome sequencing study of a single cancer type in the world. We wanted to forensically search these cancers, find all the important genes that drive breast cancer, find all the important mutation patterns that tell us something about why breast cells turn into cancer cells and then to pull it altogether for each patient. We wanted to be able to "profile" each cancer patient, to see if we could further our understanding of personal cancer genomes. In all, we had 556 female and four male patients, and they were sought from all over the world – USA, Europe and Asia. (more…)
ALS, Alzheimer's - Dementia, Author Interviews, Nature / 07.05.2016

MedicalResearch.com Interview with: Ana Pereira, MD Instructor in Clinical Medicine Bruce McEwen's laboratory Rockefeller University  MedicalResearch.com: What is the background for this study? Dr. Pereira: The neurons most susceptible to dying in Alzheimer’s disease are the ones that use glutamate as a neurotransmitter (chemical messengers that enable neurotransmission). Glutamate is the major excitatory neurotransmitter in the brain and its regulation is critical for learning and memory. When glutamate is not located in the correct place and amount, it causes several deleterious effects to neurons that can ultimately lead to cell death. Importantly, the glutamate transporter EAAT2 is the dominant regulator of glutamate levels and it is highly depressed in Alzheimer’s disease. Furthermore, glutamatergic dysregulation is implicated in several pathological mechanisms in Alzheimer’s disease including the release and toxicities of the proteins implicated in Alzheimer’s disease: amyloid-beta (which form amyloid plaques) and tau (which form neurofibrillary tangles). Better regulation of glutamatergic neural circuits is critically important to effectively treat age-related cognitive decline and Alzheimer’s disease. (more…)
Author Interviews, Cancer Research, Gastrointestinal Disease, Nature / 24.04.2016

MedicalResearch.com Interview with: Zhimin (James) Lu, M. D., Ph. D Ruby E. Rutherford Distinguished Professor Department of Neuro-Oncology MD Anderson Cancer Center Houston, TX 77030 MedicalResearch.com: What is the background for this study? Dr. Lu: Among primary liver cancers, hepatocellular carcinoma (HCC) is the most common histological subtype, accounting for 70-85% of all cases. HCC incidence is increasing in many parts of the world, including developing countries and developed countries such as the United States. HCC has a very poor prognosis, and the overall 3-year survival rate for patients with HCC is approximately 5%. The potentially curative treatments of HCC are resection and liver transplantation. However, most patients with hepatocellular carcinoma present with advanced disease and underlying liver dysfunction and are not suitable candidates for these treatments. Thus, they generally have a poor prognosis, with a median survival time of less than 1 year. The increasing incidence and mortality rates of hepatocellular carcinoma, along with a lack of effective curative treatment options for advanced HCC, have rendered this disease a major health problem worldwide. Thus, a better understanding of HCC tumorigenesis and the development of better diagnostic and therapeutic approaches based on an understanding of the molecular mechanisms that drive hepatocellular carcinoma progression are greatly needed. The liver, as a major metabolic organ, catalyzes dietary sugar. Dietary sugar encompasses several carbohydrates, including starch, sucrose, and high-fructose corn syrup, each of which is composed of glucose with or without fructose. Starch, which is found in bread and rice, is a glucose polymer. Sucrose is a disaccharide made up of 50% glucose and 50% fructose. High-fructose corn syrup, a common constituent of soft drinks, is a mixture of approximately 40% glucose and 60% fructose. Dietary fructose is also derived from fruits and vegetables. A molecule of glucose has the same caloric value as a molecule of fructose. However, the human body treats these carbohydrates quite differently. Glucose is used directly by tissues such as the muscles and brain as an energy source. Excess glucose is stored in the liver as glycogen. In contrast, dietary fructose, which is epidemiologically linked with obesity and metabolic syndrome, is almost exclusively metabolized by the liver. Hepatocellular carcinoma cells enhance glucose uptake and lactate production regardless of the oxygen supply, a phenomenon known as the Warburg effect. However, whether fructose metabolism is differentially regulated in hepatocellular carcinoma and normal liver tissue and, if so, the extent to which this altered carbohydrate metabolism contributes to hepatocellular carcinoma development is unknown. (more…)
Author Interviews, Nature, NYU, Pancreatic / 22.04.2016

MedicalResearch.com Interview with: Dr. George Miller, MD Vice Chair for research, Department of Surgery Associate Professor, Department of Surgery Associate Professor, Department of Cell Biology NYU Langone’s Perlmutter Cancer Center MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Miller: Cancer cell death is the goal of most therapeutic programs. Indeed, chemotherapy induces cancer cell death. We show that a novel form of cancer cell death entailing organized necrosis is a prominent way by which cancer cells die. However, paradoxically this form of cell death termed "necroptosis" actually accelerates pancreatic cancer growth in animals by inducing immune suppressive inflammation. MedicalResearch.com: What should clinicians and patients take away from your report? Dr. Miller: Novel agents are needed to block necroptosis in pancreatic cancer. This can potentially enhance the immune system's ability to fight the cancer. (more…)
Author Interviews, Nature, Neurological Disorders / 19.04.2016

MedicalResearch.com Interview with: Phillip G. Popovich, Ph.D. Professor, Neuroscience Director, Center for Brain and Spinal Cord Repair Ray W. Poppleton Research Designated Chair Department of Neuroscience Wexner Medical Center at The Ohio State University Columbus, Ohio  43210 MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Popovich:  People that suffer a spinal cord injury (SCI) at a high spinal level (e.g., cervical SCI), are at increased risk for developing autonomic dysreflexia (AD), a potentially life-threatening condition of sudden onset high blood pressure. In people and animals with SCI, reflexes that are activated by routine stimuli including filling of the bladder or bowel often trigger AD. We recently found that these same reflexes also suppresses the immune system (see Zhang et al., 2013; PMID 23926252) Since people with high level  spinal cord injury also are at increased risk for developing infections (e.g., pneumonia), we set out to understand how SCI changes the autonomic circuitry in the spinal cord that controls immune function. We found that after a period of one month, the number of connections between spinal cord interneurons and autonomic neurons that directly control immune function increases dramatically. Also, this newly formed circuitry is “hyperactive” and discharge of neurons in this circuit causes hormones to be released into the blood and immune organs that overstimulate immune cells, causing them to die. Fortunately, we were able to show that the hyperactive spinal cord circuitry can be silenced. We used a novel technique known as “chemogenetics” to silence excitatory interneurons in the aberrant circuit. When the circuitry was silenced, immune cells were protected in spinal cord injury mice. (more…)
Author Interviews, Nature / 12.04.2016

MedicalResearch.com Interview with: Dr. Michael V. Sofroniew, MD PhD Professor of Neurobiology David Geffen School of Medicine UCLA MedicalResearch.com: What is the background for this study? Dr. Sofroniew: For over seventy-five years, it has been thought that scars formed by cells called astrocytes actively prevent the regeneration of damaged nerve fibers (also known as axons) across injury sites in the brain and spinal cord. This view was based largely on two forms of circumstantial evidence: (1) after injury, damaged nerve fibers do not regrow past astrocyte scars and appear to be ‘stalled’ within them; (2) astrocytes (along with other cells) can produce molecules that inhibit nerve fiber growth in cell culture experiments. We also initially subscribed to this inhibitory view of astrocyte scars and about twenty years ago my lab began to develop experimental tools that allowed us to prevent astrocyte scar formation in mice. The hope was that preventing astrocyte scar formation would lead to nerve fiber regeneration across brain or spinal cord injuries. Unfortunately, although we were successful in preventing scar formation, we never saw any regrowth of nerve fibers in spite of multiple different attempts over many years of work. We were disappointed and held back from publishing those results, but kept thinking about the problem and looking for new ways to study it. Over the last five years, new tools and information became available that allowed us to return to this question and probe further. We kept getting similar kinds of results and eventually we collected enough different types of evidence to convince ourselves that the original view that astrocyte scars prevent nerve fiber regrowth was incorrect. MedicalResearch.com: What are the main findings? Dr. Sofroniew: We found that after preventing astrocyte scar formation, or after removing chronic astrocyte scars, there was no spontaneous regrowth of damaged nerve fibers and that instead, the nerve fibers retracted further back away from spinal cord injury sites. We found that both astrocytes and other cells in the injury sites produced numerous molecules that could support nerve fiber regrowth along with molecules that might repel or inhibit it. This suggested a complex molecular environment that needs to be studied more. We also found that when appropriate growth factors were applied locally into the injury site, nerve fibers could be stimulated to regrow in spite of astrocyte scar formation, and that this stimulated regrowth was significantly reduced, and not improved, when scar formation was prevented. Together, these findings show that rather than being major inhibitors of nerve fiber regrowth, scar-forming astrocytes can be supportive of such growth.  (more…)
Antibiotic Resistance, Author Interviews, Nature / 12.04.2016

MedicalResearch.com Interview with: Dr. Lingchong You PhD Paul Ruffin Scarborough Associate Professor of Engineering Duke University MedicalResearch.com: What is the background for this study? What are the main findings? Dr. You: Horizontal gene transfer (HGT) refers to the transfer of genes between organisms of the same or different species other than reproduction. In bacteria, ​Horizontal gene transfer can occur through conjugation (bacterial mating), transduction mediated by phage, or transformation. During conjugation, a donor cell makes a copy of a conjugal plasmid and passes it to a recipient cell, turning it into a transconjugant. It is well appreciated that HGT (particularly through conjugation) is the major mechanism underlying the wide spread of genes encoding antibiotic resistance.  Given this notion, it is tempting to assume that the use of antibiotics could increase the efficiency of horizontal gene transfer, creating a vicious cycle. Indeed, this has been speculated in the literature even though precise experimental measurements have been lacking. In our study, we find that antibiotics covering all major classes do not promote the probability of conjugation between donor and recipient cells. Instead, antibiotics modulate the final outcome of conjugation dynamics by imposing different degrees of selection on the donor cells, recipient cells, and the transconjugants. Depending on the antibiotic doses and how the antibiotic affects the three populations, the selection dynamics could lead to an increase or the decrease in the frequency of transconjugants. (more…)
Aging, Author Interviews, Melanoma, Nature, Wistar / 08.04.2016

MedicalResearch.com Interview with: Ashani T. Weeraratna, Ph.D. Associate Professor Melanoma Research Center The Wistar Institute Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Weeraratna: The background for this study is the fact that advancing age remains the greatest risk factor for the development of many cancers, and melanoma is no exception. We found that age-related changes in normal skin, specifically dermal fibroblasts, increase both the metastatic potential and therapeutic resistance of melanoma cells. The most fascinating thing is that even targeted therapy, which should depend solely on the interaction between the drug and the target within the tumor cell is affected by the age of the microenvironment. (more…)
Author Interviews, Nature, Transplantation / 07.04.2016

MedicalResearch.com Interview with: Muhammad M. Mohiuddin, MD Cardiothoracic Surgery Research Program National Heart, Lung, and Blood Institute MedicalResearch.com: What is the background for this study? What are the main findings?  Dr. Mohiuddin: There are around 150,000 patients waiting for organ transplants. Unfortunately, the supply of human donor organs will never be able to meet this demand. We are trying to explore if animal (pig) organs can be used for these patients. Pig organs are rejected within a few minutes by humans or baboons. Therefore, we along with our industrial partner Revivicor Inc. have modified the pig genetics to knock out molecules harmful to humans and have also expressed some human genes in these pigs. Through these modifications, along with the use of novel target-specific immunosuppressive drugs, we have extended pig heart survival in the abdomen for almost 3 years. In this experimental model, the heart is transplanted in the abdomen while the original heart stays in the chest cavity. The major advantage of this model is that the baboon is kept alive, despite the rejection of the transplanted organ in the abdomen. (more…)
Author Interviews, Genetic Research, MD Anderson, Nature, Prostate Cancer / 01.03.2016

MedicalResearch.com Interview with Dr. Dingxiao Zhang Ph.D Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Smithville, TX 78957, USA MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Zhang: Prostate cancer (PCa) is a heterogeneous malignancy harboring phenotypically and functionally diverse subpopulations of cancer cells. To better understand PCa cell heterogeneity, it is crucial to dissect the biology of normal prostate epithelial lineages. The background for the current study is to annotate the gene expression profiles of normal prostate epithelial cells, through which we hope to gain insight on Prostate cancer subtypes and the cellular heterogeneity in PCa. The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. In this study, we have performed a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. One of our major findings is that the differential gene expression profiles in basal versus luminal prostate epithelial cells account for their distinct functional properties. Specifically, basal cells preferentially express gene categories associated with stem cells, MYC-transcriptional program, neurogenesis, and ribosomal RNA (rRNA) biogenesis regulated by Pol I. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene expression profile is enriched in advanced, anaplastic, castration-resistant, and metastatic prostate cancers. Therefore, we link the cell-type specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. (more…)
Author Interviews, Hospital Acquired, Infections, Nature / 24.02.2016

MedicalResearch.com Interview with: Ashootosh Tripathi, PhD Postdoctoral Research Fellow Life Sciences Institute I Sherman lab University of Michigan Ann Arbor, MI, USA MedicalResearch: What is the background for this study? What are the main findings? Dr. Tripathi: Acinetobacter baumannii is a nosocomial opportunistic and resistant pathogen that can spread epidemically among patients causing ventilator-associated pneumonia and bacteremia. The mortality rates associated with it can be as high as 60%, representing a paradigm of pathogenesis, transmission and resistance. In addition, numerous reports have shown the startling emergence of multidrug-resistant A. baumannii in hospitals as well as the identification of pan-drug-resistant strains at some locations. Among the  various reasons for the antibiotic resistance of this pathogenic microbe, perhaps the most significant is mediated by its tendency to form biofilms (a highly structured extracellular polymeric matrix), which provide the microbe with the alarming ability to colonize medical devices. Interestingly, despite the well-understood role of bacterial biofilm behind aggravating antimicrobial resistance, there are currently no drugs specifically targeting biofilms in clinical trials to date. The study sought to solve this problem through the development of a biofilm inhibitor as a precision medicine, directed towards vulnerable patients, to avoid potential life-threatening infections. A crystal-violet based high throughput in vitro screen was developed to identify inhibitors of A. baumannii biofilms against our natural products extract (NPE) library. The vast NPE library of ~42,000 extracts has been under constant development in Prof David H. Sherman laboratory at University of Michigan, Ann Arbor, for over the past decade, from a relatively underexplored marine microbiome collected from different part of world viz., Costa Rica, Panama, Papua New Guinea, etc., and is available for any research group with a robust high-throughput screening (HTS) assay (http://www.lsi.umich.edu/centers/center-for-chemical-genomics). The HTS assay that was queried against a library of 9,831 NPEs aimed to identify extracts inhibiting biofilm formation as a primary screening. Further secondary  screening and   activity  threshold optimization revealed the extract from Streptomyces gandocaensis (collected from Costa Rica) to be of particular interest due to its ability to inhibit biofilm formation and had a limited effect on A. baumannii growth. Activity based chromatographic separation and analysis of extracts derived from S. gandocaensis resulted in the discovery of three peptidic metabolites (cahuitamycins A–C),   with cahuitamycin  C  being   the   most effective biofilm inhibitor (IC50 =14.5 µM)   with  negligible A.  baumannii growth inhibition (an important trait for ideal biofilm inhibitor). Following up on the exciting discovery, we also completely characterized the biosynthetic machinery involved in making the active molecules by S. gandocaensis, using sophisticated bioinformatics and molecular biology techniques. The knock out analysis revealed that the biosynthesis of cahuitamycin C proceeds via a convergent biosynthetic pathway, with one of the steps apparently being catalyzed by an unlinked gene encoding a 6-methylsalicylate synthase. Efforts to assess starter unit diversification through selective mutasynthesis led to production of unnatural analogues cahuitamycins D and E with increased potency (IC50=8.4 and 10.5 µM) against A. baumannii biofilm. (more…)
Author Interviews, Cancer Research, Geriatrics, Lung Cancer, Nature / 12.02.2016

MedicalResearch.com Interview with: Chiara Ambrogio, PhD Experimental Oncology Group CNIO-Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre) Melchor Fernández Almagro nº3 Madrid Spain  Medical Research: What is the background for this study? Dr. Ambrogio: The majority of preclinical studies aimed at discovering new therapeutic strategies for lung adenocarcinoma have been conducted so far in full-blown tumors. We wanted to try a new approach by studying early lung lesions in a KRasG12V mouse model in order to bypass the problems imposed by tumor heterogeneity in later stages of the disease. We reasoned that the analysis of the first steps of lung adenocarcinoma development would help us in identifying valuable targets for therapeutic intervention.  Medical Research: What are the main findings? Dr. Ambrogio: 1) We performed gene expression analysis of KRasG12V-driven mouse lung hyperplasias (≤ 500 cells) and we compared it to the gene expression profile of full-blown lung adenocarcinoma. We found that the aggressive nature of this tumor type is determined earlier than what predicted by histopathological criteria. 2) The analysis of transcriptional changes in early lesions allowed us to identify DDR1 as a drugable target in KRasG12V-driven lung adenocarcinoma. We validated its potential as a therapeutic target both genetically and pharmacologically by means of a selective DDR1 inhibitor. We demonstrated that the co-inhibition of DDR1 and NOTCH pathway, a key player in DDR1-mediated survival, exerted additive therapeutic effect. 3) We confirmed these results in human lung adenocarcinoma by reporting, for the first time, the development of an orthotopic Patient-Derived Xenograft (PDX) model as the ideal platform for the preclinical evaluation of new therapeutic strategies. (more…)
Author Interviews, Microbiome, Nature, NYU, OBGYNE / 01.02.2016

MedicalResearch.com Interview with: Maria Dominguez-Bello, PhD Associate Professor, Department of Medicine, Division of Translational Medicine NYU Langone Medical Center and Jose Clemente, PhD Assistant Professor, Departments of Genetics and Genomic Sciences, and Medicine Icahn School of Medicine at Mount Sinai       Medical Research: What is the background for this study? What are the main findings? Response: Humans and animals are a composite of their own cells and microbes. But where they get their microbes from?  For mammals, labor and birth are major exposures to maternal vaginal bacteria, and infants are born already with a microbiota acquired from the mother. Mom’s birth canal is heavily colonized by bacteria that are highly related to milk: some will use milk components and become dominant during early development, an important window for maturation of the immune system, the intestine and the brain. Thus, the maternal vaginal microbiota is thought to be of high adaptive value for newborn mammals. Indeed, studies in mice confirm that microbes acquired at birth are important to develop adequate immune and metabolic responses, and the mature adult microbiome will continue to modulate host metabolism and immunity. Humans are the only mammals that interrupt the exposure to maternal vaginal microbiota, by delivering babies by Cesarean section. C-sections save lives of babies and moms, and they are estimated necessary in 10-15% of the cases. But most Western countries have rates above 30%, with the notable exception of the Scandinavian countries, Holland and Japan, which have excellent health systems and low maternal-infant mortality rates. Previous work by us an others has shown that infants born by C-section acquire different microbiota at birth, and those differences are sustained over time, altering the normal age-dependent maturation of the microbiome. The fundamental questions are then, can we restore the microbiota of Cesarean delivered babies? And if we can, does that reduce the associated disease risks? In relation to the first question, we present here the results of a pilot study in which infants born by Cesarean delivery were exposed to maternal vaginal fluids at birth. A total of 18 infants were recruited for the study. Seven of them were vaginally delivered, the remaining 11 were born by scheduled C-section. Among the C-section infants, 4 were exposed to maternal vaginal fluids at birth and 7 were not. We sampled all infants and their mothers for the first month of life across different body sites (oral, skin, anal, maternal vagina) and determined the microbiome composition on a total of over 1,500 samples. (more…)
Author Interviews, Brigham & Women's - Harvard, Colon Cancer, Dermatology, Nature, Testosterone / 14.01.2016

More on Colon Cancer on MedicalResearch.com MedicalResearch.com Interview with: Dr. Nana Keum, PhD Department of Nutrition Harvard T.H. Chan School of Public Health Boston, MA Medical Research: What is the background for this study? What are the main findings? Dr. Keum: Male pattern baldness, the most common type of hair loss in men, is positively associated with androgens as well as IGF-1 and insulin, all of which are implicated in pathogenesis of colorectal neoplasia.  Therefore, it is biologically plausible that male pattern baldness, as a marker of underlying aberration in the regulation of the aforementioned hormones, may be associated with colorectal neoplasia.  In our study that examined the relationship between five male hair pattern at age 45 years (no-baldness, frontal-only-baldness, frontal-plus-mild-vertex-baldness, frontal-plus-moderate-vertex-baldness, and frontal-plus-severe-vertex-baldness) and the risk of colorectal adenoma and cancer, we found that frontal-only-baldness and frontal-plus-mild-vertex-baldness were associated with approximately 30% increased risk of colon cancer relative to no-baldness.  Frontal-only-baldness was also positively associated with colorectal adenoma. (more…)
Author Interviews, Breast Cancer, Nature, University Texas / 13.01.2016

Click Here for More Articles Related To Breast Cancer on MedicalResearch.com. MedicalResearch.com Interview with: Dr. Chunru Lin PhD Assistant Professor, Department of Molecular and Cellular Oncology, Division of Basic Science Research and Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center, Houston, TX MedicalResearch: What is the background for this study? What are the main findings? Dr. Lin: Triple-Negative Breast Cancer (TNBC) continues to be a serious healthcare problem despite improvements in early detection and treatment; lncRNAs are one of the emerging elements that make the process of understanding breast cancer development and progression so complex yet thorough. Thus, it is imperative to include an examination of lncRNAs when studying breast cancer, especially when researching challenging questions related to relapses and recurrences of breast cancer that occur after targeted therapeutic treatments. A perspective that incorporates lncRNAs into the discussion of breast cancer biology could be the conceptual advance that is necessary to encourage further breakthroughs. Our research reveals the biological functional roles of cytoplasmic lncRNAs as signaling pathway mediators and catalysts that serve as indispensable components of signal transduction cascades and gene networks. This understanding could transform the prevailing dogma of the field of signal transduction. This study has identified a previously unknown mechanism for HIF stabilization and signal transduction, which is triggered by the HB-EGF bound EGFR/GPNMB heterodimer and is mediated by LINK-A-dependent recruitment of two kinases, BRK and LRRK2, to phosphorylate HIF1α at two new sites, leading to HIF1α stabilization and interaction with p300 for transcriptional activation; this further results in cancer glycolytic reprogramming under normoxic conditions. LINK-A is the first demonstrated lncRNA that acts as a key mediator of biological signaling pathways, which suggests the potential for the involvement of other lncRNAs as mediators of numerous signaling pathways. Importantly, expression of LINK-A and activation of the LINK-A mediated signaling pathway are both correlated with TNBC. Targeting LINK-A with LNAs (Locked Nucleic Acids) serves as an encouraging strategy to block reprogramming of glucose metabolism in TNBC with therapeutic potential.  (more…)
Author Interviews, Cancer Research, Genetic Research, Nature / 17.12.2015

MedicalResearch.com Interview with: Dr. Li Ding PhD Director, Medical Genomics group McDonnell Genome Institute Department of Medicine Washington University in St. Louis St. Louis, Missouri Medical Research: What is the background for this study? What are the main findings? Dr. Li Ding:  Next-generation sequencing technologies have provided unprecedented opportunities for building a comprehensive catalog of point mutations, simple insertion and deletion mutations (indels) and structural variants in human cancers. Although significant progress has been made for documenting these common events through studies from individual research labs and large consortiums, there has been little progress in the discovery of complex indels after the transition from Sanger sequencing to NGS technologies.  It is well known in the scientific community that indel detection using short next generation sequencing reads is a challenging problem. Our study, for the first time, directly addresses complex indel detection that has been barely touched in the cancer field. More importantly, our analysis discovered 285 complex indels in cancer genes such as PIK3R1, GATA3, and TP53, revealing an unexpected high prevalence of these events in human cancers. (more…)
Alzheimer's - Dementia, Author Interviews, Nature, UCSF / 03.12.2015

MedicalResearch.com Interview with: Elsa Suberbielle, DVM, PhD Research Scientist Gladstone Institute of Neurological Diseases San Francisco, CA 94158 Medical Research: What is the background for this study? Dr. Suberbielle: BRCA1 is a key protein involved in DNA repair, and mutations that impair its function increase the risk for breast and ovarian cancer. Research into DNA repair mechanisms in dividing cells recently was recently rewarded by the Nobel Prize in Chemistry. In such cells, BRCA1 helps repair a type of DNA damage known as double-strand breaks that can occur when cells are injured. In neurons, though, such breaks can occur even under normal circumstances, for example, after increased brain activity, as shown by the team of Gladstone scientists in an earlier study. The researchers speculated that in brain cells, cycles of DNA damage and repair facilitate learning and memory, whereas an imbalance between damage and repair disrupts these functions. Medical Research: What are the main findings? Dr. Suberbielle In a new study published in Nature Communications, Researchers from the Gladstone Institutes demonstrates that Alzheimer’s disease is associated with a depletion of BRCA1 in neurons and that BRCA1 depletion can cause cognitive deficits. The researchers experimentally reduced BRCA1 levels in the neurons of mice. Reduction of the DNA repair factor led to an accumulation of DNA damage and to neuronal shrinkage. It also caused learning and memory deficits. Because Alzheimer’s disease is associated with similar neuronal and cognitive problems, the scientists wondered whether they might be mediated by depletion of BRCA1. They therefore analyzed neuronal BRCA1 levels in post-mortem brains of Alzheimer’s patients. Compared with non-demented controls, neuronal BRCA1 levels in the patients were reduced by 65-75%. To determine the causes of this depletion, the investigators treated neurons grown in cell culture with amyloid-beta proteins, which accumulate in Alzheimer brains. These proteins depleted BRCA1 in the cultured neurons, suggesting that they may be an important cause of the faulty DNA repair seen in Alzheimer brains. Further supporting this conclusion, the researchers demonstrated that accumulation of amyloid-beta in the brains of mice also reduced neuronal BRCA1 levels. They are now testing whether increasing BRCA1 levels in these mouse models can prevent or reverse neurodegeneration and memory problems. (more…)
Author Interviews, Infections, Nature / 02.12.2015

MedicalResearch.com Interview with: Professor Søren Riis Paludan DMSc, PhD Department of Biomedicine Aarhus University Denmark Medical Research: What is the background for this study? What are the main findings? Prof. Paluden: We were interested in understanding the first immune reactions that occur when an organism meets an infectious agent (virus or bacteria). The main finding is that we have identified an immune reaction that is activated as the microbe disturbed the mucus layer at mucosal surfaces. This is an immune reaction occuring earlier than what has been thought previously, and may represent a mechanism that enables the organism to fight most microbes that we meet without mounting strong immune responses. This is important, since strong immune reactions - in addition to contributing to elimination of microbes - also have negative effects such as fever, etc. (more…)
Author Interviews, Hepatitis - Liver Disease, Nature / 01.12.2015

MedicalResearch.com Interview with: Prof. Yaakov Nahmias PhD Director of the Alexander Grass Center for Bioengineering Hebrew University of Jerusalem Medical Research: What is the background for this study? Prof. Nahmias: The liver has a limitless capacity of the human liver to regenerate from even a massive loss of mass. However, the intrinsic capacity of liver cells to proliferate is lost when cells are removed from the body. Medical Research: What are the main findings? Prof. Nahmias: We found that a weak expression of Human Papilloma Virus (HPV) proteins released hepatocytes from cell-cycle arrest and permitted the cells to multiply in response to Oncostatin M (OSM) an immune cytokine recently found to be involved in liver regeneration. While previous efforts caused hepatocytes to multiply without control, converting hepatocytes  into tumor cells with little metabolic ability, we selected colonies that only multiply in response to OSM. Activation with OSM triggered cell growth with a doubling time of 40 hours. Removal of OSM caused  growth to stop, allowing the cells to regain a high level of metabolic activity within 4 days. We produced hepatocytes from ethnically diverse individuals. Importantly, the growing hepatocytes  showed a similar toxicology response to normal human hepatocytes across 23 different drugs. (more…)
Author Interviews, Genetic Research, Nature, Weight Research / 26.11.2015

MedicalResearch.com Interview with: Dr. Andrew Whittle, joint first-author of the paper and a postdoc in the Prof. Vidal-Puig’s lab at the time the research was conducted. Medical Research: What is the background for this study? Dr. Whittle: Antonio Vidal-Puig heads the disease model core of the University of Cambridge Metabolic Research Laboratories at the Wellcome Trust-MRC Institute of Metabolic Science (IMS). His laboratory has a long-standing interest in the mechanisms that regulate how adipose tissue stores, burns or releases energy. The group studies mice that have increased or reduced susceptibility to obesity and its metabolic complications, in order to dissect the molecular pathways that underpin these phenotypes. Their long-term goal is to develop more effective strategies to manipulate the body’s own regulatory pathways, both to reduce obesity itself or limit the negative impact that excess lipids have on other important metabolic organs. Professor Hideaki Bujo from Toho University Medical Center in Japan has been working for a number of years to understand the role of specific lipoprotein receptors in vascular biology. Specifically he has shown that LR11 is cleaved to release a short soluble for of the protein, sLR11, which can effect changes to vascular smooth muscle cell migration. To further his studies he generated a knock-out mouse model completely lacking LR11. One of the first observations his group made was that these mice remained leaner than control animals. I and Meizi Jiang (a postdoc in the Bujo lab) conducted a collaborative study of the LR11 knockout mice (Lr11-/-), to investigate the mechanisms by which a lack of LR11 resulted in mice being protected from diet-induced obesity.  (more…)
Author Interviews, Breast Cancer, Nature / 23.11.2015

MedicalResearch.com Interview with: Paul K Newton PhD Professor of Aerospace & Mechanical Engineering, Mathematics, and Norris Comprehensive Cancer Center USC Viterbi University of Southern California University Park Campus Los Angeles, CA  90089-4012  Medical Research: What is the background for this study? What are the main findings? Dr. Newton: We obtained a longitudinal data set of 446 breast cancer patients from Memorial Sloan Kettering Cancer Center, tracked from 1975 to 2009. All of the patients had primary breast cancer at the time they entered, with no metastatic tumors. All subsequently developed metastatic breast cancer. From this time-resolved data set, we first developed what we called tree-ring diagrams showing the full spatiotemporal patterns of progression. We then used this information to develop a Markov chain dynamical model of metastatic breast cancer. This is a model based on the concept that where the disease currently is located strongly influences where it will spread next. The systemic nature of metastatic breast cancer is clearly shown in these kinds of network based models. The main findings are that survival depends very strongly on where the first metastatic tumor develops. For example, if the first metastatic tumor appears in the bone, as happens in roughly 35% of the patients, survival is much better than if it appears in the brain (less than 5% of the patients). Furthermore, for those patients with a first met to the bone, survival is far better for those who develop their next met in the lung area, as compared with those that develop it in the liver. Metastatic sites are categorized as `spreader’ sites, or `sponge’ sites. Bone and chest wall are generally the primary spreader sites of metastatic breast cancer, dynamically involved in spreading the disease throughout the metastatic process. On the other hand, liver seems to be a key sponge site, where circulating tumor cells most likely accumulate. If one were to focus on an active therapeutic program targeting metastatic sites, most likely the spreader sites would give the most bang-for-buck in terms of survival. (more…)
Author Interviews, Nature, NYU, Weight Research / 28.10.2015

MedicalResearch.com Interview with: Dr. Margaret E. Rice, PhD Professor, Department of Neuroscience and Physiology Neurosurgery NYU Langone Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Rice: Insulin is released from the pancreas into the bloodstream in response to a rise in circulating glucose levels when we eat. In most cells in the body, including those of liver and muscle, insulin acts at insulin receptors to promote glucose transport and other metabolic functions. Insulin also enters the brain and acts at brain insulin receptors, particularly in the hypothalamus where insulin acts as a satiety signal to indicate that we are full and should stop eating. The rising incidence of obesity, in which circulating insulin levels are chronically elevated, suggests insulin may play a role in other brain regions, as well, including regions that regulate motivation and reward. Indeed, our new studies introduce a new role for insulin as a reward signal that acts in the dorsal striatum to enhance release of dopamine.  Dopamine is a key neurotransmitter in reward systems; most drugs of abuse enhance release of dopamine, which contributes to their addictive properties. We found that insulin, at levels found in the brain by the end of a meal, enhances dopamine release by activating insulin receptors on acetylcholine-containing striatal cells that boost dopamine release. Consistent with a role of insulin in signaling reward, companion behavioral studies in rodents indicate that insulin signaling in the striatum communicates the reward value of an ingested meal, and thereby influences food choices. These studies reveal the dual nature of insulin in the brain, which not only tells us when to stop eating, but also influences what we eat. (more…)
Author Interviews, Kidney Disease, Nature / 27.10.2015

MedicalResearch.com Interview with: Daniele Zink PhD Institute of Bioengineering and Nanotechnology Singapore  Medical Research: What is the background for this study? Dr. Zink: The kidney is one of the main target organs for toxic effects of drugs, environmental toxicants and other compounds. Renal proximal tubular cells (PTCs) are frequently affected due to their roles in compound transport and metabolism. Validated and accepted assays for the prediction of PTC toxicity in humans currently do not exist. Recently, we have developed the first and only pre-validated assays for the accurate prediction of PTC toxicity in humans 1, 2. This previous work was performed with human primary renal proximal tubular cells (HPTCs) or embryonic stem cell-derived HPTC-like cells. HPTCs are associated with a variety of issues that apply to all kinds of primary cells, such as cell sourcing problems, inter-donor variability and limited proliferative capacity. Embryonic stem cell-derived cells are associated with ethical and legal issues. These are the main reasons why induced pluripotent stem cell (iPSC)-derived cells are currently a favored cell source for in vitro toxicology and other applications. The problem was that stem cell-based approaches were not well-established with respect to the kidney. Recently, the group of IBN Executive Director Prof. Jackie Y. Ying developed the first protocol for differentiating embryonic stem cells into HPTC-like cells, and my group has contributed to characterizing these cells and publishing the results 3.  In the work published in Scientific Reports ,4we have applied a modified version of this protocol to iPSCs. In this way, we have established the simplest and fastest protocol ever for differentiating iPSCs into HPTC-like cells. The cells can be used for downstream applications after just 8 days of differentiation. These cells can also be applied directly without further purification due to their high purity of > 90%. By using these cells, we have developed the first and only iPSC-based model for the prediction of PTC toxicity in humans. This was achieved by combining our iPSC-based differentiation protocol with our previously developed assay based on interleukin (IL)6/IL8 induction 1, 2 and machine learning methods 5. Machine learning methods were used for data analysis and for determining the predictive performance of the assay. The test accuracy of the predictive iPSC-based model is 87%, and the assay is suitable for correctly identifying injury mechanisms and compound-induced cellular pathways. (more…)
Author Interviews, Genetic Research, Kidney Disease, Nature, Stem Cells / 24.10.2015

MedicalResearch.com Interview with: Benjamin Freedman, Ph.D. Assistant Professor | University of Washington Department of Medicine | Division of Nephrology Member, Kidney Research Institute Member, Institute for Stem Cell and Regenerative Medicine Seattle WA 98109  Medical Research: What is the background for this study? What are the main findings? Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy. Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney 'organoids' that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific 'symptoms' of these two different diseases in the petri dish. (more…)
Author Interviews, Cancer Research, MD Anderson, Nature / 23.10.2015

MedicalResearch.com Interview with: Dihua Yu, M.D., Ph.D. Professor and Deputy Chair Dept.  of Molecular and Cellular Oncology Hubert L. and Olive Stringer Distinguished Chair in Basic Science University Distinguished Teaching Professor Co-Director, Center of Biological Pathways Univ. of TX MD Anderson Cancer Center Houston, TX 77030 Medical Research: What is the background for this study? What are the main findings? Dr. Yu: Metastasis is the number one cause of cancer-related mortality. Despite the continuous advancement of modern medicine in better controlling primary cancer progress, brain metastasis incidence constantly and steadily increases. Major neoplastic diseases such as melanoma, lung, breast, and colon cancers have high incidences of brain metastases. One-year survival after diagnosis of brain metastasis is less than 20%. Cancer cells dynamically interacts with specific organ microenvironments to establish metastasis as depicted by the “seed and soil” hypothesis. Many research have focused on how tumor cells modulate the metastatic microenvironment, but the reciprocal effect of the organ microenvironment on tumor cells has been overlooked. The brain tissue is very distinct from primary tumor environment for metastatic cancer cells. Brain metastasis frequently manifests in the late stages of cancer, and a long period of dormancy often precedes relapse. This implies that additional regulations imposed by the brain microenvironment are essential for metastatic colonization and outgrowth. Yet it is unclear when and how disseminated tumor cells acquire the essential traits from the brain microenvironment that primes their subsequent metastatic outgrowth. (more…)
ADHD, Author Interviews, Mental Health Research, Nature, NYU / 22.10.2015

MedicalResearch.com Interview with: Michael M. Halassa, MD, PhD, Assistant professor Departments of Psychiatry and Neuroscience and Physiology The Neuroscience Institute Depts. of Psychitatry Langone Medical Center New York, NY 10016 Medical Research: What is the background for this study? What are the main findings? Dr. Halassa:  Attention is a vital aspect of our daily life and our minds are not merely a reflection of the outside world, but rather a result of careful selection of inputs that are relevant. In fact, if we indiscriminately open up our senses to what’s out there, we would be totally overwhelmed. Selecting relevant inputs and suppressing distractors is what we call attention, and as humans we are able to attend in a highly intentional manner. Meaning, we choose what to pay attention to, and we do so based on context. If you’re driving and getting directions from your GPS, you’ll be intentionally splitting your attention between your vision and hearing. Now, in one context, you might have just updated the GPS software, so you know it’s reliable; this would allow you to intentionally pay attention more to the voice coming from the GPS. In another context, the GPS software may be outdated making voice instructions unreliable. This context would prompt you to direct your attention more towards using visual navigation cues and less to the GPS voice. How the brain intentionally and dynamically directs attention based context is unknown. The main strength of our study is that we were able to study context-dependent attention in mice. Mice are unique models because they provide genetic tools to study brain circuits. Meaning, we can turn circuits on and off very precisely in the mouse, and in a way we cannot do in other experimental animals. The inability to do these types of manipulations has been the major roadblock for progress in understanding what brain circuits mediate attention and its intentional allocation. Because we couldn’t train mice to drive and listen to the GPS, we decided to do something much simpler. Based on context (the type of background noise in the experimental enclosure), a mouse had to select between conflicting visual and auditory stimuli in order to retrieve a milk reward. Mice love milk; it turns out, and will work tirelessly to do well on getting it. Each trial, the mouse is told ‘you need to pick the light flash’ or ‘you need to pick the auditory sweep’; these stimuli appeared on either side of the mouse randomly so the animal really had to pay attention in order to get its reward. It also had to take the context into account. We found that mice did this task, and as humans would do, they were reliant on the prefrontal cortex for determining the appropriate context. The major finding was that the prefrontal cortex changed the sensitivity of the brain to incoming stimuli (meaning, made the visual stimulus brighter when the mouse cared about vision and made the auditory stimulus louder when the mouse cared about hearing), by influencing activity in the thalamus. The thalamus is the major early relay station in the brain. The prefrontal cortex does that by instructing the brain’s switchboard, known as the thalamic reticular nucleus (TRN) to control how much visual or auditory information the thalamus was letting through. So in a sense, we discovered that executive function, represented by the prefrontal cortex, can talk to ‘attentional filters’ in the thalamus to determine what ultimately is selected from the outside environment to build our internal world. (more…)
Author Interviews, Nature, NYU / 25.08.2015

Robert C. Froemke, PhD, Assistant professor NYU Langone and Skirball Institute of Biomolecular Medicine New York MedicalResearch.com Interview with: Robert C. Froemke, PhD, Assistant professor NYU Langone and Skirball Institute of Biomolecular Medicine New York Medical Research: What is the background for this study? What are the main findings? Dr. Froemke: We studied how a brain area called the ‘locus coeruleus’ is involved in hearing. The locus coeruleus is the brain’s alarm clock, it’s a small region deep in the brainstem that is responsible for arousal and wakefulness, activated by surprising or potentially dangerous events. The locus coeruleus releases the neurochemical noradrenalin (similar to adrenalin) throughout the brain to greatly increase brain activity, and so might convey the significance of sounds related to past events that were very important or startling in some way (like the sound of an alarm, a baby crying, or other sounds that require immediate attention). We found that sounds related to surprising events can come to directly activate the locus coeruleus, meaning that this brain area can learn from past experience. This learning happens quickly (within seconds to minutes) and can be incredibly long-lasting, up to weeks as measured in our study, and we suspect indefinitely or all life-long. We studied this by training lab rats to respond to sounds, poking their nose in a hole to get a food reward whenever they heard a certain sound. We activated the locus coeruleus briefly in some of these animals, and observed that they were much more sensitive to this sound and learned much faster than other unstimulated animals. We made recordings of electrical activity in the locus coeruleus and the auditory cortex, one of the major ‘hearing’ parts of the brain. In stimulated animals, sounds activated the locus coeruleus within tens of milliseconds, releasing noradrenalin into the auditory cortex to greatly boost the audio processing there- making almost every neuron respond very vigorously to that special sound. (more…)
Author Interviews, Brigham & Women's - Harvard, Genetic Research, Heart Disease, Nature / 18.08.2015

Susan A. Slaugenhaupt PhD Professor of Neurology, Harvard Medical School Associate Geneticist, Department of Neurology, Molecular Neurogenetics Unit Center for Human Genetic Research Massachusetts General HospitalMedicalResearch.com Interview with: Susan A. Slaugenhaupt PhD Professor of Neurology, Harvard Medical School Associate Geneticist, Department of Neurology, Molecular Neurogenetics Unit Center for Human Genetic Research Massachusetts General Hospital   Medical Research: What is the background for this study? What are the main findings? Dr. Slaugenhaupt: Mitral valve prolapse (MVP) is one of the most common human diseases affecting 1 out of every 40 people worldwide.  The mitral valve is found between two chambers of the heart, and mitral valve prolapse results when the valve does not close properly.  By studying families in which multiple members have mitral valve prolapse, we have identified a biological explanation for the disease.  Mutations in the DCHS1 gene cause mitral valve prolapse in three families, and suggest that early defects in heart valve formation during development contribute to the progressive deterioration of the valve. (more…)