Roundup Of Roundups

The following research papers and grants of note were highlighted on the Einstein website in a section called "Research Roundup." You can explore all of the discoveries published in this special section of our website throughout the year by visiting the Research landing page of our website.

Visualizing How Neurons Develop in the Fruit Fly Eye—Proneural bHLH proteins are transcription factors that regulate the development of key nerve cells needed for vision (including rod and cone photoreceptors and corneal nerves) and for maintaining the health of the eye. It is known that the ability of bHLH transcription factors to bind to DNA is antagonized by other proteins known as the ID-class of HLH proteins. Nicholas Baker, Ph.D., has received a four-year, $1.3 million grant from the National Institutes of Health to better understand the function of this network of interacting proteins. The research is expected to reveal new regulators of neural development that are important in the eye. It may also lead to new strategies for maintaining and regenerating healthy eye function. Dr. Baker is professor of genetics, of developmental & molecular biology and of ophthalmology & visual sciences and is also the Harold and Muriel Block Chair in Genetics and director of the division of molecular genetics at Einstein. (1R01EY028990-01A1)

Tuesday, April 23, 2019

Treating Hepatitis C-Infected Injection Drug Users—Hepatitis C virus (HCV) leads to more than 15,000 deaths annually in the U.S. Antiviral drugs capable of curing HCV infection were introduced several years ago. Yet people who inject drugs—who are at the heart of the country’s HCV epidemic—are rarely offered anti-HCV therapy, due to concerns over poor medication adherence. In a study evaluating whether intensive treatment interventions improves adherence researchers including first author, Matthew Akiyama, M.D., M.Sc., and senior author and principal investigator Alain Litwin, M.D., M.P.H., of Clemson University and Prisma Health randomly assigned 150 HCV-positive people participating in an opioid treatment program to one of three antiviral treatment models: medication administered in directly observed therapy (DOT); medication in a group-therapy (GT) setting, or self-administered individual treatment (SIT), the control group. The findings were published online on April 9 in the Annals of Internal Medicine. High HCV cure rates were observed in all three groups: 98% for DOT patients, 94% for GT patients, and 90% for SIT patients. The findings indicate that HCV therapy should not be withheld for injection drug users, particularly those undergoing treatment for opioid use disorder.  Dr. Akiyama is an assistant professor of medicine at Einstein and attending physician in infectious diseases and in internal medicine at Montefiore.

Friday, April 19, 2019

Unraveling the B-Cell Response Against TB—The bacterial species Mycobacterium tuberculosis (Mtb) caused 1.3 million tuberculosis (TB)-related deaths in 2017. Infection triggers a well-studied T-cell response against Mtb, but the B-cell immune response leading to antibody production is not clearly  understood. John Chan, M.D., received a five-year, $3.5 million grant from the National Institute of Allergy and Infectious Diseases to investigate the role of IgM antibodies in the host immune response to Mtb. Dr. Chan and colleagues will use mouse and ex vivo macaque TB models to better understand the role, importance, and regulation of IgM in immune regulation during the early and chronic stages of TB.  Findings from this study may lead to novel therapies against TB infection. Dr. Chan is professor of medicine and of microbiology & immunology at Einstein and an attending physician in infectious diseases at Montefiore. (1R01AI139297-01A1)

Monday, April 08, 2019

Severing the Brain Injury-Epilepsy Link—Traumatic brain injury (TBI) can cause epilepsy, which involves recurring seizures. The more severe the TBI, the greater the chance that epilepsy will develop. Two years ago, Solomon Moshé, M.D., and Aristea Galanopoulou, M.D., Ph.D., received a NIH major grant to develop better ways to prevent epilepsy following TBI. They have now co-edited a supplement to the March 2019 issue of Neurobiology of Disease on preventing TBI-caused epilepsy, including findings from their research. The supplement describes the scope of the TBI/epilepsy problem; steps to identify biomarkers in humans and in animal models; and how to use those biomarkers to design preventive treatments in the laboratory that might work in humans. Drs. Moshé and Galanopoulou are both professors in the Saul R. Korey Department of Neurology, and the Dominick P. Purpura Department of Neuroscience. Dr. Moshé is also the director of the Isabelle Rapin division of child neurology and clinical neurophysiology at Einstein and Montefiore.

Tuesday, March 26, 2019

Investigating the Effects of Social Support on Aging—Strong social support can protect older adults from cognitive and physical decline. The neural underpinnings of social support’s cognition boost, however, are not well understood. In a study published on February 28 in The Journals of Gerontology: Series B, Helena Blumen, Ph.D., and colleagues identified neural networks associated with social support. The researchers used a computational approach to identify neural networks in elderly study participants and linked those networks to the degree of participants’ social support as measured by the Medical Outcomes Study Social Support Survey. Having broad social support was associated with neural networks involving the prefrontal cortex, hippocampus, cingulate cortex, and thalamus— brain regions known to be involved in memory and executive function. These findings suggest that strengthening social support among elderly people may reduce cognitive decline and dementia. Dr. Blumen is assistant professor of medicine and in the Saul R. Korey Department of Neurology at Einstein.

Monday, March 25, 2019

Brain Imaging and Walking—Studies in older adults have found a link between walking speed and executive function (mental skills that help people plan, organize and complete tasks). The brain’s frontal cortex is known to control gait in older adults. In a study published online on January 30 in NeuroImage, Mark Wagshul, Ph.D.,Roee Holtzer, Ph.D.,and colleagues investigated whether changes in frontal-cortex structure influence its activation during walking. In a study of healthy older adults using MRI and functional near-infrared spectroscopy (a technique that can measure blood flow in the brain during walking), they found a clear link between increased brain activation during walking (a known risk for falls) and structural changes in the brain. During complex walking tasks, individuals with smaller frontal cortices required greater activation compared with individuals with larger frontal cortices, possibly an indication of inefficient brain utilization.  The researchers hope to use similar measures to predict the risk of falling in older adults. Dr. Wagshul is an associate professor of radiology and is an assistant professor of physiology & biophysics at Einstein. Dr. Holtzer is a professor in the Saul R. Korey Department of Neurology at Einstein.

Monday, March 25, 2019

Insight Into HIV-associated Cardiovascular Disease—Cardiovascular disease (CVD) is a major health problem for people living with HIV. Antiretroviral drugs, viral load, immune-cell activation and inflammation all contribute to HIV-associated CVD. Biomarkers are needed for predicting CVD risk among these individuals. In a study published online on February 14 in Circulation, Qibin Qi, Ph.D., and Wei Zhao, M.S., found that levels of ceramides (a class of circulating blood lipids) correlate with the risk of developing carotid artery plaque (indicating greater likelihood of CVD events) during the course of HIV-infection and use of antiretroviral drugs. The findings suggest that targeting ceramides among people living with HIV might help to treat CVD or prevent its onset.  Dr. Qi is an associate professor of epidemiology & population health Einstein. Wei Zhao is a medical student at Einstein.

Friday, March 22, 2019

Understanding Kidney Cancer Progression—Clear cell renal cell carcinoma (CCRCC) is the most common type of kidney cancer. In a study published online on January 31 in the Journal of Clinical Investigation, Niraj Shenoy, MD., M.S., Amit K. Verma, M.B.B.S., and colleagues describe a new prognostic biomarker for this type of cancer called 5-hydroxymethylcytosine (5hmC). As kidney cancer advances, tumor levels of 5hmc progressively decrease. The researchers found that loss of 5hmC occurs because an aberrant metabolic intermediate inhibits enzymes called TET (Ten-eleven Translocation). Furthermore, the presence of ascorbic acid (Vitamin C) prevents the aberrant intermediate from affecting TET and restores 5hmC levels. High-dose intravenous ascorbic acid inhibited kidney cancer growth in a mouse model and increased 5hmc within the tumors. These findings have led to an ongoing multicenter randomized phase 2 clinical trial of vitamin C as an adjunct to standard of care treatment for metastatic and unresectable CCRCC. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. Dr. Shenoy is an assistant professor of medicine at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care.

Thursday, March 21, 2019

A Recipe for Making Therapeutic Liver Cells—So-called pluripotent stem cells can develop into any type of cell in the body—cells that could especially help in treating human diseases in which tissue loss has occurred. However, the signals that direct pluripotent stem cells to develop into desired cell types aren’t well understood. In a new study published online on January 28 in Differentiation, Sanjeev Gupta, M.D., and colleagues showed that human pluripotent stem cells differentiate into hepatocytes (liver cells) when cultured in a medium in which fetal hepatocytes had been grown. Surprisingly, the signals triggering differentiation were identified as small metabolomics products rather than proteins made by fetal hepatocytes. When the hepatocytes resulting from stem cells were transplanted into mice with acute liver failure, they promoted tissue repair and liver regeneration in the mice, indicating that hepatocytes derived in this way possess therapeutic potential. The U.S. Patent and Trademark Office has allowed claims for a patent to Einstein for Dr. Gupta’s differentiation method. Dr. Gupta is professor of medicine and of pathology and is the Eleazar and Feige Reicher Chair in Translational Medicine at Einstein and is an attending physician and hepatologist at Montefiore.

Wednesday, March 13, 2019

New Triple-Negative Breast Cancer Target—Up to 20 percent of breast cancers aretriple negative breast cancer (TNBC), an aggressive form of the disease with few treatment options. In looking for genes that promote TNBC metastasis and might be knocked out as a treatment strategy, Harry Ostrer, M.D., and colleagues from Einstein and Montefiore identified Otoconin 90 (OC90)—a gene normally expressed in the ear’s cochlea to form the little calcium stones that help to control equilibrium. But the gene has been repurposed and over-expressed in TNBC as well as prostate and lung cancers to serve a novel and pernicious function. In a cohort of TNBC patients, the researchers found that the altered expression of three genes associated with OC90 overexpression —HMGA2, POLE2 and TRIB3—predicts a greater likelihood that the patients will die from the disease. The findings were published online on February 14 in PLOS ONE. Dr. Ostrer is professor of pathology and of pediatrics at Einstein.

Wednesday, February 27, 2019

Investigating the Obesity-asthma Connection—Obesity ranks as an important cause of asthma in children. Compared with their lean asthmatic counterparts, children with obese non-allergic asthma tend to have worse asthma control and don’t respond well to treatment. In investigating why obese children face an increased risk for asthma, Deepa Rastogi, M.D., M.B.B.S., found that obese asthmatic children have abnormally active genes in a signaling pathway involving CDC42, a protein that helps activate T cells.  Now the National Heart, Lung, and Blood Institute has awarded Dr. Rastogi a five-year $2.2 million grant to further investigate the CDC42 pathway’s role in non-allergic obesity-related asthma. Using cell samples from obese asthmatics and normal-weight control asthmatics, she and her colleagues will determine the cell types in which the CDC42 pathway is activated and whether it could be targeted for treating obesity-related asthma. Dr. Rastogi is associate professor of pediatrics and the Joseph S. Blume Faculty Scholar in Pediatric Development at Einstein and attending physician at Montefiore. (1R01HL141849-01A1)

Thursday, February 21, 2019

Learning How Neural Networks Form—In two recent papers involving the roundworm C. elegans, Hannes E. Buelow, Ph.D., and colleagues shed light on how neural networks are assembled during development. Dendrites are string-like extensions of neurons that sample the environment or connect with other neurons at junctions called synapses. Electrical impulses from a neuron’s dendrites are conveyed by the neuron’s other long projection—its axon—to the next neuron in the network. Sensory nerves often form elaborately branched dendritic trees, or “arbors,” so that they can collect information or sample the environment appropriately. Researchers have long known that an axon’s neuronal activity can shape the dendrites of neurons with which they are connected. In a study published on January 17 in Developmental Cell, Dr. Buelow and his team report that axons can also shape dendrites of certain C. elegans sensory neurons, known as PVD neurons, by acting as scaffolds; the researchers identified several conserved genes involved in this process. The second paper, which published January 29 in eLife, uncovers an additional mechanism involved in forming dendritic arbors. Dr. Buelow and colleagues describe how three different proteins interact within the extracellular matrix to help form the PVD dendrites and regulate the growth of dendritic branches. Psychiatric conditions such as autism spectrum disorders and schizophrenia may result from incorrectly interconnected neural networks. So defects in any one or more of these conserved genes, or in genes coding for the interacting proteins, may be a cause of those disorders. Dr. Buelow is professor of genetics and in the Dominick P. Purpura Department of Neuroscience at Einstein.

Wednesday, February 13, 2019

Recognizing Early-Stage TB—Tuberculosis is a leading cause of global mortality, responsible for around 1.6 million deaths each year. Some people who test negative based on sputum testing still have active pulmonary tuberculosis (PTB); diagnosing and treating them is vital for preventing the development of disease that can spread. Moreover, sputum culture-negative PTB is an early stage of the disease that can be treated with fewer drugs for a shorter time than sputum-culture positive PTB. To gauge the frequency of culture-negative PTB among adult PTB patients, Jacqueline Achkar, M.D., M.Sc., and colleagues analyzed data reported to the New York City Department of Health from 2011 through 2013 on 796 patients with active PTB. A significant number of patients—116, or 15 percent—were culture-negative. Compared with people with culture-positive PTB, culture-negative individuals tended to have fewer symptoms such as coughing and weight loss and had fewer abnormalities on radiographic imaging. Awareness of these findings could improve the detection and treatment of this early-disease state and reduce PTB transmission. Dr. Achkar is associate professor of medicine and of microbiology & immunology. The first author of the study, which published online on February 8 in JAMA Network Open, is Minh-Vu H. Nguyen, M.D., M.Sc., who was an Einstein medical student and a scholar of Einstein’s Master of Science Clinical Research Training Program (CRTP).

Friday, February 08, 2019

Inhibiting a Cell-Execution Protein—Apoptosis is a normal cellular process that enables damaged or defective cells to self-destruct—but uncontrolled apoptosis can be harmful.  For example, the death of heart-muscle tissue following heart attacks is largely due to apoptotic cell death. In a study published online on February 4 in Nature Chemical Biology, Evripidis Gavathiotis, Ph.D., describes previously unknown, small molecules that bind to and inhibit BAX, the protein that plays a key role in causing apoptosis. Dr. Gavathiotis and colleagues also identified a pocket within the BAX protein to which these novel inhibitors bind, thereby stabilizing BAX and preventing it from triggering apoptosis. In in vitro experiments, Dr. Gavathiotis and colleagues showed that the inhibitors protected mouse fibroblasts from apoptotic stimulation. Such BAX inhibitors could potentially be used as drugs to prevent cell death during heart attacks, strokes, neurodegenerative diseases, and chemotherapy or radiation treatment. Dr. Gavathiotis is an associate professor of biochemistry and of medicine at Einstein.

Thursday, February 07, 2019

First Imaging of Powerful Antiviral Proteins—Interferon-induced transmembrane proteins (IFITMs) are broadly active against deadly viruses, from flu to Ebola, and play an important role in defending humans from viral infections. But because IFITMs are tiny, researchers haven’t been able to easily observe how they work. Now, in a study published online on January 14 in Nature Chemical Biology, Jennifer Spence, Ph.D., and Kartik Chandran, Ph.D., used fluorescence microscopy to live-image IFITMs for the first time in cells while the proteins were fighting viruses. Drs. Spence and Chandran found that IFITMs 1, 2, and 3 worked together to prevent viruses from penetrating cellular membranes and entering the cytoplasm. Once viruses entered cells, IFITM3 fused with the virus-bearing compartments and helped carry them into the lysosomes, where they are digested. The results show that this imaging technique could be useful for future research into antiviral mechanisms. Dr. Chandran is professor of microbiology & immunology and the Harold and Muriel Block Faculty Scholar in Virology at Einstein. Dr. Spence is a research assistant professor of microbiology & immunology at Einstein.

Thursday, February 07, 2019

Insight into a Sex Development Disorder—Disorders of sex development (DSDs) affect approximately one in every 2000 live births. One such DSD is 46,XY gonadal dysgenesis (46,XY DSDs), also known as Swyer syndrome. Harry Ostrer, M.D., and colleagues previously showed that mutations in the MAP3K1 gene are one of the most common causes of 46,XY DSDs. They found that MAP3K1 mutations give the expressed protein new functions that override the normal testes-determining pathway. In their new study, published online on January 4 in Human Molecular Genetics, they show how those mutations alter MAP3K1’s structure and function and describe a previously uncharacterized domain of the protein. Their research reveals two distinct mechanisms by which MAP3K1 mutations co-opt the normal male sex-determining pathway. These findings can offer people with 46,XY DSDs greater insight into their disorder. Dr. Ostrer is professor of pathology and of pediatrics at Einstein.

Wednesday, February 06, 2019

Investigating the Causes of Lung Disease—Lung disease results from complex molecular and cellular interactions that may involve genetic alterations occurring over time and environmental factors, such as cigarette smoking. The National Heart, Lung, and Blood Institute has awarded Simon D. Spivack, M.D., M.P.H., and Jan Vijg, Ph.D., a four-year, $2.6 million grant to study age- and tobacco-related molecular alterations that affect human lungs. By shedding light on how aging and smoking interact in the lung, the research could lead to better strategies for diagnosing, preventing, and treating lung cancer and other lung diseases. Dr. Spivack is professor of medicine, of epidemiology & population health, and of genetics at Einstein. Dr. Vijg is professor and chair of genetics, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein. (1U01HL145560-01)

Monday, February 04, 2019

Extending Plasma Cells' Lifespan—Following infection or vaccination, long-lived antibody secreting cells (LLASCs) are chiefly responsible for producing the antibodies that combat infections. However, protein-based vaccines poorly induce LLASCs, and multiple boosters are often needed to generate sufficient numbers of antibodies. The National Heart, Lung, and Blood Institute has awarded David Fooksman, Ph.D., a five-year, $2.3 million grant to investigate how greater numbers of vaccine-induced antibodies can be produced. Dr. Fooksman recently found that, after vaccination, expression of the cell-surface receptor CD138 promotes potent antibody responses by giving antibody-producing LLASCs a survival advantage over new ASCs. He will explore ways to increase CD138 expression to enhance the survival of LLASs after vaccination. Dr. Fooksman is an assistant professor of pathology and of microbiology & immunology at Einstein. (3R01HL141491-01S1)

Friday, February 01, 2019

Insight into Autoimmunity-Fighting Cells—T regulatory (Treg) cells are essential for suppressing the body’s immune response. Understanding how Treg cells mature in the thymus gland could shed light on treating fatal autoimmune disorders like IPEX syndrome, which is caused by mutations in the Foxp3 gene. In a study published online on December 18 in Nature Communications, Gregoire Lauvau, Ph.D., and colleagues provide important information on how Treg cells mature and acquire their functional identity in mice. The interleukin-2 (IL-2) cytokine is known to trigger Treg cell development, followed by expression of the gene that encodes the Foxp3 transcription factor. The work reveals that IL-2 is also essential to control a genome organizing protein called SATB1 needed for Treg cells to develop and function normally prior to Foxp3 expression.  The findings suggest that earlier use of current low-dose IL-2 therapy could reprogram Treg cells and help them reach maturity before autoimmunity appears. Dr. Lauvau is professor of microbiology and immunology at Einstein.

Wednesday, January 30, 2019

Depression and Diabetes Management—People with both type 2 diabetes (T2D) and depression tend to neglect their medication regimen. In a study published online on December 7 in Journal of Diabetes and Its Complications, Jeffrey Gonzalez, Ph.D., and Claire Hoogendoorn, Ph.D., clarify this link among 376 low-income, racially diverse adults with poorly managed T2D. Those with self-reported depressive symptoms had a nearly three-fold increased risk for low medication adherence compared with non-depressed individuals. Surprisingly, compared to non-fatigued patients, those with fatigue unrelated to depression were 71 to 77 percent more likely to have low adherence. The findings suggest depression and unrelated fatigue increase the chance for inadequate disease management among low-income T2D patients. The study was supported by the Einstein–Mount Sinai Diabetes Research Center and the New York Regional Center for Diabetes Translation Research. Dr. Gonzalez is an associate professor of medicine and of epidemiology and population health at Einstein. Dr. Hoogendoorn is a research associate and adjunct assistant professor at Ferkauf Graduate School of Psychology.

Monday, January 28, 2019