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.

Investigating Chronic Fatigue Syndrome—The NIH has established four new centers for mylagic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which affects more than one million Americans. There is no treatment and no laboratory test to diagnose the disease, which is characterized by profound fatigue that does not improve with rest and may include cognitive dysfunction and pain. Now, John Greally, M.B., B.Ch., Ph.D., has been awarded a five-year, $2.17 million grant from the National Institute of Allergy and Infectious Diseases to lead a subproject core at the center based at Columbia’s Mailman School for Public Health. The Einstein lab has access to blood samples from newly diagnosed and existing ME/CFS patients and will look for transcriptional changes in peripheral blood mononuclear cells—a type of immune cell shown by previous studies to function abnormally in ME/CFS patients. Dr. Greally is a clinical geneticist at Montefiore and professor of genetics, of medicine and of pediatrics and is director of the Center for Epigenomics at Einstein. (1U54AI138370)

Tuesday, October 10, 2017

Curbing Appetite with Oxytocin—The rare neurodevelopmental genetic disorder Prader-Willi Syndrome (PWS) is characterized by compulsive eating (hyperphagia). The resulting obesity is the leading cause of deaths for people with PWS. Signaling by the hormone oxytocin—which normally acts on brain receptors to inhibit people from eating—is inadequate in PWS, and giving supplemental oxytocin to mouse models of the disorder is known to reduce food intake and body weight. Eric Hollander, M.D., has received a three-year, $1.49 million grant from the U.S. Food and Drug Administration to study whether oxytocin can be safely and effectively given intranasally PWS patients to reduce hyperphagia. Dr. Hollander is professor of psychiatry and behavioral sciences at Einstein and director of the Autism and Obsessive Compulsive Spectrum Program at Montefiore Health System and Einstein. (1R01FD005106-01A3)

Wednesday, October 04, 2017

New Niemann-Pick Treatment Shows Promise—In the genetic disorder Niemann-Pick disease type C1 (NPC1), abnormally high levels of lipids accumulate in cells and damage organs including the liver, spleen and brain. NPC1 is usually diagnosed when children develop neurological symptoms such as clumsiness or learning difficulties. Symptoms progressively worsen and patients usually die 10 to 15 years following diagnosis. No FDA-approved treatment exists. Steven Walkley, D.V.M., Ph.D., has co-authored a study in the August 10 issue of The Lancet showing that the drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) can safely slow NPC1’s progression. Patients received monthly or bi-weekly spinal injections of the drug for 18 months. Following the treatment period, biochemical and neurological tests showed that, compared with historical data for patients the same age, patients treated with the drug experienced significantly less cognitive dysfunction, with minimal side effects. Dr. Walkley is director of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center and professor in the Dominick P. Purpura Department of Neuroscience, in the department of pathology, and in the Saul R. Korey Department of Neurology at Einstein.

Monday, October 02, 2017

Communicating Through Tunnels—After they become activated, the immune system’s macrophages recruit neighboring macrophages and other immune cells to inflammation sites and tumors. But the mechanisms by which activated macrophages contact distant cells are not well understood. In a paper published online on August 17 in Scientific Reports, Dianne Cox., Ph.D., and colleagues described how macrophages use a network of channels called tunneling nanotubes (TNTs) to communicate with other cells at long distances. Using multiple imaging techniques including super-resolution microscopy and live-cell imaging, the authors identified a group of essential molecules that macrophages use to assemble TNTs. The authors found that depletion of any of these molecules can impair signal transfer between cells and could potentially disturb normal physiological immune responses. The study’s first author is Ph.D. candidate Samer Hanna. Dr. Cox is associate professor of anatomy and structural biology and of developmental and molecular biology.

Thursday, September 28, 2017

Investigating the Cause of Myelodysplastic Syndrome—Within the bone marrow, hematopoietic stem cells (HSCs) occupy niches that include stromal and mesenchymal cells. In myelodysplastic syndromes (MDS), which precede acute myeloid leukemia, HSCs behave abnormally, either because of genetic aberrations or epigenetic alterations to DNA that influence whether genes are expressed or not. In a study published online on July 6 in Cancer Research, collaborators found that novel epigenetic alterations in the bone marrow microenvironment are critically important in causing MDS to progress. More specifically, the presence of an abnormally high number of methyl groups (hypermethylation) in stromal cells activated the Wnt/β-catenin signaling pathway in MDS stem cells, stimulating their progression to leukemia. The findings suggest that drugs that inhibit DNA methyltransferases (DNMTs) that are used to treat MDS can exert their beneficial actions via influencing the surrounding cells of the bone marrow. Senior author, Amit Verma, M.B.B.S., is professor of medicine and of developmental and molecular biology. First author Tushar Bhagat, Ph.D., is a postdoctoral fellow in Dr. Verma’s lab at Einstein.

Tuesday, September 26, 2017

Memories Are Made of This—Long-term potentiation (LTP) strengthens synapses (specialized junctions where neurons come together to communicate) by repetitively stimulating them. It’s considered a key mechanism underlying learning and memory. In their study of hippocampal mossy cells and granule cells of the brain’s hippocampus, Pablo Castillo, M.D., Ph.D., and colleagues identified a novel form of LTP in which synaptic strengthening depends on the presynaptic neuron (which releases the neurotransmitter into the synapse) rather than on the postsynaptic neuron (which receives the neurotransmitter). This form of LTP may be involved in learning as well as the neuronal excitation that causes temporal lobe epilepsy. The researchers reported their findings online on August 16 in Neuron. Dr. Castillo is professor in the Dominick P. Purpura Department of Neuroscience and of psychiatry and behavioral sciences, as well as the Harold and Muriel Block Chair in Neuroscience.

Wednesday, September 20, 2017

A Key Cervical Cancer Virus in the Crosshairs—A dozen human papillomaviruses cause cervical cancer, and one of them—HVP16—accounts for more than half of all cases. In a paper published online on September 7 in Cell, researchers analyzed the HPV16 genomes in 5,570 HPV16-infected cell and tissue samples from cases (women with cervical cancer or pre-cancer) and controls (women with benign HPV16 infections). Compared to the HPV16 genomes in the benign infections, significantly fewer differences were detected in the HPV16 genomes associated with the cancer and precancer cases. This genomic pattern was also clearly observed when researchers focused on the cancer-causing E7 gene, indicating that HPV16’s potent carcinogenicity depends on retaining the E7 gene in a conserved form. The findings suggest that drugs that disable the E7 gene or the protein it expresses could help to treat or even prevent cervical cancer. One of the paper’s co-senior authors was Robert Burk, M.D., professor of pediatrics, of microbiology & immunology, of epidemiology & population health and of obstetrics & gynecology and women’s health at Einstein.

Monday, September 18, 2017

9/11 Firefighters and Early Cancer Detection—9/11 firefighters were exposed to known and suspected carcinogens in the dusts and gases at the World Trade Center site. An Einstein study of exposed firefighters found an increased incidence of certain cancers in those firefighters compared with non-exposed firefighters. Now, the Einstein researchers have received a three-year, $1.49 million grant from the Centers for Disease Control and Prevention to conduct an extensive follow-up study of 9/11 firefighters to look for blood cancers, which were among those cancers found to be more common among exposed firefighters. The researchers will check specifically for multiple myeloma, chronic lymphocytic leukemia, myelodysplastic syndromes, and their associated precursor conditions. Early detection of these cancers could prove crucial for successfully treating any cases found. The research team is led by Amit Verma, M.D., professor of medicine and of developmental and molecular biology at Einstein; David Prezant, M.D., professor of medicine at Einstein and attending physician at Montefiore; and Ola Landgren, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center. (1U01OH011475-01)

Friday, September 15, 2017

Insights into Autism Spectrum DisorderNoboru Hiroi, Ph.D., has been awarded a five-year, $1.8 million grant from the National Institute on Deafness and Other Communication Disorders to investigate the interplay among genes, early social communication and neonatal maternal care in determining the severity of autism spectrum disorder (ASD). Working with a genetic mouse model of ASD, Dr. Hiroi’s lab has observed that newborn mice display an unusual vocalization or “call,” to communicate with their mothers and that this abnormal call reduces the level of maternal care that newborns receive. The researchers will study whether abnormal newborn-to-mother vocalization is caused by ASD-related gene variants and whether this early experience of social communication gone awry worsens ASD-like behaviors through the epigenetic modification of these gene variants. Dr. Hiroi is professor in the Dominick P. Purpura Department of Neuroscience and of psychiatry and behavioral sciences. (1R01DC015776-01A1)

Wednesday, September 13, 2017

Studying Brain Functions with Near-Infrared Light—Technologies that reveal information about neuronal activity in model animals could provide important information about how the brain functions. The National Institute of Neurological Disorders and Stroke has awarded Vladislav Verkhusha, Ph.D., a three-year, $1.8 million BRAIN Initiative grant to engineer and apply genetically encoded calcium biosensors to neuronal imaging. Dr. Verkhusha and colleagues will develop two new biosensor classes that report on neuronal levels of calcium by emitting light in the near-infrared portion of the light spectrum. This light will pass through the skin to provide images of neuron activity in the brain’s cortex and deeper. The biosensors will also be combined with optogenetic tools that modulate the brain activity. These tools can be activated with the light of the different wavelength, independently of the near-infrared biosensors. The overall approach will increase knowledge of brain function and should lead to new treatments for brain disorders. Dr. Verkhusha is professor of anatomy and structural biology. (1U01NS103573-01)

Monday, September 11, 2017

Focusing on HIV-Related Neurological Problems—Thanks to antiretroviral drugs, many fewer HIV-infected people experience frank dementia anymore. Nevertheless, more than half of HIV-positive patients treated with antiretrovirals suffer from milder, lifelong HIV-associated neurocognitive disorders, or HAND. Joan W. Berman, Ph.D., professor of pathology and of microbiology & immunology, recently received two NIH grants totaling $7.4 million to study the sequence of events that lead to HAND, examine how certain drugs of abuse increase the risk for HAND, and develop strategies for preventing the disorder. Dr. Berman also holds the Irving D. Karpas M.D. Chair for Excellence in Medical Research.

HAND occurs after HIV-infected white blood cells manage to cross the blood brain barrier, resulting in inflammation, damage to neurons, and persistent reservoirs of virus in the brain. Dr. Berman and Susan Morgello, M.D., of Mount Sinai Icahn School of Medicine, were awarded a five-year, $3.6 million grant from the National Institute of Mental Health to study a particular population of white cells known to be responsible for HAND. The researchers will follow the migration of these cells in HIV-positive patients and study the proteins that regulate the transit of white cells across the blood brain barrier. The research may lead to therapies that block HIV-infected white cells from entering the brain. (1R01MH112391-01A1)

Drugs of abuse and even certain antiretroviral therapies appear to increase the risk for developing HAND. Dr. Berman and Harris Goldstein, M.D., have been awarded a five-year, $3.8 million grant from the National Institute on Drug Abuse (NIDA) to study the interactions among methamphetamines and other drugs of abuse, antiretroviral therapeutics and HIV infection. The researchers hypothesize that methamphetamines and some antiretrovirals weaken the integrity of the blood brain barrier, making it easier for HIV-infected white blood cells to enter the brain. Their research will also use a mouse model of HIV. Dr. Goldstein is professor of pediatrics and of microbiology & immunology and director of the Einstein-Rockefeller-CUNY Center for AIDS Research. He also holds the Charles Michael Chair in Autoimmune Diseases at Einstein. (1R01DA044584-01)

Tuesday, September 05, 2017

Preventing Cancer Spread—Using mouse models of metastatic breast and pancreatic cancer, Einstein researchers have found that the drug rebastinib significantly reduces changes in tumors that promote metastasis and dramatically improves the survival of animals with breast tumors. Breast tumor cells invade blood vessels and spread through the body via doorways called Tumor Microenvironment of Metastasis (TMEM) that are found on blood vessels of tumors and consist of three different cell types in direct physical contact: a tumor cell that expresses Mena, a protein that encourages tumor cell invasion; a macrophage; and an endothelial cell. Rebastinib inhibits TMEM function, thereby preventing TMEM-associated tumor cells from invading blood vessels and causing metastasis. The drug specifically blocks a subset of macrophages found in TMEM that express the receptor tyrosine kinase Tie2. Both Tie2-expressing macrophages and TMEM function can become elevated following chemotherapy. Rebastinib may therefore prevent chemotherapy-induced metastasis from occurring. The research, which published August 24 in Molecular Cancer Therapeutics, was led at Einstein by John Condeelis, Ph.D., professor and co-chair of anatomy and structural biology, the Judith and Burton P. Resnick Chair in Translational Research and co-director of the Gruss-Lipper Biophotonics Center and its Integrated Imaging Program, Maja Oktay, M.D., Ph.D., professor of pathology and anatomy and structural biology and the Integrated Imaging program, with co-first authors Allison Harney, Ph.D., and George Karagiannis, D.V.M., Ph.D., bridge postdoctoral fellows in the Integrated Imaging Program at Einstein-Montefiore.

Thursday, September 07, 2017

Tackling Renal Disease in Lupus Patients—The autoimmune disease lupus can lead to serious kidney problems in up to 60 percent of patients, with 10-30 percent of patients ultimately developing end-stage renal disease (ESRD). The National Institute of Arthritis and Musculoskeletal and Skin Diseases has awarded Anna Broder, M.D., a five year, $880,000 grant to continue her research on the drug hydroxychloroquine, which  is used to treat lupus but is not widely used after lupus patients develop  ESRD. Dr. Broder will study whether hydroxychloroquine reduces mortality in lupus patients undergoing hemodialysis and kidney transplantation. This will involve analyzing data from a U.S. registry of ESRD patients and studying outcomes in lupus patient with ESRD who are being treated with hydroxychloroquine at Einstein and New York University School of Medicine. Dr. Broder is associate professor of medicine. (1K23AR068441-01A1)

Friday, August 18, 2017

Targeting a Sickle-Cell Problem—Sickle cell disease (SCD), a genetic disorder in which red blood cells are misshapen, causes serious complications. One SCD complication is painful leg ulcers, for which there is no approved treatment. Following up on her successful phase 1 study, the U.S. Food and Drug Administration has awarded Caterina Minniti, M.D., a four-year, $1.9 million grant to conduct a phase 2 trial of sodium nitrite cream for treating leg ulcers in SCD patients. When the cream is applied to the wound, sodium nitrite is converted into nitric oxide (NO), which causes blood vessels to dilate and also kills bacteria, stimulates the proliferation of keratinocytes (the main cell type in the skin’s outer layer) and decreases inflammation. These NO- induced changes aid healing. In the phase 1 study, the sodium nitrite cream decreased pain at the wound site and reduced patient’s narcotic use. Dr. Minniti is professor of medicine and of pediatrics at Einstein and director of the Sickle-Cell Center for Adults at Montefiore. (1R01FD005729-01)

Thursday, August 10, 2017

Reducing Radiation Injury—Radiation exposure from nuclear accidents or terrorism can cause mass casualties and poses a serious ongoing threat. Radiation-induced vascular injury (RIVI) is a critical component of the multi-organ failure caused by acute radiation exposure syndrome. RIVI can lead to blood problems such as anemia and thrombocytopenia and damage critical organs, especially intestines and lungs. The National Institutes of Health has awarded Chandan Guha M.B.B.S., Ph.D., a five-year, $2.3 million grant to develop measures to prevent RIVI. In collaboration with Janssen Pharmaceuticals, Inc., Dr. Guha and colleagues will test whether the drug Thrombopoietin Mimetic (TPOm) can protect against vascular injuries caused by radiation. The team will first evaluate TPOm in mice—an effort that will require developing imaging techniques to assess the extent radiation induced normal tissue injury. Dr. Guha is director of the Einstein Institute for Onco-physics, professor and vice chair of radiation oncology, as well as professor of urology and of pathology at Einstein and Montefiore. (1U01AI133608-01)

Friday, August 04, 2017

A One-two TB Knockout Punch—Mycobacterium tuberculosis, the bacterium that causes TB, has developed extensive drug resistance so that treatment is often lengthy or ineffective. In a paper published on June 26 in the Proceedings of the National Academy of SciencesMichael Berney, Ph.D.and his graduate student Erik Hasenoehrl, found a way to exploit the bacterium’s oxidative phosphorylation pathway that may lead to better treatments. Dr. Berney’s group, together with collaborators from Singapore, found that resistant TB infections require two terminal oxidases--molecular pumps that TB bacteria rely on to generate energy. Using chemical biology and genetic approaches, Dr. Berney and colleagues showed that simultaneously inactivating both pumps halts TB cell respiration leading to cell death. The researchers shut down both pumps and rapidly cleared M. tuberculosis infection in a TB mouse model by coupling deletion of one oxidase gene with use of a drug. Dr. Berney is an assistant professor of microbiology & immunology.

Thursday, July 13, 2017