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.

New Drug Target for HIV-1—Immune system proteins called chemokines mobilize at infection sites and attract pathogen-fighting immune cells to the sites. But HIV-1, the virus that causes AIDS, exploits the release of a particular chemokine—CCL2—to exit host cells so it can infect new cells and replicate further. A study by Vinayaka Prasad, Ph.D., and coworkers David O. Ajasin and Vasudev Rao, M.B.B.S., published online on June 7 in eLife, describes the novel mechanism involved. CCL2 mobilizes a protein from the host cell’s actin cytoskeleton to the cellular locations of virus budding and release.  The newly discovered mechanism is broadly applicable to the replication of numerous DNA and RNA viruses and suggests a target for drugs that could stop HIV-1 from multiplying. The many CCL2 antagonists that are currently in clinical trials for treating other diseases could be directed towards blocking the spread of HIV-1. Dr. Prasad is professor of microbiology & immunology at Einstein. Other key contributors include Einstein investigators Ganjam Kalpana, Ph.D., Anne Bresnick, Ph.D., and Andras Fiser, Ph.D.

Friday, June 28, 2019

How Lupus Occurs in the Brain—Patients with the autoimmune disease systemic lupus erythematosus (SLE) have poor outcomes despite aggressive treatment with immuno-suppressive drugs. In a study published online on June 6 in JCI Insight, Chaim Putterman, M.D., and colleagues identified how SLE develops in the central nervous system independent of its occurrence elsewhere in the body. In research involving animal models of lupus and human lupus autopsy tissue, the scientists found that the immune system forms a tertiary lymphoid structure—which functions like a lymph node—in a deep brain structure called the choroid plexus. The newly discovered structure may be the route through which the immune system promotes CNS lupus.  The findings may lead to new therapies for CNS lupus, which currently is extremely difficult to treat. Dr. Putterman is professor of medicine and of microbiology & immunology at Einstein and chief of rheumatology at Einstein and Montefiore.

Wednesday, June 26, 2019

New Strategy Against Deadly Lung Cancer—Better treatments are needed for small cell lung cancer (SCLC), an aggressive disease with poor prognosis (5-year survival rate less than 2%). Virtually all SCLCs have inactivating mutations in the same two genes, RB1 and TP53, but all efforts to design drugs to reactivate those genes have failed.  Liang Zhu, M.D., Ph.D., and Edward Schwartz, Ph.D., received a five-year, $2.2 million grant from the National Cancer Institute to try a new approach. Their preliminary studies have shown that SCLC cannot develop in mice when one of RB1’s downstream target proteins (Skp2) is inactivated. The researchers have also identified an inhibitor of that protein that kills human and mouse SCLC tumors. Their new studies could lead to clinical trials of a therapy that might benefit most SCLC patients. Dr. Zhu is professor of developmental & molecular biology, of ophthalmology & visual sciences and of medicine at Einstein. Dr. Schwartz is a professor of medicine and of molecular pharmacology at Einstein. (1R01CA230032-01A1)

Thursday, June 13, 2019

Reducing Error in Electronic Health Records—Patient safety organizations recommend that providers be limited to accessing one electronic health record at a time, to reduce the risk of writing orders for the wrong patient. Little evidence, however, supports this recommendation. William Southern, M.D., M.S., and colleagues at Montefiore Medical Center conducted a randomized trial of Epic electronic health record configurations, comparing error frequencies when 3,356 Montefiore providers were allowed access to between 1 and 4 patient records at a time. The results, published online on May 14 in the Journal of the American Medical Association (JAMA), showed no increase in errors among providers randomized to access multiple records compared with providers given access to just one electronic health record at a time. Dr. Southern is professor and chief of the division of hospital medicine at Einstein and Montefiore. Jason Adelman, M.D., M.S., the first author and principal investigator on the study, is now at Columbia Presbyterian Medical Center.

Wednesday, June 05, 2019

Linking Cognition to Sensory and Motor Function—Maintaining mobility requires intact visual-somatosensory (VS) integration, i.e., efficient communications between visual and somatosensory systems in the brain. Since sensorimotor and cognitive processes likely rely on overlapping neural circuits, could cognitive impairment affect VS integration—which in turn might cause problems with balance and gait? To find out, Jeannette R. Mahoney, Ph.D., and Joe Verghese, M.B.B.S., assessed 345 older adults. They found that, compared with cognitively normal individuals, the 52 cognitively impaired adults had significantly reduced VS integration and performed worse on tests measuring balance and gait performance. The findings, published online on May 6 in the Journal of Gerontology: Medical Sciences, emphasize the importance of successful multisensory integration in aging and suggest that interventions to improve multisensory integration could help prevent falls. Dr. Mahoney is an assistant professor in the Saul R. Korey Department of Neurology at Einstein. Dr. Verghese is chief of geriatrics at Einstein and Montefiore and director of the Montefiore Einstein Center for the Aging Brain.

Monday, June 03, 2019

Giving Kids a Healthy Start—Racial, ethnic, and socioeconomic factors greatly influence the rates of preterm birth and infant death in the U.S. For example, preterm birth rates for non-Hispanic black infants are nearly 60% higher than for non-Hispanic white infants and 50% higher than for Hispanic infants. Hal Strelnick, M.D., has received a 5-year, $5.5 million grant from the Health Resources and Services Administration to continue the Bronx Healthy Start Partnership, which provides resources to women, children and their families to reduce racial and ethnic disparities in rates of infant mortality and negative outcomes in the first 18 months of life. Dr. Strelnick is the associate dean for community engagement and professor and chief of community health in the department of family and social medicine. (H49MC30741­04)

Thursday, May 30, 2019

Mutated Splicing Factors in Blood Disease—RNA splicing links segments of messenger RNA into a “complete” template for protein synthesis and is regulated by proteins called splicing factors. Splicing-factor mutations can cause the blood diseases myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how those mutations caused disease wasn’t known. In a study published online on April 22 in Nature Cell Biology, co-first author Gaurav Choudhary, Ph.D., co-corresponding author, Amit K. Verma, M.B.B.S., and their team showed that a splicing-factor mutation triggers formation of  the protein IRAK4-L (an active form of the protein IRAK4), which leads to MDS/AML. The researchers also found that IRAK4-L’s expression in MDS/AML is mediated by the mutated U2AF1 splicing factor. IRAK4-L inhibitors suppressed leukemic growth of AML cells—a strategy that worked even better when the cells had U2AF1 mutations, indicating that U2AF1 mutations make IRAK4-L more targetable.  IRAK4 inhibitors will soon be tested in MDS clinical trials. 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. The research was co-led by Daniel Starczynowski, Ph.D., of Cincinnati Children’s Hospital and Jacqueline Boultwood, Ph.D., of the University of Oxford.

Tuesday, May 28, 2019

How Students View Implicit Bias Training—To address health disparities and improve patient-physician interactions, many medical schools now offer implicit bias training to their students. Cristina Gonzalez, M.D., M.Ed., led a study that assessed New York medical students’ views on implicit bias instruction and identified obstacles to effective training. The results, published online on April 16 in the Journal of General Internal Medicine, indicate that some students resist training because they think it’s unnecessary while others feel ashamed about publicly revealing their biases. Competing educational priorities, lack of student body diversity, and lack of faculty development for most instructors also hamper student engagement in implicit bias instruction. The findings may lead to better implicit-bias curricula in medical schools and improve health outcomes for vulnerable and marginalized populations that physicians serve. Dr. Gonzalez is an associate professor of medicine at Einstein and an attending physician in internal medicine at Montefiore Health System.

Thursday, May 23, 2019

Confirming Age-Related Mutations—Mutations that accumulate with age in somatic (non-reproductive) cells are thought to contribute to aging and cancer. But testing whether somatic mutations do increase with age has been difficult, since mutations differ from cell to cell. In a study published online on April 16 in Proceedings of the National Academy of Sciences, Jan Vijg, Ph.D., Lei Zhang, Ph.D., and Xiao Dong, Ph.D., looked for somatic mutations in human B lymphocytes across a wide age span—from newborns to centenarians. They used a recently developed method for sequencing the entire genomes of single cells. B lymphocytes play key roles in the immune response, and immune deficiency is a well-known hallmark of aging. The number of mutations--many in the functional part of the B cell genome--increased from hundreds in newborns to more than 3,000 in centenarians. The study is the first to show that the number of mutations accumulating in normal human somatic cells is high enough to cause adverse effects. Dr. Vijg is professor and chair of genetics, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein. Drs. Zhang and Dong are postdoctoral research fellows in the Vijg lab.

Tuesday, May 21, 2019

Targeting Aging to Prevent Alzheimer's—When somatotropic signaling (i.e., signaling that stimulates body growth) is diminished, the result is delayed aging and longer lifespans in both model organisms and people. Centenarians, in fact, have several mutations that weaken somatotropic signaling. Sofiya Milman, M.D., has received a five-year, $4 million grant from the National Institute on Aging to identify genes and gene functions that inhibit growth-related signaling. Dr. Milman and her colleagues will study participants in Einstein’s LonGenity study—a cohort of 1,400 older adults, half of whom are the offspring of centenarians. The researchers will investigate the role that somatotropic signaling plays in the brains of aging humans. They hope to identify mechanisms that confer cognitive resilience by delaying aging—findings that could lead to therapies that protect against Alzheimer’s and other diseases associated with aging. Dr. Milman is an associate professor of medicine and of genetics at Einstein and an attending physician in medicine at Montefiore. (1R01AG061155-01A1)

Friday, May 17, 2019

Preventing HIV Infection Among High-Risk Women—Imbalances among microbes in the vagina, collectively known as the vaginal microbiome, can increase a woman’s risk for contracting HIV and may affect how well pre-exposure prophylaxis (PrEP) works. The Eunice Kennedy Shriver National Institute of Child Health & Human Development has awarded a five-year, $2.6 million grant to Betsy C. Herold, M.D., to study how the vaginal microbiome affects PrEP efficacy. The findings could help in developing better preventive measures for young women at high risk for HIV infection. The study will identify which of several new PrEP formulas remain effective when used by women with different microbiomes under real-world conditions. Dr. Herold is the Harold and Muriel Block Chair in Pediatrics, director of the Translational Prevention Research Center, professor and chief of the division of pediatric infectious diseases, and vice chair for research in the department of pediatrics. Her co-investigators are Marla J. Keller, M.D., Tao Wang, M.D., Ph.D. (both at Einstein) and Greg Buck, Ph.D., of Virginia Commonwealth University School of Medicine. (1R01HD098977-01)

Wednesday, May 15, 2019

Finding a New Viral Cause of Cervical Cancer—Virtually all cases of cervical cancer are caused by high-risk types of human papillomavirus (HPV).  In a study published online on April 9 in International Journal of Cancer, Ana Gradissimo, Ph.D., and Robert D. Burk, M.D., provide the first molecular evidence showing that HPV73—now classified as “possibly oncogenic”—definitely can cause cervical cancer. The findings are a matter of public health concern for two key reasons: HPV screening tests aimed at preventing cervical cancer don’t test for HPV73; and since current HPV vaccines don’t include HPV73, they won’t be able to prevent HPV73--related cervical disease.  The researchers recommend that the International Agency for Research on Cancer upgrade HVP73’s classification from possibly carcinogenic to carcinogenic and that public health officials monitor of HPV73’s prevalence in cervical cancer across populations.  Dr. Burk is professor of pediatrics, of microbiology & immunology, of epidemiology & public health, of obstetrics & gynecology and women’s health, and an attending physician at Montefiore. Dr. Gradissimo is a postdoctoral research fellow at Einstein.

Thursday, May 09, 2019

Metabolomics and Diabetes—Type 2 diabetes (T2D) is a major public health challenge, but its causes still aren’t fully understood. Analysis of metabolites (metabolomics) in the blood can reveal subtle changes in metabolic pathways that that may precede T2D’s onset. Qibin Qi, Ph.D., has received a 4-year, $2.2 million grant from National Institute of Diabetes and Digestive and Kidney Diseases to conduct a large-scale study linking plasma metabolites with diet, lifestyle, and gut microbiota in relation to T2D in both Hispanics and non-Hispanics. The research, involving both individuals with T2D and matched controls, may provide new insight into the role of diet, lifestyle, and gut microbiota in the development of T2D and could help identify novel modifiable factors to prevent the development of T2D. Dr. Qi is associate professor and associate director of the Center for Population Cohorts in the department of epidemiology & population health at Einstein. (1R01DK119268-01)

Tuesday, May 07, 2019

Finding the Root Causes of Blood Cancers—The enzyme TET2 play a key role in causing blood cancers, but how it become activated wasn’t known. In a study published online on April 3 in Cancer Discovery, co-senior authors Amit K. Verma, M.B.B.S., and Amittha Wickrema, Ph.D., of the University of Chicago report that the enzyme kinase JAK2 activates TET2 through phosphorylation. The researchers also discovered that JAK2V617F, a JAK2 mutation seen in blood cancers, is associated with increased TET2 activity, increased hydroxymethylation (an epigenetic alteration commonly found in blood cancers) and the overexpression of oncogenic genes.  These findings indicate that the phosphorylation and consequent activation of TET2, mediated byJAK2V617F, leads to epigenetic and oncogenic changes that may underlie the development of blood cancers. 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.

Wednesday, May 01, 2019