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Investigating the Causes of Lung Disease

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

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

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

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
 
Suffocating Persistent TB

Suffocating Persistent TB—Tuberculosis (TB) is one of the world’s leading causes of mortality, associated with 1.6 million deaths in 2017. Antibiotics help eliminate Mycobacterium tuberculosis (Mtb), the bacterial species that causes TB. But a subpopulation of Mtb resists antibiotic treatment, remaining dormant until all too often reviving to cause active disease. Michael Berney, Ph.D., received a five-year, $3.2 million grant from the National Institute of Allergy and Infectious Diseases to determine if respiration inhibitors can eliminate Mtb persisters—suffocating them by inhibiting two critical enzymes (cytochrome bc1:aa3 and cytochrome bd oxidase) in Mtb’s respiration pathway. He will study the role of these enzymes during TB pathogenesis and test combinations of existing and novel enzymatic inhibitors in vitro and in animal models of TB. Dr. Berney will also develop new inhibitors in collaboration with Dr. Kevin Pethe (Nanyang Technical University, Singapore) and Dr. Garrett Moraski (Montana State University).  The findings may enhance the effectiveness of current TB treatments and reduce fatalities. Dr. Berney is an assistant professor of microbiology & immunology at Einstein. (1R01AI139465-01A1)

Wednesday, January 16, 2019
 
Effective Treatment for Ebola

Effective Treatment for Ebola—Two companion papers published online on January 9 in Cell Host & Microbe show that a new human antibody cocktail works against all three major disease-causing ebolaviruses: Ebola virus (formerly known as “Ebola Zaire”), Sudan virus and Bundibugyo virus. In the first study, a team led by Kartik Chandran, Ph.D. described MBP134, a cocktail of two monoclonal antibodies (mAbs)—one isolated from a human Ebola survivor, the other from the same survivor but further engineered to recognize and neutralize Sudan virus. MBP134 inhibited infection by all three ebolaviruses in guinea pigs. An improved version called MBP134AF harnessed the power of natural killer immune cells and proved more effective than any previous anti-Ebola mAbs. In the second study, a team led by Zachary Bornholdt, Ph.D., tested the MBP134AF cocktail in ferrets and macaques infected with the three ebolaviruses. The cocktail was not only protective against all three pathogens, but just a single dose inhibited viral infection and reversed disease in the macaques. The development of MBP134AF could be a model for quickly engineering new drugs against emerging pathogens. Dr. Chandran is professor of microbiology & immunology and the Harold and Muriel Block Faculty Scholar in Virology at Einstein. Dr. Bornholdt is director of antibody discovery at Mapp Biopharmaceutical, Inc.

Read a Q&A with Dr. Chandran

Wednesday, January 09, 2019
 
Engineering Better Antibodies Against Flaviviruses

Engineering Better Antibodies Against Flaviviruses—Recent outbreaks of members of the flavivirus genus, such as dengue and Zika virus, highlight the need for new and effective treatment options. Monoclonal antibodies (mAbs) could help in this effort. But developing mAbs with broad neutralizing ability against several different flaviviruses has posed a major challenge for researchers. The National Institute of Allergy and Infectious Diseases has awarded Andras Fiser, Ph.D., a five-year, $2 million grant to use computational and experimental methods identify such mAbs. To identify candidate mAbs, Dr. Fiser will develop pharmacophores: computer-generated models containing molecular features that ensure optimal binding between a monoclonal antibody and the flavivirus antigen that it targets. He will also use phage-display technology to build libraries of antibodies that are likely to be effective against flaviviruses. Dr. Fiser is professor of biochemistry and systems & computational biology at Einstein. (1R01AI141816-01)

Monday, January 07, 2019
 
Looking at the Origins of Leukemia

Looking at the Origins of Leukemia—Myelodysplastic syndromes (MDS) are precancerous blood conditions that frequently progress to acute myeloid leukemia (AML). MDS and AML are both characterized by the presence of blast cells (defective blood-forming stem cells), with higher levels present in AML. Both conditions also originate from clones (i.e., single defective stem cells). In a study published online on December 3 in Nature Medicine, Amit K. Verma, M.B.B.S., and Ulrich Steidl M.D., Ph.D., examined how stem cells evolve into MDS and AML. Jiahao Chen, Ph.D., a researcher in Dr. Steidl’s laboratory, used single-cell sequencing to compare the MDS and AML stem cells of seven patients whose MDS had progressed to AML. The study revealed that stem cell subclones not detectable in MDS blasts became dominant upon progression to AML. These results suggest that the current bulk-cell approach to analyzing cancer-related stem cells may overlook pre-existing rare aberrant stem cells that drive disease progression and the transformation of MDS to AML. 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. Steidl is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research, director of the Stem Cell Isolation and Xenotransplantation Facility and a professor of cell biology and of medicine at Einstein and associate chair for translational research in oncology at Montefiore.

Monday, December 10, 2018
 
Targeting Blood Cancers

Targeting Blood Cancers—Myelodysplastic Syndrome (MDS) often progresses to acute myeloid leukemia (AML). Both conditions are triggered by mutations in hematopoietic stem cells (HSCs), which generate all of a person’s blood cells. Mutated HSCs have so far proven resistant to treatment efforts. But in a new study, published online on  September 25 in  the Journal of Clinical Investigation, Aditi Shastri, M.B.B.S., Britta Will, Ph.D., Amit Verma M.B.B.S., Ulrich Steidl, M.D., Ph.D., and colleagues describe a new therapeutic strategy that might work. Dr. Verma and Dr. Steidl’s team had previously found that overexpression of the gene that codes for the transcription factor STAT3 is associated with MDS/AML cases that have a poor prognosis. In the study, they tested the experimental STAT3 inhibitor AZD9150 on MDS/AML stem cells from patients and on MDS/AML mouse models and found that AZD9150 successfully suppressed both STAT3 production and HSC proliferation. These promising preclinical results suggest that AZD9150 may be an effective MDS/AML therapy. Dr. Shastri is an assistant professor of medicine at Einstein and an attending physician in oncology at Montefiore Einstein Center for Cancer Care. 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. Will is an assistant professor of medicine and of cell biology at Einstein. Dr. Steidl is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research, director of the Stem Cell Isolation and Xenotransplantation Facility and a professor of cell biology and of medicine at Einstein and associate chair for translational research in oncology at Montefiore.

Friday, December 07, 2018
 
New Pathway for Fighting TB

New Pathway for Fighting TB—Drug-resistant strains of Mycobacterium tuberculosis (Mtb)—the bacterium that causes tuberculosis—are on the rise, and better treatments are needed. Previous research has shown that the isoniazid (INH) and vitamin C work by generating Mtb-killing molecules called reactive oxygen species (ROS), but how that happens wasn’t clear. In a study published on August 24 in the Proceedings of the National Academy of Sciences, Einstein researchers, Sangeeta Tiwari, Ph.D., and William R. Jacobs, Jr., Ph.D., found that INH and vitamin C disrupted a previously unsuspected arginine biosynthesis pathway. They found that disruption of the pathway produces ROS, which quickly sterilizes Mtb in vitro and in mice. Compounds that target enzymes in this pathway could be promising candidates for drugs to neutralize Mtb and prevent it from becoming resistant. Dr. Jacobs is the Leo and Julia Forchheimer Chair in Microbiology and Immunology and a professor of genetics and microbiology and immunology at Einstein. Dr. Tiwari is an associate in Dr. Jacobs’ lab at Einstein.

Wednesday, December 05, 2018
 
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