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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
A Link Between Dietary Restriction and Aging

A Link Between Dietary Restriction and Aging—Findings from animal studies show that dietary restriction extends lifespan by slowing metabolic decline during aging. But how caloric reduction affects metabolites—the chemicals that result from metabolism—isn’t well understood. In a study published online on October 16 in Cell Reports, Derek M. Huffman, Ph.D., identified sarcosine as a chemical that may link dietary restriction and longevity. The researchers found that aging was associated with reduced levels of sarcosine in both rats and humans and that reductions in caloric consumption raised sarcosine levels. In addition, feeding sarcosine to elderly rats raised their sarcosine levels and boosted aspects of cellular to a more youthful state. The findings suggest that high levels of sarcosine may help maintain healthy metabolism and play an important role in extending lifespan. Dr. Huffman is an associate professor of molecular pharmacology and medicine, and is co-director of the Chronobiosis and Energetics/Metabolism of Aging Core (CEAC) at Einstein.

Tuesday, December 04, 2018
Cardiovascular Risk & HIV

Cardiovascular Risk & HIV—People living with HIV face an increased risk for cardiovascular disease (CVD). Antiretroviral drugs may contribute to CVD risk by raising cholesterol and triglyceride levels, and emerging evidence suggests that gut microbiota (GMB) may also play a role. The National Heart, Lung, and Blood Institute has awarded Qibin Qi, Ph.D., a five-year, $3.26 million grant to investigate the link between GMB and CVD in patients with HIV. The study focuses on how the GMB contributes to inflammation and immune activation, which are closely involved in CVD development. The findings should advance understanding of the disease mechanism that leads to HIV-related CVD and lead to strategies for preventing and treating CVD in HIV+ individuals. They may also have important public health implications, since it may be possible to reduce the risk for CVD in the general population by altering the GMB. Dr. Qi is an associate professor of epidemiology & population health at Einstein. (1R01HL140976)

Wednesday, November 28, 2018
Funding Extends Childhood Development Study

Funding Extends Childhood Development Study—Judy Aschner, M.D., received a five-year, $17 million grant from the National Institutes of Health to continue her Environmental Influences on Child Health Outcomes (ECHO) study, which initially launched in 2016. This new grant will expand the types of assessments and duration of longitudinal follow-up of former preterm infants to determine the factors that influence multiple health outcomes in children. Dr. Aschner’s research focuses on whether exposures to chemicals, metals and stress in the Neonatal Intensive Care Units may contribute to adverse health outcomes during early and middle childhood. Such chemicals include phthalates which are used in plastic medical equipment to make them more flexible and durable. The ECHO study will enroll 50,000 children across the United States and includes researchers from the Icahn School of Medicine at Mount Sinai, New York University, Columbia University, the New York State Psychiatric Institute, and the Feinstein Institute for Medical Research. Dr. Aschner is professor of pediatrics and obstetrics & gynecology and women's health at Einstein. (4UH3OD023320-03)

Wednesday, November 28, 2018
Uncovering Autoimmune Triggers

Uncovering Autoimmune Triggers—Dendritic cells, and the MHC II proteins they possess, play a crucial role in the body’s immune response. The MHC II bind peptides that dendritic cells then present to T cells. Depending on whether dendritic cells present “non-self” or “self” peptides, T cells will attack disease-causing microbes or cancer cells—or will cause autoimmune disease by attacking the body’s own tissues. Dendritic cells present different peptides depending on where the cells are located and whether resting or inflammatory conditions prevail. The National Institute of Allergy and Infectious Diseases has awarded Laura Santambrogio, M.D., Ph.D., a five-year, $4.1 million grant  to determine how dendritic cells behave depending on where they originate, and under resting and inflammatory conditions. The study’s goal is to determine how the sets of MHC II-presented peptides presented to T cells maintain tolerance to self or instead lead to autoimmune diseases such as type 1 diabetes. Dr. Santambrogio is professor of pathology and of microbiology & immunology at Einstein. (1R01AI137198-01A1)

Wednesday, November 28, 2018
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