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Major Study of Epigenetics in Aging

Major Study of Epigenetics in Aging—The National Institute on Aging has awarded John M. Greally, D.Med., Ph.D., a five-year, $3.6 million grant to conduct the most comprehensive study to date of cellular epigenetic events in aging, focused on understanding why DNA methylation changes with age.  DNA methylation is a modification of DNA associated with changes in gene expression and has consistently been found to change with age, but the mechanism responsible for this epigenetic change remains unknown. Dr. Greally will focus on cellular epigenetic changes to T lymphocytes, which are white blood cells implicated in a number of age-related diseases. He will assess whether age-associated cellular epigenetic changes in T lymphocytes result from events such as reprogramming of cells or from other factors, including chronic exposure to stress hormones. The study will offer insights into how T lymphocytes are involved in age-related diseases. Dr. Greally is professor of genetics, of medicine and of pediatrics and is director of the Center for Epigenomics at Einstein and a clinical geneticist at Montefiore. (1R01AG057422-01A1)

Wednesday, November 28, 2018
 
Combatting Myelodysplastic Syndrome

Combatting Myelodysplastic Syndrome—In the bone marrow disorder Myelodysplastic Syndrome (MDS), hematopoietic (blood-forming) stem cells give rise to poorly formed or defective blood cells. The National Heart, Lung, and Blood Institute has awarded Amit K. Verma, M.B.B.S., and Ulrich G. Steidl, M.D., Ph.D., a five-year, $2.1 million grant to study the role played by the IL8/CXCR2 pathway in causing MDS and to see if  targeting that pathway can prevent the syndrome from developing.  The research could lead to new insights into treating MDS as well as blood cancers such as leukemia. Dr. Verma is a 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. (1R01HL139487)

Wednesday, November 28, 2018
 
Boosting Blood Stem Cell Levels

Boosting Blood Stem Cell Levels—Eltrombopag is used for treating thrombocytopenia (abnormally low platelet levels in blood). The drug stimulates thrombopoietin receptors on immature hematopoietic progenitor cells in the bone marrow, leading to increased platelet production. In a study published online on September 12 in Science Translational Medicine, Britta Will, Ph.D., and Ulrich Steidl, M.D., Ph.D., describe a previously unknown molecular mechanism by which eltrombopag stimulates immature hematopoietic stem cells (HSC) to produce multilineage progenitor cells (i.e., capable of differentiating into many different types of blood cells). The authors found that eltrombopag chelates (binds) iron inside immature HSCs, leading to a transient reduction in intracellular iron levels which, in turn, stimulates stem cell self-renewal. This iron chelation-dependent mechanism of eltrombopag could be clinically important for preserving healthy levels of HSCs under stressful conditions such as chemotherapy or irradiation. 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.

Thursday, November 15, 2018
 
Diagnosing Lung Cancer Noninvasively

Diagnosing Lung Cancer Noninvasively—DNA mutations cause cancer and are signs that genome sequence integrity has been lost. The National Institute of Environmental Health Sciences has awarded Jan Vijg, Ph.D., and Simon Spivack, M.D., M.P.H., a five-year, $3.3 million grant to assess genome integrity in normal human cells. The researchers will use a sequencing-based assay they recently developed for detecting most if not all types of mutations using bulk DNA and single cell-based approaches. They will use the assay to measure the mutagenic effects of tobacco smoke, to see if mutations in blood or buccal (cheek) mucosal cells reflect mutations that are found in lungs of smokers and nonsmokers, and are associated with lung cancer. The work could, for the first time, allow someone’s risk for lung cancer to be assessed noninvasively, using sequencing-based assays on blood or buccal cells. Dr. Vijg is professor and chair of genetics, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein. Dr. Spivack is professor of medicine, of epidemiology and of genetics at Einstein, and chief of pulmonary medicine at Einstein-Montefiore.

Thursday, November 08, 2018
 
New Protein Engineering Tool

New Protein Engineering Tool—Split inteins arise from gene sequences embedded and separated within a host gene. Upon protein expression, individual intein fragments associate with each other and facilitate the intact host protein’s assembly in a process called protein splicing. Their efficient protein splicing ability makes inteins useful in protein engineering. In a study published article online on August 29 in the Journal of the American Chemical Society, David Cowburn, Ph.D., in collaboration with the laboratory of professor Tom Muir (Princeton University), describe a new group of atypically split inteins—split internally at an unusual location. To characterize atypical intein assembly and chemistry, they engineered a novel atypical intein with superior robustness and stability, called Cat, and demonstrated that this intein shows association mediated by hydrophobic interactions and distinct host sequence dependence properties. Cat is the fastest atypical split intein to date and should find immediate use in various technical applications. Dr. Cowburn is professor of biochemistry and of physiology and biophysics at Einstein.

Monday, November 05, 2018
 
Investigating Proteins that Regulate Chromosomes

Investigating Proteins that Regulate Chromosomes—The chromosomes of eukaryotic organisms are made of chromatin, a complex of macromolecules consisting of DNA, RNA and proteins. Dmitry Fyodorov, Ph.D., and Arthur Skoultchi, Ph.D., have received a four-year, $1.5 million grant from the National Institute of General Medical Sciences to study the functions of H1 linker histones, a major family of chromatin proteins. Using the fruit fly Drosophila as a model organism, the researchers will investigate how H1 linker histones regulate the structure and activity of chromosomes. H1 histones are essential for normal development, and mutations in H1 histone genes are associated with several human diseases including cancer. Dr. Skoultchi is professor and chair of cell biology and is the Judith and Burton P. Resnick Chair in Cell Biology at Einstein. Dr. Fyodorov is an associate professor of cell biology at Einstein. (1 R01 GM129244-01)

Monday, October 15, 2018
 
Interrupting the Formation of Blood Cancers

Interrupting the Formation of Blood Cancers—Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are usually incurable blood cancers that are highly associated with aging. They result from hematopoietic (blood-forming) stem cells (HSCs) that have acquired function-changing molecular alterations. To develop curative therapies, scientists must distinguish between alterations compatible with healthy, aged HSC function and alterations that cause HSCs to turn cancerous. The National Cancer Institute has awarded Britta Will, Ph.D., a five-year, $1.9 million grant to investigate the role played by the aging-related decline of chaperone-mediated autophagy (one of the systems cells use to digest and recycle waste products, particularly under stress conditions) in blood-cancer stem cell formation. Findings from this research could yield fundamentally new therapies for patients with MDS/AML, as well as other stem cell-derived cancers. Dr. Will is an assistant professor of medicine and of cell biology at Einstein. (1 R01 CA230756-01)

Monday, October 08, 2018
 
HPV and Cervical Cancer in HIV-Positive Women

HPV and Cervical Cancer in HIV-Positive Women—Women who are HIV-positive have a high risk of becoming infected with human papillomavirus (HPV) and later developing cervical cancer. A five-year, $3.2 million National Cancer Institute grant will allow Howard Strickler, M.D., and Robert Burk, M.D., to use sophisticated gene sequencing techniques to study whether the risk of cervical precancer in HIV-positive women is largely due previously acquired sexually transmitted HPV that has become reactivated, which commonly happens in immune suppressed women with HIV. They will also study how the methylation of HPV DNA affects precancer risk and how the cervovaginal microbiome influences HPV methylation and cervical precancer in these women. Dr. Strickler is professor of epidemiology & population health and the Harold and Muriel Block Chair in Epidemiology & Population Health at Einstein. Dr. Burk is professor of pediatrics, of microbiology & immunology, of obstetrics & gynecology and women’s health and of epidemiology & population health at Einstein and an attending physician at Montefiore Health System. (1R01CA230331-01)

Friday, October 05, 2018
 
New Mutations Found in Rare Lymphoma/Leukemias

New Mutations Found in Rare Lymphoma/Leukemias—Adult T-cell leukemia/lymphoma (ATLL) is a rare but lethal cancer involving CD4 T-cells. ATLL is diagnosed most often in Japan and in the Caribbean, where the prognosis is worse for reasons that have been unclear. In a study published online on August 13 in Blood, Murali Janakiram, M.D., Amit K. Verma, M.B.B.S., B. Hilda Ye, Ph.D., and colleagues sequenced the genomes of cells from 30 Caribbean-American ATLL patients. Compared to Japanese patients, the Caribbean-American ATLL patients had a distinct genomic profile and a significantly higher frequency of epigenetic mutations, which is associated with a worse prognosis. The findings support a clinical trial testing whether Caribbean-American ATLL patients can benefit from DNA methyltransferase (DNMT) inhibitors, which can “correct” epigenetic mutations. Dr. Janakiram is an assistant professor of medicine. 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. Ye is an associate professor of cell biology at Einstein.

Wednesday, October 03, 2018
 
Teaching Old Brains New Tricks

Teaching Old Brains New Tricks—The brain’s prefrontal cortex not only manages cognition—our ability to think—but influences walking as well. In a study published online on August 13 in the Journal of Gerontology: Medical Sciences, Roee Holtzer, Ph.D., and colleagues showed for the first time that training adults 65 and older to execute cognitive tasks while walking improves prefrontal cortex activation efficiency. Participants walked under two conditions: walking without doing a cognitive task (Single-task-walk) and walking while performing a cognitive task (Dual-task-walk).  During both walking conditions, neural activity in the prefrontal cortex was measured using functional-Near-Infrared Spectroscopy. The researchers found that after just one session dual-task walking performance improved and was coupled with enhanced activation efficiency in the prefrontal cortex. In contrast, performance and neural activity associated with single task walking—which is more automatic and less dependent on the prefrontal cortex—did not change after practice. The findings show that aging brains can be made sharper relatively quickly, which may help in reducing falls and other adverse outcomes among older adults. Dr. Holtzer is a professor in the Saul R. Korey Department of Neurology at Einstein.

Friday, September 28, 2018
 
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