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"Lewis, Alexander M"
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A systematic review and meta-analysis of obesity and COVID-19 outcomes
Some studies report that obesity is associated with more severe symptoms following SARS-CoV-2 infection and worse COVID-19 outcomes, however many other studies have not reproduced these findings. Therefore, it is uncertain whether obesity is in fact associated with worse COVID-19 outcomes compared to non-obese individuals. We conducted a systematic search of PubMed (including MEDLINE) and Google Scholar on May 18, 2020 to identify published studies on COVID-19 outcomes in non-obese and obese patients, covering studies published during the first 6 months of the pandemic. Meta-analyses with random effects modeling was used to determine unadjusted odds ratios (OR) and 95% confidence intervals (CI) for various COVID-19 outcomes in obese versus non-obese patients. By quantitative analyses of 22 studies from 7 countries in North America, Europe, and Asia, we found that obesity is associated with an increased likelihood of presenting with more severe COVID-19 symptoms (OR 3.03, 95% CI 1.45–6.28,
P
= 0.003; 4 studies, n = 974), developing acute respiratory distress syndrome (ARDS; OR 2.89, 95% CI 1.14–7.34,
P
= 0.025; 2 studies, n = 96), requiring hospitalization (OR 1.68, 95% CI 1.14–1.59,
P
< 0.001; 4 studies, n = 6611), being admitted to an intensive care unit (ICU; OR 1.35, 95% CI 1.15–1.65,
P
= 0.001; 9 studies, n = 5298), and undergoing invasive mechanical ventilation (IMV; OR 1.76, 95% CI 1.29–2.40,
P
< 0.001; 7 studies, n = 1558) compared to non-obese patients. However, obese patients had similar likelihoods of death from COVID-19 as non-obese patients (OR 0.96, 95% CI 0.74–1.25,
P
= 0.750; 9 studies, n = 20,597). Collectively, these data from the first 6 months of the pandemic suggested that obesity is associated with a more severe COVID-19 disease course but may not be associated with increased mortality.
Journal Article
Identification of a chemical probe for NAADP by virtual screening
Research into the biological role of the Ca
2+
-releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with similar three-dimensional shape and electrostatic properties. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca
2+
increases in mouse pancreatic beta cells.
Journal Article
Navigational restrictions within the new LOS context : geographical implications for the United States
In Navigational Restrictions within the New LOS Context, J. Ashley Roach faithfully edits and presents the like-titled report prepared by Dr. Lewis M. Alexander for the U.S. Department of Defense in 1986.
eBook
TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment
Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies, and there is an urgent need for the development of improved therapies for TP53-mutant leukemias. Here, we identified mutations in TET2 as the most common co-occurring mutation in patients with TP53-mutant acute myeloid leukemia (AML). In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared with deletion of either gene alone. Tp53/Tet? double-KO mice developed serially transplantable AML. Both mice and patients with AML with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors, which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant noncanonical МЕ-кВ signaling. Mice with Tp53/Tet2 loss had expansion of monocytic myeloid-derived suppressor cells (MDSCs), which impaired T cell proliferation and activation. Moreover, mice and patients with AML with combined TP53/TET2 alterations displayed increased expression of the TIGIT ligand, CD155, on malignant cells. TIGIT-blocking antibodies augmented NK cell-mediated killing of Tp53/Tet2 double-mutant AML cells, reduced leukemic burden, and prolonged survival in Tp53/Tet2 double-KO mice. These findings describe a leukemia-promoting link between TET2 and TP53 mutations and highlight therapeutic strategies to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.
Journal Article
TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment
Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies, and there is an urgent need for the development of improved therapies for TP53 -mutant leukemias. Here, we identified mutations in TET2 as the most common co-occurring mutation in patients with TP53- mutant acute myeloid leukemia (AML). In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared with deletion of either gene alone. Tp53/Tet2 double-KO mice developed serially transplantable AML. Both mice and patients with AML with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors, which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant noncanonical NF-κB signaling. Mice with Tp53/Tet2 loss had expansion of monocytic myeloid-derived suppressor cells (MDSCs), which impaired T cell proliferation and activation. Moreover, mice and patients with AML with combined TP53/TET2 alterations displayed increased expression of the TIGIT ligand, CD155, on malignant cells. TIGIT-blocking antibodies augmented NK cell–mediated killing of Tp53/Tet2 double-mutant AML cells, reduced leukemic burden, and prolonged survival in Tp53/Tet2 double-KO mice. These findings describe a leukemia-promoting link between TET2 and TP53 mutations and highlight therapeutic strategies to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.
Journal Article
