Faculty Bibliography

BACKGROUND:The authors sought to study the risk factors associated with severe outcomes in hospitalized coronavirus disease 2019 (COVID-19) patients with cancer. METHODS:The authors queried the New York University Langone Medical Center's records for hospitalized patients who were polymerase chain reaction-positive for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and performed chart reviews on patients with cancer diagnoses to identify patients with active cancer and patients with a history of cancer. Descriptive statistics were calculated and multivariable logistic regression was used to determine associations between clinical, demographic, and laboratory characteristics with outcomes, including death and admission to the intensive care unit. RESULTS:A total of 4184 hospitalized SARS CoV-2+ patients, including 233 with active cancer, were identified. Patients with active cancer were more likely to die than those with a history of cancer and those without any cancer history (34.3% vs 27.6% vs 20%, respectively; P < .01). In multivariable regression among all patients, active cancer (odds ratio [OR], 1.89; CI, 1.34-2.67; P < .01), older age (OR, 1.06; CI, 1.05-1.06; P < .01), male sex (OR for female vs male, 0.70; CI, 0.58-0.84; P < .01), diabetes (OR, 1.26; CI, 1.04-1.53; P = .02), morbidly obese body mass index (OR, 1.87; CI, 1.24-2.81; P < .01), and elevated D-dimer (OR, 6.41 for value >2300; CI, 4.75-8.66; P < .01) were associated with increased mortality. Recent cancer-directed medical therapy was not associated with death in multivariable analysis. Among patients with active cancer, those with a hematologic malignancy had the highest mortality rate in comparison with other cancer types (47.83% vs 28.66%; P < .01). CONCLUSIONS:The authors found that patients with an active cancer diagnosis were more likely to die from COVID-19. Those with hematologic malignancies were at the highest risk of death. Patients receiving cancer-directed therapy within 3 months before hospitalization had no overall increased risk of death. LAY SUMMARY/UNASSIGNED:Our investigators found that hospitalized patients with active cancer were more likely to die from coronavirus disease 2019 (COVID-19) than those with a history of cancer and those without any cancer history. Patients with hematologic cancers were the most likely among patients with cancer to die from COVID-19. Patients who received cancer therapy within 3 months before hospitalization did not have an increased risk of death.

Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 cells/µL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101-200 and 6.2% ≤100 cells/µL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 ≤100 cells/µL and 3.2% (1/31) in CrAg-positive CD4 101-200 cells/µL.

Dermal invasion is a hallmark of malignant melanoma. Thought the molecular alterations driving the progression of primary melanoma to metastatic disease have been studied extensively, the early progression of non-invasive primary melanoma to an invasive state is poorly understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase A1 (Rps6ka1; RSK1) drives tumor invasion. Transcriptomic analysis of ribosomal protein S6 kinase A1-activated tumors identified metabolic changes, including up-regulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator activated receptor gamma (PPARG) coactivator 1 alpha (PPARGC1A), also known as PPARG coactivator-1α (PGC1α), has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens, PGC1α protein expression was found to be positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species scavenger scavenger receptor class A member 3 . PGC1α depletion modulated cellular processes associated with primary melanoma growth and invasion, including oxidative stress. These results support a role for PGC1α in mediating glutamine-driven oxidative phosphorylation to facilitate the invasive growth of primary melanoma.

Translational control of long-term synaptic plasticity via Mechanistic Target Of Rapamycin Complex 1 (mTORC1) is crucial for hippocampal learning and memory. The role of mTORC1 is well characterized in excitatory principal cells but remains largely unaddressed in inhibitory interneurons. Here, we used cell-type-specific conditional knock-out strategies to alter mTORC1 function selectively in somatostatin (SOM) inhibitory interneurons (SOM-INs). We found that, in male mice, upregulation and downregulation of SOM-IN mTORC1 activity bidirectionally regulates contextual fear and spatial memory consolidation. Moreover, contextual fear learning induced a metabotropic glutamate receptor type 1 (mGluR1)-mediated late long-term potentiation (LTP) of excitatory input synapses onto hippocampal SOM-INs that was dependent on mTORC1. Finally, the induction protocol for mTORC1-mediated late-LTP in SOM-INs regulated Schaffer collateral pathway LTP in pyramidal neurons. Therefore, mTORC1 activity in somatostatin interneurons contributes to learning-induced persistent plasticity of their excitatory synaptic inputs and hippocampal memory consolidation, uncovering a role of mTORC1 in inhibitory circuits for memory.SIGNIFICANCE STATEMENT Memory consolidation necessitates synthesis of new proteins. Mechanistic Target Of Rapamycin Complex 1 (mTORC1) signaling is crucial for translational control involved in long-term memory and in late long-term potentiation (LTP). This is well described in principal glutamatergic pyramidal cells but poorly understood in GABAergic inhibitory interneurons. Here, we show that mTORC1 activity in somatostatin interneurons, a major subclass of GABAergic cells, is important to modulate long-term memory strength and precision. Furthermore, mTORC1 was necessary for learning-induced persistent LTP at excitatory inputs of somatostatin interneurons that depends on type I metabotropic glutamatergic receptors in the hippocampus. This effect was consistent with a newly described role of these interneurons in the modulation of LTP at Schaffer collateral synapses onto pyramidal cells.

BACKGROUND:Cryptococcal meningitis accounts for 15% of AIDS-related mortality. Cryptococcal antigen (CrAg) is detected in blood weeks before onset of meningitis, and CrAg positivity is an independent predictor of meningitis and death. CrAg screening for patients with advanced HIV and preemptive treatment is recommended by the World Health Organization, though implementation remains limited. Our objective was to evaluate costs and mortality reduction (lives saved) from a national CrAg screening program across Uganda. METHODS:We created a decision analytic model to evaluate CrAg screening. CrAg screening was considered for those with a CD4<100 cells/μL per national and international guidelines, and in the context of a national HIV test-and-treat program where CD4 testing was not available. Costs (2016 USD) were estimated for screening, preemptive therapy, hospitalization, and maintenance therapy. Parameter assumptions were based on large prospective CrAg screening studies in Uganda, and clinical trials from sub Saharan Africa. CrAg positive (CrAg+) persons could be: (a) asymptomatic and thus eligible for preemptive treatment with fluconazole; or (b) symptomatic with meningitis with hospitalization. RESULTS:In the base case model for 1 million persons with a CD4 test annually, 128,000 with a CD4<100 cells/μL were screened, and 8,233 were asymptomatic CrAg+ and received preemptive therapy. Compared to no screening and treatment, CrAg screening and treatment in the base case cost $3,356,724 compared to doing nothing, and saved 7,320 lives, for a cost of $459 per life saved, with the $3.3 million in cost savings derived from fewer patients developing fulminant meningitis. In the scenario of a national HIV test-and-treat program, of 1 million HIV-infected persons, 800,000 persons were screened, of whom 640,000 returned to clinic, and 8,233 were incident CrAg positive (CrAg prevalence 1.4%). The total cost of a CrAg screening and treatment program was $4.16 million dollars, with 2,180 known deaths. Conversely, without CrAg screening, the cost of treating meningitis was $3.09 million dollars with 3,806 deaths. Thus, despite the very low CrAg prevalence of 1.4% in the general HIV-infected population, and inadequate retention-in-care, CrAg screening averted 43% of deaths from cryptococcal meningitis at a cost of $662 per death averted. CONCLUSION:CrAg screening and treatment programs are cost-saving and lifesaving, assuming preemptive treatment is 77% effective in preventing death, and could be adopted and implemented by ministries of health to reduce mortality in those with advanced HIV disease. Even within HIV test-and-treat programs where CD4 testing is not performed, and CrAg prevalence is only 1.4%, CrAg screening is cost-effective.

Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naïve adults with advanced HIV/AIDS can reduce the incidence of cryptococcal meningitis (CM) and all-cause mortality. We modeled the cost-effectiveness of laboratory-based "reflex" CrAg screening for ART-naïve CrAg-positive patients with CD4<100 cells/µL (those currently targeted in guidelines) and ART-experienced CrAg-positive patients with CD4<100 cells/µL (who make up an increasingly large proportion of individuals with advanced HIV/AIDS). Methods: A decision analytic model was developed to evaluate CrAg screening and treatment based on local CD4 count and CrAg prevalence data, and realistic assumptions regarding programmatic implementation of the CrAg screening intervention. We modeled the number of CrAg tests performed, the number of CrAg positives stratified by prior ART experience, the proportion of patients started on pre-emptive antifungal treatment, and the number of incident CM cases and CM-related deaths. Screening and treatment costs were evaluated, and cost per death or disability-adjusted life year (DALY) averted estimated. Results: We estimated that of 650,000 samples undergoing CD4 testing annually in Botswana, 16,364 would have a CD4<100 cells/µL and receive a CrAg test, with 70% of patients ART-experienced at the time of screening. Under base model assumptions, CrAg screening and pre-emptive treatment restricted to ART-naïve patients with a CD4<100 cells/µL prevented 20% (39/196) of CM-related deaths in patients undergoing CD4 testing at a cost of US$2 per DALY averted. Expansion of preemptive treatment to include ART-experienced patients with a CD4<100 cells/µL resulted in 55 additional deaths averted (a total of 48% [94/196]) and was cost-saving compared to no screening. Findings were robust across a range of model assumptions. Conclusions: Reflex laboratory-based CrAg screening for patients with CD4<100 cells/µL is a cost-effective strategy in Botswana, even in the context of a relatively low proportion of advanced HIV/AIDS in the overall HIV-infected population, the majority of whom are ART-experienced.

Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.

PURPOSE/OBJECTIVE:Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) was a trial to examine the effects of a physical activity intervention (PA) compared with a health education control (SA) on measures of disability risk in sedentary older adults (N = 424). We examined adherence to the LIFE-P PA intervention for the first 12 months of the trial. METHODS:The PA intervention consisted of walking, strength, flexibility, and balance training supplemented with behavioral skills training modules, and it used a phased, center-based schedule of adoption (3x wk(-1), weeks 1-8), transition (2x wk(-1), weeks 9-24), and maintenance (1x wk(-1), weeks 25 to end of trial) while transitioning to primarily home-based physical activity. SA consisted of weekly (weeks 1-26) transitioning to monthly health education workshops. RESULTS:Participation in moderate-intensity physical activity increased from baseline to months 6 and 12 in PA compared with SA (P < 0.001). At 12 months, PA participants who reported > or = 150 min x wk(-1) of moderate activity demonstrated a significantly greater improvement in their Short Physical Performance Battery score compared with participants who reported < 150 min.wk of moderate activity (P < 0.017). For the PA arm, center-based attendance was 76.3 +/- 24.5, 65.4 +/- 28.6, and 49.8 +/- 35.8% in the adoption, transition, and maintenance phases, respectively. CONCLUSIONS:Adherence to physical activity in LIFE-P was associated with greater improvement in SPPB score and was consistent with adherence in physical activity trials of shorter duration in this subgroup of older adults. Older individuals at risk for disability can adhere to a regular program of physical activity in a long-term randomized trial.