Faculty Bibliography

Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16^INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.

Caucasian Americans (CA) compared with African Americans (AA) have a twofold increased incidence of multiple myeloma (MM) and have an earlier age of diagnosis. However, there is sparse information regarding underlying biological differences across racial/ethnic groups. We characterized genetic alterations using a targeted next-generation sequencing assay called myTYPE, developed at MSKCC, allowing capture of somatic mutations, IgH translocations, gains/losses, and hyperdiploidy. Samples were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort. In total, 68 patient samples were successfully sequenced and manually curated based on well-established databases. Of the 68 patient samples (47 CA, 21 AA), 84% had at least one type of genomic alteration. Importantly, the IgH translocation, t(11;14), was observed more frequently in the AA group (0 vs. 29%, p = 0.001). Known oncogenic somatic non-synonymous mutations were found in 18 genes and indels in 2 genes. KRAS mutations were the most common mutation found in 16% of patients followed by NRAS and BRAF mutations. TP53 somatic mutations appeared to be more common in CA but lacked significance. This proof-of-principle study indicates the presence of varying underlying tumor biology between racial groups and supports the need of future prospective trials to capture these molecular characteristics.

OBJECTIVE:Persons living with HIV (PLWH) well-treated on antiretroviral therapies remain at risk for ensuing arterial disease. We investigated the relationship between adipose depots and biomarkers of arterial injury and inflammation to gain insight into the link between body composition and CVD risk. DESIGNS/METHODS/UNASSIGNED:155 HIV-infected and 70 non-HIV-infected individuals were well-phenotyped for body composition. Adipose depots were assessed via single-slice abdominal CT. Circulating markers of arterial disease and generalized inflammation [lipoprotein-associated phospholipase A2 (LpPLA2), oxidized LDL (oxLDL), high sensitivity cardiac troponin T (hs-cTnT), high sensitivity C reactive protein (hsCRP)] were evaluated. RESULTS:Despite similar BMI and visceral adipose tissue (VAT), HIV-infected individuals had significantly lower subcutaneous adipose tissue (SAT, 199[126,288] vs. 239[148,358]cm, P = .04) compared to non-HIV-infected individuals. Among HIV-infected individuals, reduced SAT inversely correlated with LpPLA2 (ρ = -0.19, P = .02) and hs-cTnT (ρ = -0.24, P = .004), whereas increased VAT significantly and positively related to LpPLA2 (ρ = 0.25, P = .003), oxLDL (ρ = 0.28, P = .0005), hs-cTnT (ρ = 0.28, P = .0007), and hsCRP (ρ = 0.32, P =  < .0001). Similar analyses among the non-HIV-infected individuals revealed significant relationships between SAT and LpPLA2 (ρ = -0.24, P = .05), as well as VAT and LpPLA2 (ρ = 0.37, P = .002), oxLDL (ρ = 0.24, P = .05), and hsCRP (ρ = 0.29, P = .02). In modeling performed among the HIV group, simultaneously controlling for VAT, SAT, age, and relevant HIV-related parameters, reduced SAT was an independent predictor of LpPLA2 (P = .04) and hs-cTnT (P = .005) and increased VAT was an independent predictor of LpPLA2 (P = .001), oxLDL (P = .02), hs-cTnT (P = .04), and hsCRP (P = .04) CONCLUSION:: Fat redistribution phenotypes, characterized by SAT loss and/or VAT accumulation, may be linked to arterial injury and inflammation in HIV.

Many practicing health care providers find themselves ill-prepared to meet the complex care needs of older adults. The Geriatric Certificate Program (GCP) represents a collaborative partnership leveraging existing educational courses, with new courses developed to fill existing education gaps, aimed at improving quality of care for older adults. This paper describes the GCP and examines its impact on knowledge, skills, clinical practice, as well as confidence, comfort, and competence in providing geriatric care. Upon program completion, all graduates (N = 146; 100%) completed an online evaluation survey. The majority of graduates reported (5-point scale: 1 = much less now; 5 = much more now) being more confident (88%), comfortable (83%), and competent (89%) to provide optimal geriatric care than prior to the program. The GCP provides a significant opportunity for health care providers to build their capacity for the care of older adults. Key lessons learned in implementing the GCP and suggestions for further development are discussed.

Sugar-sweetened beverages (SSBs) increase risk of cardiometabolic disease. Young people consume the largest amounts of SSBs and have experienced the greatest relative gains in obesity in the past several decades. There is evidence of addictive properties of both caffeine and sugar, the primary ingredients in SSBs, but little research into such properties of SSBs in naturally occurring consumption patterns. Thus, in this exploratory study, we sought to examine potentially addictive properties of SSBs during a 3-day SSB cessation intervention in overweight and obese adolescents who typically consume ≥3 SSBs daily. Participants (n = 25) were aged 13-18 years, mostly female (72%), and African American (56%) or Hispanic (16%) with a BMI≥95th percenttile (76%). Withdrawal symptoms and SSB craving were assessed approximately 1-week apart, during both regular SSB consumption and a 3-day period of SSB cessation in which participants were instructed to drink only plain milk and water. During SSB cessation, adolescents reported increased SSB cravings and headache and decreased motivation, contentment, ability to concentrate, and overall well-being (uncorrected Ps < 0.05). After controlling the false discovery rate, changes in motivation, craving, and well-being remained significant (corrected Ps < 0.05). Using 24-hr recalls and drink journals, participants reported lower total daily consumption of sugar (-80 g) and added sugar (-16 g) (Ps < 0.001) during cessation. This study provides preliminary evidence of withdrawal symptoms and increased SSB cravings during cessation in a diverse population of overweight or obese adolescents.

For individuals who are food insecure, food pantries can be a vital resource to improve access to adequate food. Access to adequate food may be conceptualized within five dimensions: availability (item variety), accessibility (e.g., hours of operation), accommodation (e.g., cultural sensitivity), affordability (costs, monetary or otherwise), and acceptability (e.g., as related to quality). This study examined the five dimensions of access in a convenience sample of 50 food pantries in the Bronx, NY. The design was cross-sectional. Qualitative data included researcher observations and field notes from unstructured interviews with pantry workers. Quantitative data included frequencies for aspects of food access, organized by the five access dimensions. Inductive analysis of quantitative and qualitative data revealed three main inter-related findings: (1) Pantries were not reliably open: only 50% of pantries were open during hours listed in an online directory (several had had prolonged or indefinite closures); (2) Even when pantries were open, all five access dimensions showed deficiencies (e.g., limited inventory, few hours, pre-selected handouts without consideration of preferences, opportunity costs, and inferior-quality items); (3) Open pantries frequently had insufficient food supply to meet client demand. To deal with mismatch between supply and demand, pantries developed rules for food provision. Rules could break down in cases of pantries receiving food deliveries, leading to workarounds, and in cases of compelling client need, leading to exceptions. Adherence to rules, versus implementation of workarounds and/or exceptions, was worker- and situation-dependent and, thus, unpredictable. Overall, pantry food provision was unreliable. Future research should explore clients' perception of pantry access considering multiple access dimensions. Future research should also investigate drivers of mismatched supply and demand to create more predictable, reliable, and adequate food provision.