Faculty Bibliography

As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC₅₀s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen.IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs.

BACKGROUND:Asthma, gastroesophageal reflux disease (GERD), posttraumatic stress disorder (PTSD) and depression have each been linked to exposure to the September 11, 2001 World Trade Center (WTC) terrorist attacks (9/11). We described the prevalence and patterns of these conditions and associated health-related quality of life (HRQOL) fifteen years after the attacks. METHODS:We studied 36,897 participants in the WTC Health Registry, a cohort of exposed rescue/recovery workers and community members, who completed baseline (2003-2004) and follow-up (2015-16) questionnaires. Lower respiratory symptoms (LRS; cough, dyspnea, or wheeze), gastroesophageal reflux symptoms (GERS) and self-reported clinician-diagnosed asthma and GERD history were obtained from surveys. PTSD was defined as a score > 44 on the PTSD checklist, and depression as a score > 10 on the Patient Health Questionnaire (PHQ). Poor HRQOL was defined as reporting limited usual daily activities for > 14 days during the month preceding the survey. RESULTS:In 2015-16, 47.8% of participants had ≥1 of the conditions studied. Among participants without pre-existing asthma, 15.4% reported asthma diagnosed after 9/11; of these, 76.5% had LRS at follow up. Among those without pre-9/11 GERD, 22.3% reported being diagnosed with GERD after 9/11; 72.2% had GERS at follow-up. The prevalence of PTSD was 14.2%, and of depression was 15.3%. HRQOL declined as the number of comorbidities increased, and was particularly low among participants with mental health conditions. Over one quarter of participants with PTSD or depression reported unmet need for mental health care in the preceding year. CONCLUSIONS:Nearly half of participants reported having developed at least one of the physical or mental health conditions studied by 2015-2016; comorbidity among conditions was common. Poor HRQOL and unmet need for health were frequently reported, particularly among those with post-9/11 PTSD or depression. Comprehensive physical and mental health care are essential for survivors of complex environmental disasters, and continued efforts to connect 9/11-exposed persons to needed resources are critical.

A primary service provided by home care is medication management. Issues with medication management at home place older adults at high risk for hospital admission, readmission, and adverse events. This study sought to understand medication management challenges from the home care provider perspective. A qualitative secondary data analysis approach was used to analyze program evaluation interview data from an interprofessional educational intervention study designed to decrease medication complexity in older urban adults receiving home care. Directed and summative content analysis approaches were used to analyze data from 90 clinician and student participants. Medication safety issues along with provider-provider communication problems were central themes with medication complexity. Fragmented care coordination contributed to medication management complexity. Patient-, provider-, and system-level factors influencing medication complexity and management were identified as contributing to both communication and coordination challenges.

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.

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.