Abstract: Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17 92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy.

Abstract: The aim of this study was to describe anthropometric and food intake data related to the frailty syndrome in the elderly. This was a cross-sectional study in individuals >/= 60 years of age in a household survey in the Manguinhos neighborhood of Rio de Janeiro, Brazil (n = 137). Frailty syndrome was diagnosed according to Fried et al., anthropometric measures were taken, and a food frequency questionnaire was applied and the results compared to Brazilian Ministry of Health guidelines. In the pre-frail and frail groups, body mass index and measures of central adiposity showed higher levels, while lean muscle parameters showed lower values, proportional to the syndrome's gradation. Frail elderly consumed higher amounts of grains and lower amounts of beans and fruit; pre-frail elderly consumed more vegetables, dairy products, and high-sugar and high-fat foods; the two groups consumed similar amounts of meat. Thus, diagnosis of the syndrome, anthropometric evaluation, and dietary assessment should be included in health policies for the elderly, since they assist in early identification of risk and favor interventions for disease prevention and health and nutritional promotion.

Abstract: BACKGROUND: Contacts of tuberculosis index cases are at increased risk of developing tuberculosis. Screening, preventive therapy, and surveillance for tuberculosis are underused interventions in contacts, particularly adults. We developed a score to predict risk of tuberculosis in adult contacts of tuberculosis index cases. METHODS: In 2002-06, we recruited contacts aged 15 years or older of index cases with pulmonary tuberculosis who lived in desert shanty towns in Ventanilla, Peru. We followed up contacts for tuberculosis until February, 2016. We used a Cox proportional hazards model to identify index case, contact, and household risk factors for tuberculosis from which to derive a score and classify contacts as low, medium, or high risk. We validated the score in an urban community recruited in Callao, Peru, in 2014-15. FINDINGS: In the derivation cohort, we identified 2017 contacts of 715 index cases, and median follow-up was 10.7 years (IQR 9.5-11.8). 178 (9%) of 2017 contacts developed tuberculosis during 19 147 person-years of follow-up (incidence 0.93 per 100 person-years, 95% CI 0.80-1.08). Risk factors for tuberculosis were body-mass index, previous tuberculosis, age, sustained exposure to the index case, the index case being in a male patient, lower community household socioeconomic position, indoor air pollution, previous tuberculosis among household members, and living in a household with a low number of windows per room. The 10-year risks of tuberculosis in the low-risk, medium-risk, and high-risk groups were, respectively, 2.8% (95% CI 1.7-4.4), 6.2% (4.8-8.1), and 20.6% (17.3-24.4). The 535 (27%) contacts classified as high risk accounted for 60% of the tuberculosis identified during follow-up. The score predicted tuberculosis independently of tuberculin skin test and index-case drug sensitivity results. In the external validation cohort, 65 (3%) of 1910 contacts developed tuberculosis during 3771 person-years of follow-up (incidence 1.7 per 100 person-years, 95% CI 1.4-2.2). The 2.5-year risks of tuberculosis in the low-risk, medium-risk, and high-risk groups were, respectively, 1.4% (95% CI 0.7-2.8), 3.9% (2.5-5.9), and 8.6%. (5.9-12.6). INTERPRETATION: Our externally validated risk score could predict and stratify 10-year risk of developing tuberculosis in adult contacts, and could be used to prioritise tuberculosis control interventions for people most likely to benefit. FUNDING: Wellcome Trust, Department for International Development Civil Society Challenge Fund, Joint Global Health Trials consortium, Bill & Melinda Gates Foundation, Imperial College National Institutes of Health Research Biomedical Research Centre, Foundation for Innovative New Diagnostics, Sir Halley Stewart Trust, WHO, TB REACH, and Innovation for Health and Development.