MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research

A systematic review of the effectiveness of mental health promotion interventions for young people in low and middle income countries.

BACKGROUND: This systematic review provides a narrative synthesis of the evidence on the effectiveness of mental health promotion interventions for young people in low and middle-income countries (LMICs). Commissioned by the WHO, a review of the evidence for mental health promotion interventions across the lifespan from early years to adulthood was conducted. This paper reports on the findings for interventions promoting the positive mental health of young people (aged 6-18 years) in school and community-based settings. METHODS: Searching a range of electronic databases, 22 studies employing RCTs (N = 11) and quasi-experimental designs conducted in LMICs since 2000 were identified. Fourteen studies of school-based interventions implemented in eight LMICs were reviewed; seven of which included interventions for children living in areas of armed conflict and six interventions of multicomponent lifeskills and resilience training. Eight studies evaluating out-of-school community interventions for adolescents were identified in five countries. Using the Effective Public Health Practice Project (EPHPP) criteria, two reviewers independently assessed the quality of the evidence. RESULTS: The findings from the majority of the school-based interventions are strong. Structured universal interventions for children living in conflict areas indicate generally significant positive effects on students' emotional and behavioural wellbeing, including improved self-esteem and coping skills. However, mixed results were also reported, including differential effects for gender and age groups, and two studies reported nonsignficant findings. The majority of the school-based lifeskills and resilience programmes received a moderate quality rating, with findings indicating positive effects on students' self-esteem, motivation and self-efficacy. The quality of evidence from the community-based interventions for adolescents was moderate to strong with promising findings concerning the potential of multicomponent interventions to impact on youth mental health and social wellbeing. CONCLUSIONS: The review findings indicate that interventions promoting the mental health of young people can be implemented effectively in LMIC school and community settings with moderate to strong evidence of their impact on both positive and negative mental health outcomes. There is a paucity of evidence relating to interventions for younger children in LMIC primary schools. Evidence for the scaling up and sustainability of mental health promotion interventions in LMICs needs to be strengthened

Combined mTOR and MEK inhibition attenuates cellular proliferation and increases the apoptotic response.

<p>(<b>A</b>) The indicated cells were treated for 24 hrs. with rapamycin or BEZ235 and immunoblotted with the indicated antibodies. (<b>B</b>) 786-0 and RCC4 cells were treated increasing doses of GSK212 for 24 hrs. and immunoblotted with the indicated antibodies. (<b>C</b>) 786-0 and RCC4 cells were treated for 24 hrs with rapamycin and BEZ235 in the presence of Edu. Edu incorporation was assessed by flow cytometry. (<b>D</b>) 786-0 and RCC4 cells were treated with the indicated compounds for 24 hrs. Whole cell extracts were immunoblotted for the cell cycle related proteins indicated. (<b>E</b>) 786-0 and RCC4 cells were treated with indicated drugs and assessed for viability on day 4 using CellTiter-Glo 4. (<b>F</b>) 786-0 and RCC4 cells were plated, allowed to attach, and treated with the indicated drug(s). Photographs of wells containing 786-0 (day 11) and RCC4 (day 17) cells fixed with 4% PFA and stained with 0.1% crystal violet. (<b>G</b>) 786-0 and RCC4 cells were treated with the indicated compounds for 24 hrs. Whole cell extracts were immunoblotted with the indicated antibodies.</p

Catalytic mTOR inhibitors block mTORC1 signaling more fully than allosteric mTOR inhibition.

<p>The indicated cell lines were treated with the allosteric and catalytic mTOR inhibitors (rapamycin and BEZ235 respectively) at the indicated concentrations for 24 hrs. Whole cell extracts were then immunoblotted with the indicated antibodies.</p

Novel renal cell carcinoma cell lines lack VHL and overexpress HIF.

<p>(<b>A</b>) Photomicrographs of H&E stains (left panels) and bright field images (right panels) of UNC-R1 and UNC-R2 PDX derived cell lines. (<b>B</b>) Whole cell extracts from UNC-R1 and UNC-R2s were immunoblotted with the indicated antibodies. RCC4 2-1 (VHL null) and RCC4 3–14 (VHL positive) were included as controls.</p

Catalytic mTOR inhibition attenuates proliferation and induces apoptosis better than allosteric mTOR inhibition.

<p>(<b>A</b>) The indicated cell lines were assessed for viability on the indicated days using CellTiter-Glo. Statistical significance was determined by comparing rapamycin and BEZ235 treated groups. (<b>B</b>) The indicated cell lines were treated with rapamycin and BEZ235 for 48 hours and immunoblotted with the indicated antibodies. (<b>C</b>) The indicated cell lines were treated with rapamycin and BEZ235 for 48 hours and assessed for apoptosis by flow cytometry analysis of the Annexin V+/PI – fraction. (<b>D</b>) 786-0 cells were stably infected with shRNAs targeting Raptor (mTORC1) or Rictor (mTORC2) and confirmed for knock-down by western blot. (<b>E</b>) Whole cell extracts from 786-0 shNS, shRaptor, and shRictor cells were immunoblotted with the indicated antibodies.</p

Comparative genomics of Vibrio Cholerae from Haiti, Asia, and Africa

Cholera was absent from the island of Hispaniola at least a century before an outbreak that began in Haiti in the fall of 2010. Pulsed-field gel electrophoresis (PFGE) analysis of clinical isolates from the Haiti outbreak and recent global travelers returning to the United States showed indistinguishable PFGE fingerprints. To better explore the genetic ancestry of the Haiti outbreak strain, we acquired 23 whole-genome Vibrio cholerae sequences: 9 isolates obtained in Haiti or the Dominican Republic, 12 PFGE pattern-matched isolates linked to Asia or Africa, and 2 non matched outliers from the Western Hemisphere. Phylogenies for whole-genome sequences and core genome single-nucleotide polymorphisms showed that the Haiti outbreak strain is genetically related to strains originating in India and Cameroon. However, because no identical genetic match was found among sequenced contemporary isolates, a definitive genetic origin for the outbreak in Haiti remains speculative