Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution

Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival

Recent evidence suggests CML stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, following re-transplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off, were able to persist in vivo and re-initiate leukemia in secondary recipients upon Bcr-Abl re-expression. Bcr-Abl knockdown in human CD34+ CML cells cultured for 12 days in physiological growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%, however the surviving fraction was enriched for primitive leukemic cells capable of growth in long-term culture initiating cell assay and expansion upon removal of dasatinib and addition of growth factors. Together these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance

Standard setting: Comparison of two methods

BACKGROUND: The outcome of assessments is determined by the standard-setting method used. There is a wide range of standard – setting methods and the two used most extensively in undergraduate medical education in the UK are the norm-reference and the criterion-reference methods. The aims of the study were to compare these two standard-setting methods for a multiple-choice question examination and to estimate the test-retest and inter-rater reliability of the modified Angoff method. METHODS: The norm – reference method of standard -setting (mean minus 1 SD) was applied to the 'raw' scores of 78 4th-year medical students on a multiple-choice examination (MCQ). Two panels of raters also set the standard using the modified Angoff method for the same multiple-choice question paper on two occasions (6 months apart). We compared the pass/fail rates derived from the norm reference and the Angoff methods and also assessed the test-retest and inter-rater reliability of the modified Angoff method. RESULTS: The pass rate with the norm-reference method was 85% (66/78) and that by the Angoff method was 100% (78 out of 78). The percentage agreement between Angoff method and norm-reference was 78% (95% CI 69% – 87%). The modified Angoff method had an inter-rater reliability of 0.81 – 0.82 and a test-retest reliability of 0.59–0.74. CONCLUSION: There were significant differences in the outcomes of these two standard-setting methods, as shown by the difference in the proportion of candidates that passed and failed the assessment. The modified Angoff method was found to have good inter-rater reliability and moderate test-retest reliability

Alcohol marketing and drunkenness among students in the Philippines: findings from the nationally representative Global School-based Student Health Survey

BACKGROUND: A largely unaddressed issue in lower income countries and the Philippines, in particular, is the role of alcohol marketing and its potential link to early alcohol use among youth. This study examines the associations between exposures to alcohol marketing and Filipino youths’ drinking prevalence and drunkenness. METHODS: Cross-sectional analyses were used to examine the Global School-based Student Health Survey (GSHS) conducted in Philippines (2011). The self-administered questionnaires were completed by students primarily 13 to 16 years of age (N = 5290). Three statistical models were computed to test the associations between alcohol marketing and alcohol use, while controlling for possible confounding factors. RESULTS: Alcohol marketing, specifically through providing free alcohol through a company representative, was associated with drunkenness (AOR: 1.84; 95% CI = 1.06–3.21) among youths after controlling for demographic and psychosocial characteristics, peer environment, and risky behaviors. In addition, seeing alcohol ads in newspapers and magazines (AOR: 1.65, 95% CI = 1.05–2.58) and seeing ads at sports events, concerts or fairs (AOR: 1.50, 95% CI = 1.06–2.12) were significantly associated with increased reports of drunkenness. CONCLUSIONS: There are significant associations between alcohol marketing exposure and increased alcohol use and drunkenness among youth in the Philippines. These findings highlight the need to put policies into effect that restrict alcohol marketing practices as an important prevention strategy for reducing alcohol use and its dire consequences among vulnerable youth

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

e Glasgow and Manchester Experimental Cancer Medicine Centres (ECMC), which are funded by CR-UK and the Chief Scientist’s Office (Scotland). We acknowledge the funders who have contributed to this work: MRC stratified medicine infrastructure award (A.D.W.), CR-UK C11074/A11008 (F.P., L.E.M.H., T.L.H., A.D.W.); LLR08071 (S.A.A., E.C.); LLR11017 (M.C.); SCD/04 (M.C.); LLR13035 (S.A.A., K.D., A.D.W., and A.P.); LLR14005 (M.T.S., D.V.); KKL690 (L.E.P.); KKL698 (P.B.); LLR08004 (A.D.W., A.P. and A.J.W.); MRC CiC (M.E.D.); The Howat Foundation (FACS support); Friends of Paul O’Gorman (K.D. and FACS support); ELF 67954 (S.A.A.); BSH start up fund (S.A.A.); MR/K014854/1 (K.D.)

Paper Session II-C - Advanced Concept Architecture Test; ACAT

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