Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The motivations for the adoption of management innovation by local governments and its performance effects

This article analyses the economic, political and institutional antecedents and performance effects of the adoption of shared Senior Management Teams (SMTs) – a management innovation (MI) that occurs when a team of senior managers oversees two or more public organizations. Findings from statistical analysis of 201 English local governments and interviews with organizational leaders reveal that shared SMTs are adopted to develop organisational capacity in resource‐challenged, politically risk‐averse governments, and in response to coercive and mimetic institutional pressures. Importantly, sharing SMTs may reduce rather than enhance efficiency and effectiveness due to redundancy costs and the political transaction costs associated with diverting resources away from a high‐performing partner to support their lower‐performing counterpart

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

A retrospective evaluation of the GDF/Suez merger: Effects on gas hub prices

We present an ex-post analysis of the effects of GDF’s acquisition of Suez in 2006 created one of the world’s largest energy companies. We perform an econometric analysis, based on Difference-in-Difference techniques on the market for trading on the Zeebrugge gas hub in Belgium. Removing barriers to entry and facilitating access to the hub through ownership unbundling were an important part of the objectives of the remedies imposed by the European Commission. Our analysis shows a price decline after the merger. This decline suggests the remedies were effective in limiting the potential anti-competitive effects of the merger. Moreover, it suggests that ownership unbundling has generated improved access to the hub. Therefore, the remedies may have done more than simply mitigate the potential anti-competitive effects of the merger; they may have effectively created competition.nrpages: 35status: publishe

A Retrospective Evaluation of the GDF/Suez Merger: Effects on Gas Hub Prices

We present an ex-post analysis of the effects of GDF\u2019s acquisition of Suez in 2006 created one of the world\u2019s largest energy companies. We perform an econometric analysis, based on Difference-in-Difference techniques on the market for trading on the Zeebrugge gas hub in Belgium. Removing barriers to entry and facilitating access to the hub through ownership unbundling were an important part of the objectives of the remedies imposed by the European Commission. Our analysis shows a price decline after the merger. This decline suggests the remedies were effective in limiting the potential anti-competitive effects of the merger. Moreover, it suggests that ownership unbundling has generated improved access to the hub. Therefore, the remedies may have done more than simply mitigate the potential anticompetitive effects of the merger; they may have effectively created competition

Development of a new dipstick (Cholkit) for rapid detection of Vibrio cholerae O1 in acute watery diarrheal stools

Recognizing cholera cases early, especially in the initial phase of an outbreak and in areas where cholera has not previously circulated, is a high public health priority. Laboratory capacity in such settings is often limited. To address this, we have developed a rapid diagnostic test (RDT) termed Cholkit that is based on an immunochromatographic lateral flow assay for the diagnosis of cholera cases using stool. Cholkit contains a monoclonal antibody (ICL-33) to the O-specific polysaccharide (OSP) component of V. cholerae O1 lipopolysaccharide, and recognizes both Inaba and Ogawa serotypes. We tested the Cholkit dipstick using fresh stool specimens of 76 adults and children presenting with acute watery diarrhea at the icddr,b hospital in Dhaka, Bangladesh. We compared Cholkit’s performance with those of microbial culture, PCR (targeting the rfb and ctxA genes of V. cholerae) and the commercially available RDT, Crystal VC (Span Diagnostics; Surat, India). We found that all stool specimens with a positive culture for V. cholerae O1 (n = 19) were positive by Cholkit as well as Crystal VC. We then used Bayesian latent class modeling to estimate the sensitivity and specificity of each diagnostic assay. The sensitivity of Cholkit, microbiological culture, PCR and Crystal VC was 98% (95% CI: 88–100), 71% (95% CI: 59–81), 74% (95% CI: 59–86) and 98% (95% CI: 88–100), respectively. The specificity for V. cholerae O1 was 97% (95% CI: 89–100), 100%, 97% (95% CI: 93–99) and 98% (95% CI: 92–100), respectively. Of note, two Crystal VC dipsticks were positive for V. cholerae O139 but negative by culture and PCR in this area without known circulating epidemic V. cholerae O139. In conclusion, the Cholkit dipstick is simple to use, requires no dedicated laboratory capacity, and has a sensitivity and specificity for V. cholerae O1 of 98% and 97%, respectively. Cholkit warrants further evaluation in other settings

Abstract TMP64: Association Of Brain Arterial Diameters With Demographic And Anatomical Factors In A Multi-national Pooled Analysis Of Cohort Studies

Byline: Victor J Del Brutto, Univ of Miami, Miami, FL; Farid Khasiyev, SLU Sch of Medicine, St. Louis, MT; Minghua Liu, Columbia Univ, New York, NY; Antonio Spagnolo-Allende, New York, NY; Ye Qiao, JOHNS HOPKINS UNIVERISITY, Baltimore, MD; Jesus D Melgarejo Arias, Universidad del Zulia, Maracaibo, Venezuela, Bolivarian Republic of; Vanessa A Guzman, Columbia university medical center, New York, NY; Danurys Sanchez, New York, NY; Howard Andrews, New York State Psychiatric Institute, New York, NY; Jeffrey D Pyne, Columbia Univ, New York, NY; Clarissa D Morales, Columbia Univ, New York, NY; Tatjana Rundek, MILLER SCHL OF MEDICINE UNIV M, Miami, FL; Clinton B Wright, NATIONAL INSTITUTES OF HEALTH, Rockville, MD; Meagan T Farrell, Harvard T.H. Chan Sch of Public Health, Boston, MA; Sudha Seshadri; Jose R Romero, BOSTON UNIVERSITY SCHOOL OF MEDICIN, Boston, MA; Gladys E Maestre, Univ of Texas Rio Grande Vall, Brownsville, TX; OSCAR DEL BRUTTO, CLINICA KENNEDY, Guayaquil, Ecuador; Adam Brickman, Columbia Univ, New York, NY; Jennifer Manly, New York, NY; Richard P Mayeux, Columbia Univ, New York, NY; Ralph L Sacco, UNIVERSITY OF MIAMI, Miami, FL; Mitchell Elkind; Christopher Chen, NATIONAL UNIVERSITY OF SINGAPORE, Singapore; Hilal Saima, National Univ of Singapore, Singapore, Singapore; Bruce Wasserman, John Hopkins Med Institute, Baltimore, MD; Jose Gutierrez, COLUMBIA UNIVERSITY MEDICAL CE, New York, NY Objectives: Brain arterial dilation is an increasingly recognized cerebrovascular disease marker. However, demographic and anatomical factors may influence brain arterial diameters within the normal spectrum. We hypothesize that age, sex, height, total cranial volume (TCV) and fetal posterior cerebral arteries (fPCA) presence correlate with brain arterial diameters across diverse populations. Methods: We included participants with available time-of-flight MRA from 9 cohort studies across the United States (4), Ecuador (1), Venezuela (1), South Africa (1) and Singapore (2). Arterial diameters of the basilar artery (BA), cavernous internal carotid arteries (ICAs) and middle cerebral arteries (MCAs) were measured using LKEB Automated Vessel Analysis (LAVA) software. Linear regression models were fitted to assess the association between brain arterial diameters and exposures. The R-squared was calculated to assess the extent of brain arterial diameter variation explained by the variables studied. Results: The sample included 6,269 participants (mean age 68 years; 42% men). Unilateral fPCA was found in 12.6% and bilateral fPCAs in 3.0%. Older age, male sex and TCV were uniformly correlated with larger BA, ICA and MCA diameters (Table). Unilateral and bilateral fPCAs showed a negative correlation with BA diameter and a positive correlation with ICA diameters in a dose-dependent manner. Models fitted for age, sex, TCV, and fPCA presence explained on average 24, 16 and 12 % of the BA, ICAs and MCA diameter interindividual variation, respectively. Using height instead of TCV decreased the R-squared by 2% on average. Conclusions: In this pooled analysis of cohort studies, we found brain arterial diameters consistently correlate with age, sex, TCV and fPCA presence. These factors should be considered to define abnormal arterial diameter cut-offs across populations. If resources are limited or if bedside applicability is desired, height could be used instead of TCV.Academi