Climate change : a response surface study of the effects of CO2 and temperature on the growth of French beans

The possible impact of global rises in atmospheric CO2 concentration and temperature on the growth and development of French beans (Phaseolus vulgaris) was examined using growth cabinets. Five CO2 concentrations of 350, 450, 550, 650 and 750 vpm and five temperatures of 14·5, 15·5, 16·5, 17·5 and 18·5°C were tested using a fractional factorial design comprising nine treatment combinations of the two factors. Plants were grown under constant irradiance, common atmospheric humidities (vpd 0·5 kPa) and non-limiting supplies of water and mineral nutrients. The plant growth response was modelled by fitting polynomial response function curves to the times to first flower opening, first bean set, 50% maturity and the number and yield of beans. The effects of temperature were large and positive for most of the measured variables, whereas the effects of CO2 were small and negative or non-existent. Increased temperature substantially reduced the time to flowering and the time from bean set to 50% maturity and increased the number and yield of mature beans whereas increased CO2 concentration had little effect on plant growth except that bean yield was very slightly reduced. There was no significant evidence of interaction between the CO2 concentration effects and the temperature effects. The time to maturity and yield of mature beans was simulated for the 2020s (2010 to 2039) and the 2050s (2040 to 2069) using the fitted polynomial models and four climate change scenarios suggested by the UK Climate Impacts Programme. These simulations showed that, depending upon the assumed scenario, the 2020s yields could rise by 39–84% and time to maturity reduce by between 6 and 15 days whereas the 2050s yields could rise by 51–118% and time to maturity reduce by between 9 and 25 days

Vulnerability of horticultural crop production to extreme weather events

The potential impact of future extreme weather events on horticultural crops was evaluated. A review was carried out of the sensitivities of a representative set of crops to environmental challenges. It confirmed that a range of environmental factors are capable of causing a significant impact on production, either as yield or quality loss. The most important of these were un-seasonal temperature, water shortage or excess,and storms. Future scenarios were produced by the LARS-WG1, a stochastic weather generator linked with UKCIP02 projections of future climate. For the analyses, 150 years of synthetic weather data were generated for baseline, 2020HI and 2050HI scenarios at defined locations. The output from the weather generator was used in case studies, either to estimate the frequency of a defined set of circumstances known to have impact on cropping, or as inputs to models of crop scheduling or pest phenology or survival. The analyses indicated that episodes of summer drought severe enough to interrupt the continuity of supply of salads and other vegetables will increase while the frequency of autumns with sufficient rainfall to restrict potato lifting will decrease. They also indicated that the scheduling of winter cauliflowers for continuity of supply will require the deployment of varieties with different temperature sensitivities from those in use currently. In the pest insect studies, the number of batches of Agrotis segetum (cutworm) larvae surviving to third instar increased with time, as did the potential number of generations of Plutella xylostella (diamond-back moth) in the growing season, across a range of locations. The study demonstrated the utility of high resolution scenarios in predicting the likelihood of specific weather patterns and their potential effect on horticultural production. Several limitations of the current scenarios and biological models were also identified

The effect of cultural and environmental factors on potato seed tuber morphology and subsequent sprout and stem development

Seed crops of the variety Estima were grown in each of 2 years using two planting dates, two harvest dates, two plant densities and two irrigation regimes to produce seed tubers which had experienced different cultural and environmental conditions. The effects of these treatments on tuber characteristics, sprout production and stem development in the ware crop were then determined in subsequent experiments using storage regimes of 3 and 10 °C. Time of planting the seed crop affected numbers of eyes, sprouts and above ground stems in the subsequent ware crop because environmental conditions around the time of tuber initiation appeared to alter tuber shape. Cooler, wetter conditions in the 7 days after tuber initiation were associated with tubers which were longer, heavier and had more eyes, sprouts and above ground stems. In contrast, the time of harvesting the seed crop did not affect tuber shape or numbers of above ground stems and there was no interaction with tuber size. The density of the seed crop had no effect on any character measured and irrigation well after tuber initiation did not affect tuber shape, numbers of sprouts or numbers of stems. Seed production treatments, which resulted in earlier dormancy break, were associated with tubers that produced more sprouts and above ground stems, in contrast to the conventional understanding of apical dominance. Storage at 3 °C gave fewer sprouts, a lower proportion of eyes with sprouts and fewer stems than storage at 10 °C. The major effects on stem production appear to result from environmental conditions at the time of tuber initiation of the seed crop and sprouting temperature

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

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

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