A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

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Not AvailableAn experiment was conducted to assess the effects of bioregulators applied as a foliar spray for mitigating the adverse effects of saline water on growth and yield of Isabgol (Plantago ovata) under drip irrigation. Grain yield of Isabgol remained unchanged as the levels of salinity of irrigation water increased from 0.25 dS m-1 (best 1 available water-control) to 4 dS m-1. However, at 8 dS m-1, significant reduction of 20.5 and 22.4 per cent in grain yield was recorded as compared to control (787 kg ha-1) and 4 dS m-1 (807 kg ha-1). Grain yield increased 1 by 21.5, 7.8 and 12.1 per cent over control, ascorbic acid and benzyl adenine, respectively because of foliar spray of K2SO4 (200 mg L-1). Combined effect of treatments was found significant in case of chlorophyll content K2 O4 and membrane stability index only. Among different bio-regulators, K2SO4 was found most effective particularly K2 O4 with increased salinity of irrigation waterICA

Unveiling the Evolution Journey from Pangea to Present Himalayan Orogeny with Relation to Seismic Hazard Assessment

The objective is to understand incessant seismic activities in Northwest and Central Himalayan regions. GPS data acquired (2017–2020, Nepal; 2015–2019, Uttarakhand) from 65 GNSS stations are used to generate velocity solutions with respect to International Terrestrial Reference Frame 2014 & Indian fixed reference frame to determine the site’s precise position. These velocities are further used to calculate the strain rate and prevailing convergence rate by the respective Triangulation method and Okada’s formulation. The estimated mean maximum and minimum principal strain rate are 12.19 nano strain/yr. and − 102.94 nano strain/yr. respectively. And the respective mean shear strain and dilatation are 115.13 nano strain/yr. −90.75 nano strain, which implies that Higher Himalaya observes high compression rate compared to Outer and Lesser Himalayan region. Estimations have also elucidated presence of extensional deformation in the Northwestern part of the Himalayan arc. Accordingly, in Central Himalaya, paleoliquefaction investigations have deciphered turbidites, confirming that the seismic ruptures did not reach the surface during the 2015 Gorkha earthquake. The best-fit locking depth of 14 km and convergence rate of 21 mm/yr. (Nepal) & 18 mm/yr. (Uttarakhand) are obtained. The strain budget analysis indicates that Northwest and Central Himalaya can beckon a megathrust earthquake in the future

Reducing planning target volume margins decreases dose to parotid glands in head and neck cancers - a dosimetric analysis

Introduction: Radiotherapy in head and neck cancers is treated for several weeks and daily setup and reproducibility is a challenge. This daily variability causes setup errors which accounts planning target volume margins. Reduced PTV margins have to be taken to decrease the dose to the parotid glands, without compromising on loco regional control rates. The present study is done to identify setup errors and see the feasibility to decrease the PTV margins by creating dummy radiotherapy plans in order to decrease dose to parotid glands. Material and Methods: 420 portal images were evaluated for setup errors in three dimensions (Antero Posterior, Left to Right and Superior to Inferior) which were performed in ten patients of oropharyngeal squamous cell carcinoma. All patients were treated in supine position using immobilization cast. After target volume delineation a PTV margin of 7mm was given. Dosimetric parameters of PTV and organs at risk were assessed. PTV margins were calculated according to three methods proposed by Stroom, Van Herk and ICRU 62. Dummy radiotherapy plans were generated using new PTV margins and compared with 7mm PTV margins. The data was analyzed using 3-way ANNOVA test for statistical significance. Results: The optimum PTV margins were 4mm in LR and SI direction and 7mm in AP direction. The PTV parameters (V95, D95, Dmax, Dmean, HI and CI) had no significant difference among different radiotherapy plans with different PTV margins. There was a significant decrease in the dose to right parotid (39.12 Gy to 32.88Gy; p-0.04), left parotid (37.90 to 31.21Gy; p-0.03) and parotid combined (38.65 to 31.45 Gy; p-0.01) when 7mm PTV margins were reduced to 4mm PTV margins. The results of dummy radiotherapy plans using asymmetric PTV margins (LR-4mm, SI-4mm and AP-7mm) and symmetrical PTV margins (4mm in all directions) are compared with PTV margins (7mm in all directions), in terms of PTV and OAR dosimetric parameters. Conclusion: The decreased PTV margins of 4mm decreases the dose to the parotid significantly. The implementation of radiotherapy plans needs to be supplemented by daily IGRT

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