The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a ...screening trial of individuals at high risk of ovarian cancer.
The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.
In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).
These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.
Background
Preoperative factors, including nutritional status, may have strong correlations with postoperative morbidities. The current study evaluated preoperative prealbumin concentrations as a ...predictor of postoperative complications after gastric surgery.
Methods
A retrospective study of 1798 patients who underwent gastrectomy for gastric adenocarcinoma was performed. Information was collected on basic patient characteristics, preoperative laboratory findings, and 30 day postoperative complications. The patients were divided into three groups based on prealbumin concentrations (≥22 mg/dL, <22 to ≥15 mg/dL, and <15 mg/dL) for analysis.
Results
The overall complication rate was 21.7 %, and the infection rate was 16 %. Subgroup analysis based on prealbumin concentrations showed that complication rates were markedly elevated with decreasing concentrations of prealbumin. Multivariate analysis using a logistic regression model showed that both overall and infectious complications were strongly associated with male gender, elevated C-reactive protein (CRP), and decreased prealbumin levels (
p
< 0.05). Even in patients with a CRP level higher than 0.1 mg/dL, male gender and low prealbumin concentrations (<15 mg/dL) were significantly correlated with overall and infectious morbidities (
p
< 0.05).
Conclusions
Preoperative prealbumin concentrations are useful predictors of short-term postoperative outcomes after gastrectomy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Nicotine and nicotinic acetylcholine receptors (nAChRs) have been explored
for the past three decades as targets for pain control. The aim of this review is to introduce
readers ...particularly to α7 nAChRs in a perspective of pain and its modulation.
Methods: Developments for α7 nAChR modulators and recent animal studies related to pain are
reviewed.
Results: Accumulating evidences suggest that selective ligands for α7 nAChRs hold promise in the
treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic
receptor types.
Conclusion: This review provides the reader recent insights on α7 nAChRs from structure and
function to the latest findings on the pharmacology and therapeutic targeting of these receptors for
the treatment of pain and inflammation.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ...ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.
Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.
We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval CI = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).
Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.
Background
A gross proximal oesophageal margin greater than 5 cm is considered to be necessary for curative surgery of adenocarcinoma of the oesophagogastric junction. This study investigated whether ...a shorter proximal margin might suffice in the context of total gastrectomy for Siewert type II and III tumours.
Methods
The gross proximal margin was measured on stretched specimens just after resection. Relationships between gross proximal margin lengths and clinicopathological features were investigated in patients with Siewert type II and III adenocarcinoma of the oesophagogastric junction treated by R0–1 surgical resection. For survival analyses, only patients who had undergone R0 resection for pathological (p) T2–4 N0–3 M0 tumour via a transhiatal approach were evaluated.
Results
Of the 140 patients, 120 had a total gastrectomy. Two patients (1·4 per cent) had histologically positive proximal margins and another two (1·4 per cent) developed anastomotic recurrence. Of 100 patients with pT2–4 N0–3 M0 tumours who underwent gastrectomy via a transhiatal approach, those with gross proximal margins larger than 20 mm appeared to have better survival than those with shorter margins (P = 0·027). Multivariable analysis demonstrated that a gross proximal margin of 20 mm or less was an independent prognostic factor (hazard ratio (HR) 3·56, 95 per cent confidence interval 1·39 to 9·14; P = 0·008), as was pathological node status (HR 1·76, 1·08 to 2·86; P = 0·024).
Conclusion
Gross proximal margin lengths of more than 20 mm in resected specimens seem satisfactory for patients with type II and III adenocarcinoma of the oesophagogastric junction treated by transhiatal gastrectomy.
A 2‐cm margin is enough
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
With limited severe acute respiratory syndrome coronavirus (SARS-CoV-2) testing capacity in the United States at the start of the epidemic (January–March 2020), testing was ...focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic.
Methods
All of Us study participants in all 50 US states provided blood specimens during study visits from 2 January to 18 March 2020. Participants were considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies with the Abbott Architect SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. The sensitivity and specificity of these ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated, along with 95% confidence intervals (CIs).
Results
The estimated sensitivities of the Abbott and EUROIMMUN assays were 100% (107 of 107 95% CI: 96.6%–100%) and 90.7% (97 of 107 83.5%–95.4%), respectively, and the estimated specificities were 99.5% (995 of 1000 98.8%–99.8%) and 99.7% (997 of 1000 99.1%–99.9%), respectively. The net sensitivity and specificity of our sequential testing algorithm were 90.7% (97 of 107 95% CI: 83.5%–95.4%) and 100.0% (1000 of 1000 99.6%–100%), respectively. Of the 24 079 study participants with blood specimens from 2 January to 18 March 2020, 9 were seropositive, 7 before the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi.
Conclusions
Our findings identified SARS-CoV-2 infections weeks before the first recognized cases in 5 US states.
Seven individuals had detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G before the first confirmed cases in Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi, suggesting that SARS-CoV-2 infections occurred weeks before recognized cases in at least 5 US states.
Biobanks have become integral to improving population health. We are in a new era in medicine as patients, health professionals, and researchers increasingly collaborate to gain new knowledge and ...explore new paradigms for diagnosing and treating disease. Many large-scale biobanking efforts are underway worldwide at the institutional, national, and even international level. When linked with subject data from questionnaires and medical records, biobanks serve as valuable resources in translational research. A biobank must have high quality samples that meet researcher's needs. Biobank laboratory operations require an enormous amount of support-from lab and storage space, information technology expertise, and a laboratory management information system to logistics for sample movement, quality management systems, and appropriate facilities. A paramount metric of success for a biobank is the concept of every biospecimen coming to the repository belongs to a participant who has something to contribute to research for a healthier future. This article will discuss the importance of biorepository operations, specific to the collection and storage of participants materials. Specific focus will be given to maintaining the quality of samples, along with the various levels of support biorepositories need to fulfill their purpose and ensure the integrity of each specimen is maintained.
The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding ...sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.
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