Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic ...testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals.
We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions.
Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category.
Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.
To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging.
Previous studies reported substantial contributions of ...neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis.
Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models.
High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score.
These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.
Natural sounds, and bird song in particular, play a key role in building and maintaining our connection with nature, but widespread declines in bird populations mean that the acoustic properties of ...natural soundscapes may be changing. Using data-driven reconstructions of soundscapes in lieu of historical recordings, here we quantify changes in soundscape characteristics at more than 200,000 sites across North America and Europe. We integrate citizen science bird monitoring data with recordings of individual species to reveal a pervasive loss of acoustic diversity and intensity of soundscapes across both continents over the past 25 years, driven by changes in species richness and abundance. These results suggest that one of the fundamental pathways through which humans engage with nature is in chronic decline, with potentially widespread implications for human health and well-being.
The uptake and accumulation of metals in plants is a potential pathway for the transfer of environmental contaminants in the food chain, and poses potential health and environmental risks. In light ...of increased population growth and urbanisation, the safe disposal of sewage sludge, which can contain significant levels of toxic contaminants, remains an environmental challenge globally. The aims of this experiment were to apply municipal sludge, having undergone treatment by thermal drying, anaerobic digestion, and lime stabilisation, to permanent grassland in order to assess the bioaccumulation of metals (B, Al, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, As, Nb, Mo, Sb, Ba, W, Pb, Fe, Cd) by perennial ryegrass over a period of up to 18 weeks after application. The legislation currently prohibits use of grassland for fodder or grazing for at least three weeks after application of treated sewage sludge (biosolids). Five treatments were used: thermally dried (TD), anaerobically digested (AD) and lime stabilised (LS) sludge all from one wastewater treatment plant (WWTP), AD sludge from another WWTP, and a study control (grassland only, without application of biosolids). In general, there was no significant difference in metal content of the ryegrass between micro-plots that received treated municipal sludge and the control over the study duration. The metal content of the ryegrass was below the levels at which phytotoxicity occurs and below the maximum levels specified for animal feeds.
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•Metal accumulation in ryegrass was measured following one application of biosolids.•Thermally dried, lime stabilised and anaerobically digested biosolids were examined.•Generally, there was no significant difference in metal content between treatments.•Ryegrass metal content reduced over the study duration of 18 weeks.•The ryegrass metal content was well below the levels at which phytotoxicity occurs.
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs ...were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show ...mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.
Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.
FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).
FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
Summary Background Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological ...subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. Methods 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. Findings 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21–0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55–0·91; p=0·0080), but weak PR expression was not (1·02, 0·89–1·18; p=0·74). Interpretation PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. Funding Carraresi Foundation and others.
The impact of anthropogenic factors arising from point and non-point pollution sources at a multi commodity marine port and its surrounding ecosystems were studied using sediment samples collected ...from a number of onshore (Gladstone Harbour and Facing Island) and offshore (Heron Island and Fitzroy Reefs) sites in Australia's Central Queensland. Sediment samples were analyzed for trace metals, organic carbon, polycyclic aromatic hydrocarbons (PAH), emerging chemicals of concern (ECC) and sterols. Similarly, the biological and biochemical interaction between the reef and its environment was analyzed by the multi-omic tools of next-generation sequencing characterization of the bacterial community and microbial community metabolic profiling. Overall, the trace elements were observed at the lower end of the Australian environmental guideline values at the offshore sites, while higher values were observed for the onshore locations Nickel and copper were observed above the high trigger value threshold at the onshore sites. The levels of PAH were below limits of detection across all sites. However, some of the ECC and sterols were observed at higher concentrations at both onshore and offshore locations, notably, the cholesterol family sterols and 17α-ethynylestradiol. Multi-omic analyses also indicated possible thermal and photo irradiation stressors on the bacterial communities at all the tested sites. The observed populations of γ-proteobacteria were found in combination with an increased pool of fatty acids that indicate fatty acid synthesis and utilisation of the intermediates of the shikimate pathways. This study demonstrates the value of applying a multi-omics approach for ecological assessments, in which a more detailed assessment of physical and chemical contaminants and their impact on the community bacterial biome is obtained.
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•Multi-omics provides insight into ecosystem health and anthropogenic impacts.•Contaminants affect bacterial communities in terms of distribution, resilience and robustness.•Multi-omics provides additional information that compliments traditional monitoring data.
Abstract We present the results of an investigation of a highly variable C iv broad absorption line (BAL) feature in spectra of the quasar SBS 1408+544 ( z = 2.337) that shows a significant shift in ...velocity over time. This source was observed as a part of the Sloan Digital Sky Survey (SDSS) Reverberation Mapping project and the SDSS-V Black Hole Mapper Reverberation Mapping project, and has been included in two previous studies, both of which identified significant variability in a high-velocity C iv BAL on timescales of just a few days in the quasar rest frame. Using ∼130 spectra acquired over 8 yr of spectroscopic monitoring with SDSS, we have determined that this BAL is not only varying in strength, but is also systematically shifting to higher velocities. Using cross-correlation methods, we measure the velocity shifts (and corresponding acceleration) of the BAL over a wide range of timescales, measuring an overall velocity shift of Δ v = − 683 − 84 + 89 km s −1 over the 8 yr monitoring period. This corresponds to an average rest-frame acceleration of a = 1.04 − 0.13 + 0.14 cm s −2 , though the magnitude of the acceleration on shorter timescales is not constant throughout. We place our measurements in the context of BAL-acceleration models and examine various possible causes of the observed velocity shift.
The reuse of treated municipal sewage (‘biosolids’) on land is an effective method to divert waste away from landfill and to use an alternative, low cost method of fertilisation. While legislation ...has mainly focused on the control of nutrient and metal application rates to land, other potentially harmful emerging contaminants (ECs) may be present in biosolids. Up to 80% of municipal sewage sludge is reused in agriculture in Ireland, which is currently the highest rate of reuse in Europe. However, unlike other countries, no study has been conducted on the presence of ECs across a range of wastewater treatment plants (WWTPs) in this country. This study evaluated the concentrations of two ECs in sewage sludge, the antimicrobials triclosan (TCS) and triclocarban (TCC), and their presence in surface runoff following land application in controlled rainfall simulation studies. In 16 WWTPs, concentrations of TCS and TCC were 0.61 and 0.08µgg−1, which is at the lower end of concentrations measured in other countries. The concentrations in runoff post land application were also mainly below the limits of detection (90ngL−1 for TCS, 6ngL−1 for TCC), indicating that runoff is not a significant pathway of entry into the environment.
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•Triclosan and triclocarban measured in biosolids from 16 WWTPs in Ireland.•Agricultural surface runoff of triclocarban and triclocarban also measured.•Concentrations of triclosan and triclocarban in runoff at or below LOD.
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