Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes

Crude oil yield and properties of rice bran oil from different varieties as affected by extraction conditions using soxhterm method

The current study was employed to investigate the effect of solvent type, extraction time and bran ratio on the rice bran oil (RBO) properties from three varieties of rice bran namely Bario, lowland and upland rice. RBO was extracted by using soxtherm extraction method using methanol solvent at different extraction time (3, 4 and 5 h) and bran ratio (10, 20 and 30 g). Free fatty acid (FFA), total phenolic content (TPC) and antioxidant properties were assessed. Solvent that has low polarity exhibited the attraction of polar component of oil with the highest yield by ethanol (16.16%), followed by methanol (15.38%). FFA contents occurred higher in lowland types of rice bran in all types of solvents at P<0.05 with ethanol (12.73%), methanol (11.96%) and hexane (11.13%), while the total phenolic content and antioxidant properties were influenced by the types of rice bran and solvents used for extracting components out of the bran. The highest phenolic content in the crude oil was extracted using ethanol in lowland (0.509 mg/ml), and the lowest was extracted by hexane in Bario (0.061 mg/ml). The highest antioxidant activity was observed in RBO extracted using methanol of lowland (73.74%) and RBO extracted using ethanol of upland (73.65%), while the lowest were observed in RBO extracted using hexane. The different types of solvent have the significant impact on the crude oil yield and properties of crude oil extracted

Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study.

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer

A verified genomic reference sample for assessing performance of cancer panels detecting small variants of low allele frequency

BackgroundOncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance.ResultsIn reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100x more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels.ConclusionThese new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.Peer reviewe

Metabolite selection for machine learning in childhood brain tumour classification

MRS can provide high accuracy in the diagnosis of childhood brain tumours when combined with machine learning. A feature selection method such as principal component analysis is commonly used to reduce the dimensionality of metabolite profiles prior to classification. However, an alternative approach of identifying the optimal set of metabolites has not been fully evaluated, possibly due to the challenges of defining this for a multi‐class problem. This study aims to investigate metabolite selection from in vivo MRS for childhood brain tumour classification. Multi‐site 1.5 T and 3 T cohorts of patients with a brain tumour and histological diagnosis of ependymoma, medulloblastoma and pilocytic astrocytoma were retrospectively evaluated. Dimensionality reduction was undertaken by selecting metabolite concentrations through multi‐class receiver operating characteristics and compared with principal component analysis. Classification accuracy was determined through leave‐one‐out and k‐fold cross‐validation. Metabolites identified as crucial in tumour classification include myo‐inositol (P < 0.05, AUC = 0 . 81 ± 0 . 01 ), total lipids and macromolecules at 0.9 ppm (P < 0.05, AUC = 0 . 78 ± 0 . 01 ) and total creatine (P < 0.05, AUC = 0 . 77 ± 0 . 01 ) for the 1.5 T cohort, and glycine (P < 0.05, AUC = 0 . 79 ± 0 . 01 ), total N‐acetylaspartate (P < 0.05, AUC = 0 . 79 ± 0 . 01 ) and total choline (P < 0.05, AUC = 0 . 75 ± 0 . 01 ) for the 3 T cohort. Compared with the principal components, the selected metabolites were able to provide significantly improved discrimination between the tumours through most classifiers (P < 0.05). The highest balanced classification accuracy determined through leave‐one‐out cross‐validation was 85% for 1.5 T 1H‐MRS through support vector machine and 75% for 3 T 1H‐MRS through linear discriminant analysis after oversampling the minority. The study suggests that a group of crucial metabolites helps to achieve better discrimination between childhood brain tumours

High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

BACKGROUND: Chronic Lymphocytic Leukemia (CLL) leads to progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues. Previous findings have suggested that the mtDNA could play an important role in CLL. METHODOLOGY/PRINCIPAL FINDINGS: The mitochondrial DNA (mtDNA) control-region was analyzed in lymphocyte cell DNA extracts and compared with their granulocyte counterpart extract of 146 patients suffering from B-Cell CLL; B-CLL (all recruited from the Basque country). Major efforts were undertaken to rule out methodological artefacts that would render a high false positive rate for mtDNA instabilities and thus lead to erroneous interpretation of sequence instabilities. Only twenty instabilities were finally confirmed, most of them affecting the homopolymeric stretch located in the second hypervariable segment (HVS-II) around position 310, which is well known to constitute an extreme mutational hotspot of length polymorphism, as these mutations are frequently observed in the general human population. A critical revision of the findings in previous studies indicates a lack of proper methodological standards, which eventually led to an overinterpretation of the role of the mtDNA in CLL tumorigenesis. CONCLUSIONS/SIGNIFICANCE: Our results suggest that mtDNA instability is not the primary causal factor in B-CLL. A secondary role of mtDNA mutations cannot be fully ruled out under the hypothesis that the progressive accumulation of mtDNA instabilities could finally contribute to the tumoral process. Recommendations are given that would help to minimize erroneous interpretation of sequencing results in mtDNA studies in tumorigenesis

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

Justify your alpha

Benjamin et al. proposed changing the conventional “statistical significance” threshold (i.e.,the alpha level) from p ≤ .05 to p ≤ .005 for all novel claims with relatively low prior odds. They provided two arguments for why lowering the significance threshold would “immediately improve the reproducibility of scientific research.” First, a p-value near .05provides weak evidence for the alternative hypothesis. Second, under certain assumptions, an alpha of .05 leads to high false positive report probabilities (FPRP2 ; the probability that a significant finding is a false positive

Tritium distributions on W-coated divertor tiles used in the third JET ITER-like wall campaign

Tritium (T) distributions on tungsten (W)-coated plasma-facing tiles used in the third ITER-like wall campaign (2015–2016) of the Joint European Torus (JET) were examined by means of an imaging plate technique and β-ray induced x-ray spectrometry, and they were compared with the distributions after the second (2013–2014) campaign. Strong enrichment of T in beryllium (Be) deposition layers was observed after the second campaign. In contrast, T distributions after the third campaign was more uniform though Be deposition layers were visually recognized. The one of the possible explanations is enhanced desorption of T from Be deposition layers due to higher tile temperatures caused by higher energy input in the third campaign

Impact of ICRF on the scrape-off layer and on plasma wall interactions: From present experiments to fusion reactor

Recent achievements in studies of the effects of ICRF (Ion Cyclotron Range of Frequencies) power on the SOL (Scrape-Off Layer) and PWI (Plasma Wall Interactions) in ASDEX Upgrade (AUG), Alcator C-Mod, and JET-ILW are reviewed. Capabilities to diagnose and model the effect of DC biasing and associated impurity production at active antennas and on magnetic field connections to antennas are described. The experiments show that ICRF near-fields can lead not only to E×B convection, but also to modifications of the SOL density, which for Alcator C-Mod are limited to a narrow region near antenna. On the other hand, the SOL density distribution along with impurity sources can be tailored using local gas injection in AUG and JET-ILW with a positive effect on reduction of impurity sources. The technique of RF image current cancellation at antenna limiters was successfully applied in AUG using the 3-strap AUG antenna and extended to the 4-strap Alcator C-Mod field-aligned antenna. Multiple observations confirmed the reduction of the impact of ICRF on the SOL and on total impurity production when the ratio of the power of the central straps to the total antenna power is in the range 0.6<P$_{cen}$/P$_{total}$<0.8. Near-field calculations indicate that this fairly robust technique can be applied to the ITER ICRF antenna, enabling the mode of operation with reduced PWI. On the contrary, for the A2 antenna in JET-ILW the technique is hindered by RF sheaths excited at the antenna septum. Thus, in order to reduce the effect of ICRF power on PWI in a future fusion reactor, the antenna design has to be optimized along with design of plasmafacing components