Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

Applicability of Spray Polyurethane Foam Ventilation Guideline for Do-It-Yourself Application Events.

Small two-component spray polyurethane foam (SPF) application kits are often applied by Do-It-Yourself (DIY) consumers. The United States Environmental Protection Agency (EPA) publishes a guideline for ventilating a space where SPF is being applied to minimize exposure to mists, vapors, particles and dust. This study sought to assess the applicability of the EPA ventilation guideline in protecting non-application areas of a house from exposure to SPF-associated emissions during a DIY application. Specifically, the research sought to determine if the flame retardant in SPF, Tris(1-chloro-2-propyl)-phosphate (TCPP), migrates outside a temporarily-constructed isolation area during and after a SPF application in the basement of a test home. Tracer decay tests were used to characterize the enhanced ventilation during application. The tracer gas results highlighted the importance of setting up the house internal and external openings to achieve effective isolation and ventilation of the spray area. The DIY spray led to a statistically significant increase in the airborne TCPP concentration in the basement during the first eight hours after application. However, the basement TCPP concentrations during and immediately after the SPF application were not statistically different from the TCPP concentrations in the basement (associated with the application of SPF during construction) measured four years prior to this application. The data indicate that, for the case tested in this study, following the EPA SPF ventilation guideline protected the rest of the house from elevated TCPP concentrations. However, these results may not hold for higher loading rates, lower airflow rates, leakier isolation enclosures or non-analyzed chemicals.

An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice.

Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin-fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next-generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.

BACKGROUND: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours. METHODS: Tumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. RESULTS: Patients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients. CONCLUSIONS: Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm.

VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research.

Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile variant caller for both DNA- and RNA-sequencing data. VarDict simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on the fly for more accurate allele frequency estimation. VarDict performance scales linearly to sequencing depth, enabling ultra-deep sequencing used to explore tumor evolution or detect tumor DNA circulating in blood. In addition, VarDict performs amplicon aware variant calling for polymerase chain reaction (PCR)-based targeted sequencing often used in diagnostic settings, and is able to detect PCR artifacts. Finally, VarDict also detects differences in somatic and loss of heterozygosity variants between paired samples. VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls. We believe VarDict will greatly facilitate application of NGS in clinical cancer research.

Generation of stable PDX derived cell lines using conditional reprogramming.

Efforts to develop effective cancer therapeutics have been hindered by a lack of clinically predictive preclinical models which recapitulate this complex disease. Patient derived xenograft (PDX) models have emerged as valuable tools for translational research but have several practical limitations including lack of sustained growth in vitro. In this study, we utilized Conditional Reprogramming (CR) cell technology- a novel cell culture system facilitating the generation of stable cultures from patient biopsies- to establish PDX-derived cell lines which maintain the characteristics of the parental PDX tumor. Human lung and ovarian PDX tumors were successfully propagated using CR technology to create stable explant cell lines (CR-PDX). These CR-PDX cell lines maintained parental driver mutations and allele frequency without clonal drift. Purified CR-PDX cell lines were amenable to high throughput chemosensitivity screening and in vitro genetic knockdown studies. Additionally, re-implanted CR-PDX cells proliferated to form tumors that retained the growth kinetics, histology, and drug responses of the parental PDX tumor. CR technology can be used to generate and expand stable cell lines from PDX tumors without compromising fundamental biological properties of the model. It offers the ability to expand PDX cells in vitro for subsequent 2D screening assays as well as for use in vivo to reduce variability, animal usage and study costs. The methods and data detailed here provide a platform to generate physiologically relevant and predictive preclinical models to enhance drug discovery efforts.

Can Biochar Covers Reduce Emissions from Manure Lagoons While Capturing Nutrients?

The unique physical and chemical properties of biochars make them promising materials for odor, gas, and nutrient sorption. Floating covers made from organic materials (biocovers) are one option for reducing odor and gas emissions from livestock manure lagoons. This study evaluated the potential of floating biochar covers to reduce odor and gas emissions while simultaneously sorbing nutrients from liquid dairy manure. This new approach has the potential to mitigate multiple environmental problems. Two biochars were tested: one made via gasification of Douglas fir chips at 650°C (FC650), and the other made from a mixture of Douglas fir [ (Mirb.) Franco] bark and center wood pyrolyzed at 600°C (HF600). The HF600 biocover reduced mean headspace ammonia concentration by 72 to 80%. No significant reduction was found with the FC650 biocover. Nutrient uptake ranged from 0.21 to 4.88 mg N g biochar and 0.64 to 2.70 mg P g biochar for the HF600 and FC650 biochars, respectively. Potassium ranged from a loss of 4.52 to a gain of 2.65 mg g biochar for the FC650 and HF600 biochars, respectively. The biochars also sorbed Ca, Mg, Na, Fe, Al, and Si. In a separate sensory evaluation, judges assessed odor offensiveness and odor threshold of five biocover treatments including four biochars applied over dairy manure. Reductions in mean odor offensiveness and mean odor threshold were observed in three treatments compared with the control. These results show that biochar covers hold promise as an effective practice for reducing odor and gas emissions while sorbing nutrients from liquid dairy manure.

Model (At Least) Twice, Build Once: Experiences With the Design-Bid-Build Process for Solar Photovoltaic Arrays.

Commercial-scale solar photovoltaic (PV) arrays were designed, constructed, and are now operational on the Gaithersburg, Maryland campus of the National Institute of Standards and Technology (NIST). A design-bid-build process was followed where the contractors used photovoltaic system modeling tools both during the initial design phase and during the postbid, prebuild phase. To help investigate the specific aspects of the contractors' evolving designs, the authors conducted their own independent photovoltaic system modeling. This independent modeling helped identify design elements that could be improved and so aided efforts to maximize the annual renewable energy generation. An estimated 2.5% gain in annual energy generation is being realized as a result of this independent modeling effort. To provide context for the modeling work and the lessons learned, key events impacting the design-bid-build process are described. The installed systems are summarized and also contrasted with the proposed designs. The power generation at three sites are compared over two different 12-month intervals.

Small Changes Yield Large Results at NIST's Net-Zero Energy Residential Test Facility.

The Net-Zero Energy Residential Test Facility (NZERTF) was designed to be approximately 60 % more energy efficient than homes meeting the 2012 International Energy Conservation Code (IECC) requirements. The thermal envelope minimizes heat loss/gain through the use of advanced framing and enhanced insulation. A continuous air/moisture barrier resulted in an air exchange rate of 0.6 air changes per hour at 50 Pa. The home incorporates a vast array of extensively monitored renewable and energy efficient technologies including an air-to-air heat pump system with a dedicated dehumidification cycle; a ducted heat-recovery ventilation system; a whole house dehumidifier; a photovoltaic system; and a solar domestic hot water system. During its first year of operation the NZERTF produced an energy surplus of 1023 kWh. Based on observations during the first year, changes were made to determine if further improvements in energy performance could be obtained. The changes consisted of installing a thermostat that incorporated control logic to minimize the use of auxiliary heat, using a whole house dehumidifier in lieu of the heat pump's dedicated dehumidification cycle, and reducing the ventilation rate to a value that met but did not exceed code requirements. During the second year of operation the NZERTF produced an energy surplus of 2241 kWh. This paper describes the facility, compares the performance data for the two years, and quantifies the energy impact of the weather conditions and operational changes.

Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.

BACKGROUND: The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. METHODS: In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. FINDINGS: Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7-15.0]) than in the chemotherapy alone group (median 9.6 months [95% CI 9.1-9.7) (HR 0.51 [95% CI 0.34-0.77]; p=0.0012), especially in patients with BRCA mutations (HR 0.21 [0.08-0.55]; p=0.0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. INTERPRETATION: Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. FUNDING: AstraZeneca.

Genes contributing to pain sensitivity in the normal population: an exome sequencing study.

Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10(-4)). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.

Comparison of the acute metabolic responses to traditional resistance, body-weight, and battling rope exercises.

The purpose of this study was to quantify and compare the acute metabolic responses to resistance exercise protocols comprising free-weight, body-weight, and battling rope (BR) exercises. Ten resistance-trained men (age = 20.6 ± 1.3 years) performed 13 resistance exercise protocols on separate days in random order consisting of only one exercise per session. For free-weight exercise protocols, subjects performed 3 sets of up to 10 repetitions with 75% of their 1 repetition maximum. For the push-up (PU) and push-up on a BOSU ball protocols, subjects performed 3 sets of 20 repetitions. For the burpee and PU with lateral crawl protocols, subjects performed 3 sets of 10 repetitions. For the plank and BR circuit protocols, subjects performed 3 sets of 30-second bouts. A standard 2-minute rest interval (RI) was used in between all sets for each exercise. Data were averaged for the entire protocol including work and RIs. Mean oxygen consumption was significantly greatest during the BR (24.6 ± 2.6 ml·kg·min) and burpee (22.9 ± 2.1 ml·kg·min) protocols. For the free-weight exercises, highest mean values were seen in the squat (19.6 ± 1.8 ml·kg·min), deadlift (18.9 ± 3.0 ml·kg·min), and lunge (17.3 ± 2.6 ml·kg·min). No differences were observed between PUs performed on the floor vs. on a BOSU ball. However, adding a lateral crawl to the PU significantly increased mean oxygen consumption (19.5 ± 2.9 ml·kg·min). The lowest mean value was seen during the plank exercise (7.9 ± 0.7 ml·kg·min). These data indicate performance of exercises with BRs and a body-weight burpee exercise elicit relatively higher acute metabolic demands than traditional resistance exercises performed with moderately heavy loading.

Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.

BACKGROUND: Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. METHODS: We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545. FINDINGS: Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3-not calculable] vs 4·3 months [3·0-5·4]; HR 0·18 [0·10-0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5-10·3] vs 5·5 months [3·7-5·6]; HR 0·54 [0·34-0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64-1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45-1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63-1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population. INTERPRETATION: These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment. FUNDING: AstraZeneca.

Large-area irradiance-mode spectral response measurements of solar cells by a light-emitting, diode-based integrating sphere source.

An irradiance-mode absolute differential spectral response (SR) measurement system based on a light emitting diode (LED) array is described. The LEDs are coupled to an integrating sphere whose output irradiance is uniform to better than 2% over an area of 160 mm by 160 mm. SR measurements of solar cells when subject to diffuse irradiation, as provided by the integrating sphere, are compared with collimated irradiance SR measurements. Issues originating from the differences in angular response of the reference versus the test cells are also investigated. The SR curves of large-area cells with dimensions of up to 155 mm are measured and then used to calculate the cell's short circuit current (I(sc)), if illuminated by a defined solar spectrum. The resulting values of I(sc) agree well with the values obtained from secondary measurements.

The chemical assessment of surfaces and air (CASA) study: using chemical and physical perturbations in a test house to investigate indoor processes.

The Chemical Assessment of Surfaces and Air (CASA) study aimed to understand how chemicals transform in the indoor environment using perturbations (e.g., cooking, cleaning) or additions of indoor and outdoor pollutants in a well-controlled test house. Chemical additions ranged from individual compounds (e.g., gaseous ammonia or ozone) to more complex mixtures (e.g., a wildfire smoke proxy and a commercial pesticide). Physical perturbations included varying temperature, ventilation rates, and relative humidity. The objectives for CASA included understanding (i) how outdoor air pollution impacts indoor air chemistry, (ii) how wildfire smoke transports and transforms indoors, (iii) how gases and particles interact with building surfaces, and (iv) how indoor environmental conditions impact indoor chemistry. Further, the combined measurements under unperturbed and experimental conditions enable investigation of mitigation strategies following outdoor and indoor air pollution events. A comprehensive suite of instruments measured different chemical components in the gas, particle, and surface phases throughout the study. We provide an overview of the test house, instrumentation, experimental design, and initial observations - including the role of humidity in controlling the air concentrations of many semi-volatile organic compounds, the potential for ozone to generate indoor nitrogen pentoxide (N2O5), the differences in microbial composition between the test house and other occupied buildings, and the complexity of deposited particles and gases on different indoor surfaces.

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants in several genes have been identified as risk factors from candidate gene and linkage studies, the exome-wide spectrum of causal rare variants remains to be fully explored. To more comprehensively address their contribution, we analysed data from 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline exome/genome sequencing and one cohort with imputed array data from a population enriched in low-frequency deleterious variants. Our gene-level collapsing analysis revealed that rare damaging variants in SAMHD1 as well as genes in the DNA damage response pathway (BRCA2, ATM and CHEK2) are associated with the risk of overall prostate cancer. We also found that rare damaging variants in AOX1 and BRCA2 were associated with increased severity of prostate cancer in a case-only analysis of aggressive versus non-aggressive prostate cancer. At the single-variant level, we found rare non-synonymous variants in three genes (HOXB13, CHEK2, BIK) significantly associated with increased risk of overall prostate cancer and in four genes (ANO7, SPDL1, AR, TERT) with decreased risk. Altogether, this study provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity.

Absolute spectral responsivity measurements of solar cells by a hybrid optical technique.

An irradiance mode, absolute differential spectral response measurement system for solar cells is presented. The system is based on combining the monochromator-based approach of determining the power mode spectral responsivity of cells with an LED-based measurement to construct a curve representing the light-overfilled absolute spectral response of the entire cell. This curve can be used to predict the short-circuit current (I(sc)) of the cell under the AM 1.5 standard reference spectrum. The measurement system is SI-traceable via detectors with primary calibrations linked to the NIST absolute cryogenic radiometer. An uncertainty analysis of the methodology places the relative uncertainty of the calculated I(sc) at better than ±0.8%.

Not Your Everyday Duodenal Ulcer: Massive Gastrointestinal Bleed Secondary to Extramedullary Plasma Cell Myeloma.

The differential for gastrointestinal (GI) bleeding is broad, ranging from peptic ulcers and Helicobacter pylori infection to variceal hemorrhage and neoplasms. The rarer causes of GI bleeds are frequently overlooked and as such can ultimately be more dangerous. Extramedullary multiple myeloma, an atypical plasma cell dyscrasia arising outside of the bone marrow, involves the GI tract in <5% of cases and often presents with nonspecific symptoms. We describe a rare case of such GI involvement of a plasma cell tumor, with subsequent transmural duodenal ulceration involving the gastroduodenal artery, ultimately resulting in a fatal GI bleed.

Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment.

PURPOSE: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. PATIENTS AND METHODS: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. CONCLUSIONS: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.

Versatile light-emitting-diode-based spectral response measurement system for photovoltaic device characterization.

An absolute differential spectral response measurement system for solar cells is presented. The system couples an array of light emitting diodes with an optical waveguide to provide large area illumination. Two unique yet complementary measurement methods were developed and tested with the same measurement apparatus. Good agreement was observed between the two methods based on testing of a variety of solar cells. The first method is a lock-in technique that can be performed over a broad pulse frequency range. The second method is based on synchronous multifrequency optical excitation and electrical detection. An innovative scheme for providing light bias during each measurement method is discussed.