Renal Health Effects in Trichloroethylene and Arsenic Co-Exposed Mice

Development of a rodent model for renal cancer and disease development due to toxicant exposure is complicated by differences in renal handling of toxicants between rodents and humans as well as the tendency of rodents to develop significant background spontaneous renal disease that may mimic pre-neoplastic disease or mask more subtle lesions. Classical toxicological studies often focus on one toxicant in a genetically homogeneous population, despite attempting to model human exposure situations involving genetically heterogeneous populations and exposure to mixtures of toxicants. Given these challenges, it has become clear that toxicological studies must address the effects of genetic variability and the range of sensitivity to toxicity due to this inherent variability. Experimental paradigms that assess and control for as many of the intrinsic and extrinsic factors influencing renal response to toxicant exposure are also needed. In an effort to address these limitations, a mouse model was devised that included genetic heterogeneity, mixtures of toxicants at environmentally relevant concentrations, and diet that reflects a typical western diet to better reflect the exposure conditions of human populations. Despite development of a mouse model that more accurately reflects human environmental toxicant exposure conditions, no primary renal cell tumors were observed in the study. Differences in renal health between exposed and unexposed populations were observed as well as increased evidence of renal disease in male mice compared to females across the entire study population. In the current study TCE exposure did not cause renal cell tumors nor did it increase renal disease when combined with arsenic exposure. Evidence of reduced or equal renal damage from co-exposure was observed in some cases, and we speculate that this is due to a threshold effect of damage from a first toxicant limiting the ability of a second toxicant to cause damage. Additional studies of combined toxicant exposure are needed

Improving Metabolic Health Through Precision Dietetics in Mice

The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet’s impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or “precision dietetics,” approach to dietary recommendations may yield better health outcomes than the traditional one-size-fits-all approach

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Renal Health Effects in Trichloroethylene and Arsenic Co-Exposed Mice

Development of a rodent model for renal cancer and disease development due to toxicant exposure is complicated by differences in renal handling of toxicants between rodents and humans as well as the tendency of rodents to develop significant background spontaneous renal disease that may mimic pre-neoplastic disease or mask more subtle lesions. Classical toxicological studies often focus on one toxicant in a genetically homogeneous population, despite attempting to model human exposure situations involving genetically heterogeneous populations and exposure to mixtures of toxicants. Given these challenges, it has become clear that toxicological studies must address the effects of genetic variability and the range of sensitivity to toxicity due to this inherent variability. Experimental paradigms that assess and control for as many of the intrinsic and extrinsic factors influencing renal response to toxicant exposure are also needed. In an effort to address these limitations, a mouse model was devised that included genetic heterogeneity, mixtures of toxicants at environmentally relevant concentrations, and diet that reflects a typical western diet to better reflect the exposure conditions of human populations. Despite development of a mouse model that more accurately reflects human environmental toxicant exposure conditions, no primary renal cell tumors were observed in the study. Differences in renal health between exposed and unexposed populations were observed as well as increased evidence of renal disease in male mice compared to females across the entire study population. In the current study TCE exposure did not cause renal cell tumors nor did it increase renal disease when combined with arsenic exposure. Evidence of reduced or equal renal damage from co-exposure was observed in some cases, and we speculate that this is due to a threshold effect of damage from a first toxicant limiting the ability of a second toxicant to cause damage. Additional studies of combined toxicant exposure are needed

Initial Impacts of Community-Engaged Learning in a Pre-Service Teacher Course on Science & STEM Education

Teacher retention, especially in STEM fields, is a challenge in Appalachia, and many early childhood teachers report a need for enhanced knowledge and self-efficacy in teaching STEM. Incorporating community-engaged learning (CEL: Jacoby, 2015) with pre-service teachers in a science and STEM course could increase self-efficacy, enhance learning, and potentially increase retention, because, 1) intentional interactions with professionals have been shown to increase commitment to the profession, and 2) authentic, applied experiences that link theory to practice can lead to transformative learning. To this end, we integrated a focus on community-engaged learning into our existing Early-Elementary STEM Collaboration approach. This included visits to a children’s science museum; integration of the museum exhibits into final projects; early childhood and elementary pre-service teachers meeting across the semester; guest lectures by teachers and faculty; applied microteaching with students; and opportunities to co-write and co-present. To determine the effects of the community-engaged learning, data collected throughout the semester from 25 undergraduate pre-service teachers in CEL-enhanced Early Childhood-Elementary STEM Collaboration courses was analyzed using a convergent parallel mixed methods design. Qualitative data was coded inductively with grounded theory as the guided approach and quantitative data was analyzed using SPSS. The data collected include participants’ written reflections; a pre- and post-semester survey with open-ended questions, pedagogical content knowledge questions, and the STEBI-B instrument. Quantitative data analysis showed a statistically significant increase in the participants\u27 pre-and post-test scores for both personal science teaching self-efficacy (p \u3c .001) and outcome expectancy (p = .013). The qualitative data revealed three emerging themes which include: 1) Awareness of community resources; 2) Disequilibrium; 3) Pedagogical shifts. These findings indicate that early childhood teacher preparation courses focused on science and integrated STEM could benefit from the incorporation of a community-engaged learning component because the quantitative data indicate increases in science-teaching self-efficacy and outcome expectancy and qualitative data confirm these increases by demonstrating transformative learning for the pre-service teachers