Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T

Background: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). Methods: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan–Meier method and Cox regression. Results: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616–1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579–0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan–Meier curves for both end points began to diverge at 6 months. Conclusions: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy

A link between LEAFY and B-gene homologues in Welwitschia mirabilis sheds light on ancestral mechanisms prefiguring floral development

- Flowering plants evolved from an unidentified gymnosperm ancestor. Comparison of the mechanisms controlling development in angiosperm flowers and gymnosperm cones may help to elucidate the mysterious origin of the flower. - We combined gene expression studies with protein behaviour characterization in Welwitschia mirabilis to test whether the known regulatory links between LEAFY and its MADS-box gene targets, central to flower development, might also contribute to gymnosperm reproductive development. - We found that WelLFY, one of two LEAFY-like genes in Welwitschia, could be an upstream regulator of the MADS-box genes APETALA3/PISTILLATA-like (B-genes). We demonstrated that, even though their DNA-binding domains are extremely similar, WelLFY and its paralogue WelNDLY exhibit distinct DNA-binding specificities, and that, unlike WelNDLY, WelLFY shares with its angiosperm orthologue the capacity to bind promoters of Welwitschia B-genes. Finally, we identified several cis-elements mediating these interactions in Welwitschia and obtained evidence that the link between LFY homologues and B-genes is also conserved in two other gymnosperms, Pinus and Picea. - Although functional approaches to investigate cone development in gymnosperms are limited, our state-of-the-art biophysical techniques, coupled with expression studies, provide evidence that crucial links, central to the control of floral development, may already have existed before the appearance of flowers.This work was supported by funding from the Centre National de la Recherche Scientifique (ATIP+ to F.P.), the ANAgence Nationale de la Recherche (ANR) (Plant-TFcode to F.P. and C.P.S.), PhD fellowships from the University J. Fourier, Grenoble (to E.M. and M.M.), Grenoble Alliance for Cell and Structural Biology (ANR-10-LABX-49-01), the SYNTHESYS Project (to E.M.), the Floral Genome Project (National Science Foundation (NSF) Plant Genome Research Program project DBI-0115684 to M.W.F.) and NSF DEB-9974374 (to M.W.F.)

Species recovery in the united states: Increasing the effectiveness of the endangered species act

The Endangered Species Act (ESA) has succeeded in shielding hundreds of species from extinction and improving species recovery over time. However, recovery for most species officially protected by the ESA - i.e., listed species-has been harder to achieve than initially envisioned. Threats to species are persistent and pervasive, funding has been insufficient, the distribution of money among listed species is highly uneven, and at least 10 times more species than are actually listed probably qualify for listing. Moreover, many listed species will require ongoing management for the foreseeable future to protect them from persistent threats. Climate change will exacerbate this problem and increase both species risk and management uncertainty, requiring more intensive and controversial management strategies to prevent species from going extinct

The emergence of altruism as a social norm

Expectations, exerting influence through social norms, are a very strong candidate to explain how complex societies function. In the Dictator game (DG), people expect generous behavior from others even when they cannot enforce any sharing of the pie. Here we assume that people donate following their expectations, and that they update their expectation after playing a DG by reinforcement learning to construct a model that explains the main experimental results in the DG. Full agreement with the experimental results is reached when some degree of mismatch between expectations and donations is added into the model. These results are robust against the presence of envious agents, but affected if we introduce selfish agents that do not update their expectations. Our results point to social norms being on the basis of the generous behavior observed in the DG and also to the wide applicability of reinforcement learning to explain many strategic interactions

An Atlas of the Speed of Copy Number Changes in Animal Gene Families and Its Implications

The notion that gene duplications generating new genes and functions is commonly accepted in evolutionary biology. However, this assumption is more speculative from theory rather than well proven in genome-wide studies. Here, we generated an atlas of the rate of copy number changes (CNCs) in all the gene families of ten animal genomes. We grouped the gene families with similar CNC dynamics into rate pattern groups (RPGs) and annotated their function using a novel bottom-up approach. By comparing CNC rate patterns, we showed that most of the species-specific CNC rates groups are formed by gene duplication rather than gene loss, and most of the changes in rates of CNCs may be the result of adaptive evolution. We also found that the functions of many RPGs match their biological significance well. Our work confirmed the role of gene duplication in generating novel phenotypes, and the results can serve as a guide for researchers to connect the phenotypic features to certain gene duplications

Rapid quantification of myocardial fibrosis: a new macro-based automated analysis

Background: Fibrosis is associated with various cardiac pathologies and dysfunction. Current quantification methods are time-consuming and laborious. We describe a semi-automated quantification technique for myocardial fibrosis and validated this using traditional methods

A genome for gnetophytes and early evolution of seed plants

Genome sequencing, assembly and annotation were conducted by the Novogene Bioinformatics Institute, Beijing, China; mutual contracts were No. NHT140016 and NVT140016004. This work was supported by funding from the Scientific Project of Shenzhen Urban Administration (201519) and a Major Technical Research Project of the Innovation of Science and Technology Commission of Shenzhen (JSGG20140515164852417). Additional funding was provided in particular by the Scientific Research Program of Sino-Africa Joint Research Center (SAJL201607). We thank X.Q. Wang, G.W. Hu, Z.D. Chen and Y.H. Guo for comments on gnetophyte phylogenetic relationships and ecological issues; H. Wu and X.P. Ning for discussion of related organ development; K.K. Wan and S. Sun for additional help on the analysis of repeats. We also thank X.Y. for support of funding coordination. Y.V.d.P. acknowledges the Multidisciplinary Research Partnership ‘Bioinformatics: from nucleotides to networks’ Project (no. 01MR0310W) of Ghent University, and funding from the European Union Seventh Framework Programme (FP7/2007-2013) under European Research Council Advanced Grant Agreement 322739-DOUBLEUP

A Functional Phylogenomic View of the Seed Plants

A novel result of the current research is the development and implementation of a unique functional phylogenomic approach that explores the genomic origins of seed plant diversification. We first use 22,833 sets of orthologs from the nuclear genomes of 101 genera across land plants to reconstruct their phylogenetic relationships. One of the more salient results is the resolution of some enigmatic relationships in seed plant phylogeny, such as the placement of Gnetales as sister to the rest of the gymnosperms. In using this novel phylogenomic approach, we were also able to identify overrepresented functional gene ontology categories in genes that provide positive branch support for major nodes prompting new hypotheses for genes associated with the diversification of angiosperms. For example, RNA interference (RNAi) has played a significant role in the divergence of monocots from other angiosperms, which has experimental support in Arabidopsis and rice. This analysis also implied that the second largest subunit of RNA polymerase IV and V (NRPD2) played a prominent role in the divergence of gymnosperms. This hypothesis is supported by the lack of 24nt siRNA in conifers, the maternal control of small RNA in the seeds of flowering plants, and the emergence of double fertilization in angiosperms. Our approach takes advantage of genomic data to define orthologs, reconstruct relationships, and narrow down candidate genes involved in plant evolution within a phylogenomic view of species' diversification

Air pollution and general practitioner access and utilization: a population based study in Sarnia, 'Chemical Valley,' Ontario

<p>Abstract</p> <p>Background</p> <p>Health impacts of poor environmental quality have been identified in studies around the world and in Canada. While many of the studies have identified associations between air pollution and mortality or morbidity, few have focused on the role of health care as a potential moderator of impacts. This study assessed the determinants of health care access and utilization in the context of ambient air pollution in Sarnia, Ontario, Canada.</p> <p>Methods</p> <p>Residents of Sarnia participated in a Community Health Study administered by phone, while several ambient air pollutants including nitrogen dioxide (NO₂), sulphur dioxide (SO₂) and the volatile organic compounds benzene, toluene, ethylbenzene, mp- and o-xylene (BTEX) were monitored across the city. Land Use Regression models were used to estimate individual exposures to the measured pollutants and logistic regression models were utilized to assess the relative influence of environmental, socioeconomic and health related covariates on general practitioner access and utilization outcomes.</p> <p>Results</p> <p>The results show that general practitioner use increased with levels of exposure to nitrogen dioxide (NO₂- Odds Ratio [OR]: 1.16, <it>p </it>< 0.05) and sulphur dioxide (SO₂- OR: 1.61, <it>p </it>< 0.05). Low household income was a stronger predictor of having no family doctor in areas exposed to high concentrations of NO₂and SO₂. Respondents without regular care living in high pollution areas were also more likely to report travelling or waiting for care in excess of 20 minutes (OR: 3.28, <it>p </it>< 0.05) than their low exposure counterparts (OR: 1.11, <it>p </it>> 0.05).</p> <p>Conclusions</p> <p>This study provides evidence for inequitable health care access and utilization in Sarnia, with particular relevance to its situation as a sentinel high exposure environment. Levels of exposure to pollution appears to influence utilization of health care services, but poor access to primary health care services additionally burden certain groups in Sarnia, Ontario, Canada.</p