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Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 μg/m3 increase in PM2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 μg/m3 increase in NO2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM2.5 levels to 5.8 μg/m3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden.

Mobile phones and various electronic products contribute to the world's fastest-growing category of hazardous waste with international repercussions. We investigated the trends in potential human health impacts and ecotoxicity of waste mobile phones through quantitative life cycle impact assessment (LCIA) methods and regulatory total threshold limit concentrations. A market-dominant sample of waste basic phones and smartphones manufactured between 2001 and 2015, were analyzed for toxicity trends based on 19 chemicals. The results of the LCIA (using USEtox model) show an increase in the relative mass of toxic materials over the 15-year period. We found no significant changes in the use of toxic components in basic phones, whereas smartphones contained a statistically significant increase in the content of toxic materials from 2006 to 2015. Nickel contributed the largest risk for carcinogens in mobile phones, but the contributions of lead and beryllium were also notable. Silver, zinc and copper contents were associated with non-cancer health risks. Copper components at 45,818-77,938 PAF m3/kg dominated ecotoxicity risks in mobile phones. Overall, these results highlight the increasing importance of monitoring trends in materials use for electronic product manufacturing and electronic-waste management processes that should prevent human and environmental exposures to toxic components.

Mobile phones and various electronic products contribute to the world's fastest-growing category of hazardous waste with international repercussions. We investigated the trends in potential human health impacts and ecotoxicity of waste mobile phones through quantitative life cycle impact assessment (LCIA) methods and regulatory total threshold limit concentrations. A market-dominant sample of waste basic phones and smartphones manufactured between 2001 and 2015, were analyzed for toxicity trends based on 19 chemicals. The results of the LCIA (using USEtox model) show an increase in the relative mass of toxic materials over the 15-year period. We found no significant changes in the use of toxic components in basic phones, whereas smartphones contained a statistically significant increase in the content of toxic materials from 2006 to 2015. Nickel contributed the largest risk for carcinogens in mobile phones, but the contributions of lead and beryllium were also notable. Silver, zinc and copper contents were associated with non-cancer health risks. Copper components at 45,818-77,938 PAF m3/kg dominated ecotoxicity risks in mobile phones. Overall, these results highlight the increasing importance of monitoring trends in materials use for electronic product manufacturing and electronic-waste management processes that should prevent human and environmental exposures to toxic components.

Electronic waste is the fastest growing category of hazardous solid waste in the world. Addressing the problem will require international collaboration, economic incentives that protect labour, and management approaches that minimize adverse impacts on the environment and human health.

A number of efforts have been launched to solve the global electronic waste (e-waste) problem. The efficiency of e-waste recycling is subject to variable national legislation, technical capacity, consumer participation, and even detoxification. E-waste management activities result in procedural irregularities and risk disparities across national boundaries. We review these variables to reveal opportunities for research and policy to reduce the risks from accumulating e-waste and ineffective recycling. Full regulation and consumer participation should be controlled and reinforced to improve local e-waste system. Aiming at standardizing best practice, we alter and identify modular recycling process and infrastructure in eco-industrial parks that will be expectantly effective in countries and regions to handle the similar e-waste stream. Toxicity can be deleted through material substitution and detoxification during the life cycle of electronics. Based on the idea of "Control-Alt-Delete", four patterns of the way forward for global e-waste recycling are proposed to meet a variety of local situations.

A number of efforts have been launched to solve the global electronic waste (e-waste) problem. The efficiency of e-waste recycling is subject to variable national legislation, technical capacity, consumer participation, and even detoxification. E-waste management activities result in procedural irregularities and risk disparities across national boundaries. We review these variables to reveal opportunities for research and policy to reduce the risks from accumulating e-waste and ineffective recycling. Full regulation and consumer participation should be controlled and reinforced to improve local e-waste system. Aiming at standardizing best practice, we alter and identify modular recycling process and infrastructure in eco-industrial parks that will be expectantly effective in countries and regions to handle the similar e-waste stream. Toxicity can be deleted through material substitution and detoxification during the life cycle of electronics. Based on the idea of "Control-Alt-Delete", four patterns of the way forward for global e-waste recycling are proposed to meet a variety of local situations.

PurposeProgression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.Patients and methodsrPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.ResultsA total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.ConclusionrPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.

BackgroundDynamin 2 (Dyn2) is a ~100kDa GTPase that assembles around the necks of nascent endocytic and Golgi vesicles and catalyzes membrane scission. Mutations in Dyn2 that cause centronuclear myopathy (CNM) have been shown to stabilize Dyn2 polymers against GTP-dependent disassembly in vitro. Precisely timed regulation of assembly and disassembly is believed to be critical for Dyn2 function in membrane vesiculation, and the CNM mutations interfere with this regulation by shifting the equilibrium toward the assembled state.MethodsIn this study we use two fluorescence fluctuation spectroscopy (FFS) approaches to show that a CNM mutant form of Dyn2 also has a greater propensity to self-assemble in the cytosol and on the plasma membrane of living cells.ResultsResults obtained using brightness analysis indicate that unassembled wild-type Dyn2 is predominantly tetrameric in the cytosol, although different oligomeric species are observed, depending on the concentration of expressed protein. In contrast, an R369W mutant identified in CNM patients forms higher-order oligomers at concentrations above 1μM. Investigation of Dyn2-R369W by Total Internal Reflection Fluorescence (TIRF) FFS reveals that this mutant forms larger and more stable clathrin-containing structures on the plasma membrane than wild-type Dyn2.Conclusions and general significanceThese observations may explain defects in membrane trafficking reported in CNM patient cells and in heterologous systems expressing CNM-associated Dyn2 mutants.

BackgroundDynamin 2 (Dyn2) is a ~100kDa GTPase that assembles around the necks of nascent endocytic and Golgi vesicles and catalyzes membrane scission. Mutations in Dyn2 that cause centronuclear myopathy (CNM) have been shown to stabilize Dyn2 polymers against GTP-dependent disassembly in vitro. Precisely timed regulation of assembly and disassembly is believed to be critical for Dyn2 function in membrane vesiculation, and the CNM mutations interfere with this regulation by shifting the equilibrium toward the assembled state.MethodsIn this study we use two fluorescence fluctuation spectroscopy (FFS) approaches to show that a CNM mutant form of Dyn2 also has a greater propensity to self-assemble in the cytosol and on the plasma membrane of living cells.ResultsResults obtained using brightness analysis indicate that unassembled wild-type Dyn2 is predominantly tetrameric in the cytosol, although different oligomeric species are observed, depending on the concentration of expressed protein. In contrast, an R369W mutant identified in CNM patients forms higher-order oligomers at concentrations above 1μM. Investigation of Dyn2-R369W by Total Internal Reflection Fluorescence (TIRF) FFS reveals that this mutant forms larger and more stable clathrin-containing structures on the plasma membrane than wild-type Dyn2.Conclusions and general significanceThese observations may explain defects in membrane trafficking reported in CNM patient cells and in heterologous systems expressing CNM-associated Dyn2 mutants.

BackgroundDynamin 2 (Dyn2) is a ~100kDa GTPase that assembles around the necks of nascent endocytic and Golgi vesicles and catalyzes membrane scission. Mutations in Dyn2 that cause centronuclear myopathy (CNM) have been shown to stabilize Dyn2 polymers against GTP-dependent disassembly in vitro. Precisely timed regulation of assembly and disassembly is believed to be critical for Dyn2 function in membrane vesiculation, and the CNM mutations interfere with this regulation by shifting the equilibrium toward the assembled state.MethodsIn this study we use two fluorescence fluctuation spectroscopy (FFS) approaches to show that a CNM mutant form of Dyn2 also has a greater propensity to self-assemble in the cytosol and on the plasma membrane of living cells.ResultsResults obtained using brightness analysis indicate that unassembled wild-type Dyn2 is predominantly tetrameric in the cytosol, although different oligomeric species are observed, depending on the concentration of expressed protein. In contrast, an R369W mutant identified in CNM patients forms higher-order oligomers at concentrations above 1μM. Investigation of Dyn2-R369W by Total Internal Reflection Fluorescence (TIRF) FFS reveals that this mutant forms larger and more stable clathrin-containing structures on the plasma membrane than wild-type Dyn2.Conclusions and general significanceThese observations may explain defects in membrane trafficking reported in CNM patient cells and in heterologous systems expressing CNM-associated Dyn2 mutants.

PurposeIn the phase III study COU-AA-301, abiraterone acetate (AA) plus prednisone (P) prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel administration. In this article, we investigate the relationship between baseline serum androgen (SA) levels and OS.Patients and methodsCOU-AA-301 is a randomized, double-blind study of AA (1,000 mg every day) plus P (5 mg by mouth twice daily; n = 797) versus P alone (n = 398). Randomization was stratified by Eastern Cooperative Oncology Group performance status (0 to 1 v 2), pain (Brief Pain Inventory-Short Form over past 24 hours: 4 to 10, present; v 0 to 3, absent), prior chemotherapy (1 v 2), and progression (prostate-specific antigen v radiographic). Association of baseline SA (testosterone, androstenedione, dehydroepiandrosterone sulfate), was measured by ultrasensitive liquid-liquid extraction or protein precipitation and two-dimensional liquid chromatography coupled to mass spectrometry, with OS determined by bivariate and multivariable Cox models. OS was examined with SA as greater than median and less than or equal to the median.ResultsMedian survival increased with each quartile increase in testosterone level regardless of treatment arm. SA levels at baseline strongly associated with survival (P < .0001) in bivariate and multivariable analyses. Longer survival was observed for patients with SA above median compared with below median in both the AA and P arms (eg, testosterone, AA; hazard ratio, 0.64; 95% CI, 0.53 to 0.77; P < .0001). Treatment with AA led to longer survival versus P alone in the above- or below-median group for all androgens.ConclusionSA, measured with a novel ultrasensitive assay in COU-AA-301, is prognostic for OS and may be useful for risk stratification in mCRPC clinical trials.

In biomedical research with longitudinal designs, missing values due to intermittent nonresponse or premature withdrawal are usually ’nonignorable’ in the sense that un- observed values are related to the patterns of missingness. When missing values are simply ignored, analyses based on observed-data likelihood may yield biased estimates or invalid inferences. By drawing the framework of a shared-parameter mechanism, the process yielding the repeated count measures and the process yielding missing val- ues can be modelled separately, conditionally on a group of shared parameters. For chronic diseases, Markov transition models can be used to study the transitional fea- tures of the pathologic processes. In this paper, Markov chain Monte Carlo (MCMC) algorithms are developed to fit a random-effects Markov transition model (REMTM) for incomplete count repeated measures, within which random effects are shared by the counting process and the missing-data mechanism. Assuming a Poisson distribu- tion for the count measures, the transition probabilities are estimated using a Poisson linear regression model. The missingness mechanism is modeled with a multinomial- logit regression to calculate the transition probabilities of the missingness indicators. The method is demonstrated using both simulated data sets and a practical data set from a smoking cessation clinical trial

Biomedical research is plagued with problems of missing data, especially in clinical trials of medical and behavioral therapies adopting longitudinal design. After a comprehensive literature review on modeling incomplete longitudinal data based on the full- likelihood functions, this paper proposes a set of imputation-based strategies for implementing three advanced models for handling intermittent missing values and dropouts that are potentially nonignorable according to various criteria. In multiple partial imputation (MPI), intermittent missing values are first imputed several times. Then, each partially imputed data set is analyzed using selection, pattern-mixture, or shared-parameter models to deal with dropouts. If imputations are additionally created for dropouts, it is a 2-stage version of MPI. Depending on models used for making imputations, various strategies can offer a framework for analyzing the sensitivity of parameter estimation to the assumptions of the missingness mechanism. For illustration, both continuous and dichotomized binary data from a smoking cessation clinical trial are analyzed. Both likelihood-based and Markov Chain Monte Carlo (MCMC) based inferences are also described.

Premature withdrawal is a notable problem in biomedical research with longitudinal design. It would complicate statistical analysis with biased or invalid inferences if missing values due to dropout are simply ignored. As one solution to potentially nonignorable droput, the selection model assumes a mechanism of outcome-dependent dropout and jointly models the process of repeated measures and the mechanism of dropout. Previous applications of selec- tion models mainly resort to likelihood-based inferences using optimization methods such as simplex or EM-algorithm. This paper implements the modeling strategy using mixed-effects repeated-measures models with Bayesian inferences. Specifically, the selection model with random-effects and the one with autoregressive covariance structure are introduced. Markov Chain Monte Carlo (MCMC) algorithms based on augmented Gibbs samplers are developed in fitting the models. For demonstration, both simulated and practical data sets are analyzed.