Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis.

BACKGROUND: Tulisokibart is a tumor necrosis factor-like cytokine 1A (TL1A) monoclonal antibody in development for the treatment of moderately to severely active ulcerative colitis. A genetic-based diagnostic test was designed to identify patients with an increased likelihood of response. METHODS: We randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response. The primary analysis was performed in cohort 1; the primary end point was clinical remission at week 12. Patients with a positive test for likelihood of response from cohorts 1 and 2 were combined in prespecified analyses. RESULTS: In cohort 1, a total of 135 patients underwent randomization. A significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%; difference, 25 percentage points; 95% confidence interval [CI], 14 to 37; P<0.001). In cohort 2, a total of 43 patients underwent randomization. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%; difference, 21 percentage points; 95% CI, 2 to 38; P = 0.02). Among all the enrolled patients, the incidence of adverse events was similar in the tulisokibart and placebo groups; most adverse events were mild to moderate in severity. CONCLUSIONS: In this short-term trial, tulisokibart was more effective than placebo in inducing clinical remission in patients with moderately to severely active ulcerative colitis. (Funded by Prometheus Biosciences, a subsidiary of Merck; ARTEMIS-UC ClinicalTrials.gov number, NCT04996797.).

A Gradient-Descent Optimization of CO2-CO-NOx Emissions over the Paris Megacity─The Case of the First SARS-CoV-2 Lockdown.

Urban greenhouse gas emissions monitoring is essential to assessing the impact of climate mitigation actions. Using atmospheric continuous measurements of air quality and carbon dioxide (CO2), we developed a gradient-descent optimization system to estimate emissions of the city of Paris. We evaluated our joint CO2-CO-NOx optimization over the first SARS-CoV-2 related lockdown period, resulting in a decrease in emissions by 40% for NOx and 30% for CO2, in agreement with preliminary estimates using bottom-up activity data yet lower than the decrease estimates from Bayesian atmospheric inversions (50%). Before evaluating the model, we first provide an in-depth analysis of three emission data sets. A general agreement in the totals is observed over the region surrounding Paris (known as Île-de-France) since all the data sets are constrained by the reported national and regional totals. However, the data sets show disagreements in their sector distributions as well as in the interspecies ratios. The seasonality also shows disagreements among emission products related to nonindustrial stationary combustion (residential and tertiary combustion). The results presented in this paper show that a multispecies approach has the potential to provide sectoral information to monitor CO2 emissions over urban areas enabled by the deployment of collocated atmospheric greenhouse gases and air quality monitoring stations.

Citizen science in environmental health research: A comparison with conventional approaches and creation of a guidance tool issued from the LILAS initiative.

CONTEXT: Public interest for citizen science (CS) in environmental health is growing. The goals of environmental health research projects are diverse, as are the methods used to reach these goals. Opportunities for greater implication of the civil society and related challenges differ at each step of such projects. These methodological aspects need to be widely shared and understood by all stakeholders. The LILAS initiative (acronym for "application of citizen science approaches such as LIving LAbS to research on environmental exposures and chronic risks") aimed to 1) favor a mutual understanding of the main issues and research methods in environmental health, of their stakes for different actors, but also of the requirements, strengths and limitations of these methods and to 2) identify expected benefits and points of attention related to stronger degrees of participation as part of environmental health research projects. METHODS: The LILAS initiative gathered institutional researchers, academics and civil society representatives interested in environmental exposures. Five meetings allowed to collectively identify different types of environmental health research studies and reflect about the benefits, limitations, and methodological issues related to the introduction of growing citizen participation as part of such studies. An analytic table matrix summarizing these aspects was co-created and filled by participants, as a tool devoted to help stakeholders with the definition of future CS research projects in environmental health. RESULTS: For different fields of research (e.g.: studies for assessment of environmental exposures, interventions on these exposures, quantitative risk assessment, epidemiological studies), the matrix lists expected benefits for various stakeholders, the fundamental principles of research methods and related practical constraints, but also advantages and limitations related to the use of CS or conventional research approaches. CONCLUSION: The LILAS initiative allowed to develop a tool which provides consolidated grounds for the co-creation of research projects on environmental exposures involving CS.

Simultaneous Monitoring of Atmospheric CH4, N2O, and H2O Using a Single Gas Sensor Based on Mid-IR Quartz-Enhanced Photoacoustic Spectroscopy.

An optical sensor based on external-cavity quantum cascade laser (EC-QCL) was developed for simultaneous triple-species monitoring of CH4, N2O, and H2O vapor using off-beam quartz-enhanced photoacoustic spectroscopy (OB-QEPAS). The EC-QCL wavelength was scanned over three neighboring absorption lines of CH4 (1260.81 cm-1), N2O (1261.06 cm-1), and H2O vapor (1261.58 cm-1) by tuning the grating of the EC-QCL with a piezoelectric actuator. Molecular relaxation effects impacting the generation of the QEPAS signals resulting from light absorption by CH4 and N2O molecules were investigated in the mid-infrared region near 8 µm. A theoretical model was introduced for the mid-infrared region, including the beneficial influence of water vapor. An enhancement of the QEPAS signals by a factor of 3 for CH4 in air and of 20% for N2O in air was observed in humidified samples compared to that in dry samples. The QEPAS measurement was scaled by the calibrated reference spectrometers; detection limits of 98 ppbv for CH4, 12 ppbv for N2O, and 750 ppmv for H2O vapor were obtained with a 1σ signal-to-noise ratio (SNR = 1) in humidified gas mixtures. Real-time Kalman filtering was applied to improve the measurement precision by a factor of approximately 4 while keeping the same temporal resolution, leading to measurement precisions of 60 ppbv for CH4, 10 ppbv for N2O, and 0.07% for H2O in the measurements of 1.99 ppmv CH4 and 312 ppbv N2O humidified with 2.8% H2O vapor, with a 1 s lock-in amplifier time constant and an equivalent bandwidth of 0.1 Hz.

Expression of ABCB1, ABCC1 and 3 and ABCG2 in glioblastoma and their relevance in relation to clinical survival surrogates.

PURPOSE: Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumors in adults. Patients invariably relapse during or after first-line therapy and the median overall survival is 14.6 months. Such poor clinical response is partly ascribed to the activity of ATP-binding cassette (ABC) transporters. The activity of these proteins, severely reduces the amount of therapeutics that penetrates the tumor cells. We hypothesized that ABC transporter expression could correlate with survival surrogates. In this study, we assessed the expression of four commonly expressed ABC transporters in GBM samples and investigated if mRNA levels could serve as a prognostic biomarker. METHODS: Human specimens were analyzed by qPCR to assess ABCB1, ABCC1/3 and ABCG2 expression. Kaplan-Meier and multivariate analyses were then used to evaluate the correlation with overall survival (OS) and progression-free survival (PFS). RESULTS: Our cohort included 22 non-tumoral samples as well as 159 GBM tumor specimens. ABC transporters were significantly more expressed in GBM samples compared to non-tumoral tissue. Moreover ABCC1 and 3 mRNA expression were significantly increased at recurrence. Statistical analyses revealed that increased expression of either ABCC1 or ABCC3 did not confer a poorer prognosis. However, increased ABCC1 mRNA levels did correlate with a significantly shorter PFS. CONCLUSION: In this manuscript, the analyses we conducted suggest that the expression of the four ABC transporters evaluated would not be suitable prognostic biomarkers. We believe that, when estimating prognosis, the plethora of mechanisms implicated in chemoresistance should be analyzed as a multi-facetted entity rather than isolated units.

Assessing the Effectiveness of an Urban CO2 Monitoring Network over the Paris Region through the COVID-19 Lockdown Natural Experiment.

The Paris metropolitan area, the largest urban region in the European Union, has experienced two national COVID-19 confinements in 2020 with different levels of restrictions on mobility and economic activity, which caused reductions in CO2 emissions. To quantify the timing and magnitude of daily emission reductions during the two lockdowns, we used continuous atmospheric CO2 monitoring, a new high-resolution near-real-time emission inventory, and an atmospheric Bayesian inverse model. The atmospheric inversion estimated the changes in fossil fuel CO2 emissions over the Greater Paris region during the two lockdowns, in comparison with the same periods in 2018 and 2019. It shows decreases by 42-53% during the first lockdown with stringent measures and by only 20% during the second lockdown when traffic reduction was weaker. Both lockdown emission reductions are mainly due to decreases in traffic. These results are consistent with independent estimates based on activity data made by the city environmental agency. We also show that unusual persistent anticyclonic weather patterns with north-easterly winds that prevailed at the start of the first lockdown period contributed a substantial drop in measured CO2 concentration enhancements over Paris, superimposed on the reduction of urban CO2 emissions. We conclude that atmospheric CO2 monitoring makes it possible to identify significant emission changes (>20%) at subannual time scales over an urban region.

Relationships between greenness and low birth weight: Investigating the interaction and mediation effects of air pollution.

BACKGROUND: Associations between residential greenness and improved birth weight have been increasingly reported, but underlying mechanisms and interactions with other environmental exposures are still unclear. OBJECTIVES: To study the relationships between low birth weight (LBW, <2500 g), residential greenness, and the potential influence of air pollution in these relationships (interaction and mediation) in California, over the period 2001-2008. METHODS: Residential greenness around maternal homes was characterized using the Normalized Difference Vegetation Index (NDVI). Complementary indicators of air pollution exposure reflected its main components. Birth weight and maternal characteristics were obtained from birth certificate records. In this case-cohort study, associations between greenness and LBW were investigated using multi-level Poisson regression with random effect at the hospital level. We investigated potential interaction of greenness and air pollutants on both additive and multiplicative scales. Mediation analyses were conducted to estimate the potential contribution of local variations in air pollutant concentrations associated with greenness on LBW risk. RESULTS: In total 72,632 LBW cases were included. A reduction of LBW risk was associated with an increase in NDVI (adjusted risk ratio per inter-quartile range in NDVI: 0.963; 95% confidence interval: 0.947; 0.978). We observed no interaction between NDVI and air pollution on LBW risk. The estimated mediating effect of fine particulate matter in the impact of greenness on LBW was 12%. CONCLUSION: This large study confirms that residential greenness is associated with a reduced risk of LBW and suggests that greenness might benefit to LBW partly through a local reduction in air pollution.

Analysis of the association between ionizing radiation and mortality in uranium workers from five plants involved in the nuclear fuel production cycle in France.

PURPOSE: The aim is to investigate associations between mortality and exposure to ionizing radiation in a cohort of uranium workers with potential for internal and external radiation exposures. METHODS: Workers employed for at least 6 months between 1958 and 2006 in five plants involved in the French nuclear fuel cycle were included and followed up between 1968 and 2013. Cause-specific standardized mortality ratios were calculated. Analyses of associations between individual cumulative radiation dose (both internal and external, lagged by 5-15 years) and mortality were conducted using Poisson regression. RESULTS: The cohort includes 4541 workers. The mean cumulative external dose was 11.12 mGy. Mean cumulative internal doses ranged, depending on modelling hypotheses, from 0.05 to 0.09 mGy (liver) and from 4.22 to 10.90 mGy (lung). At the end of the follow-up, 838 workers were deceased and 28 lost to follow-up. A healthy worker effect was observed. The risk of prostate and lung cancers mortality was significantly higher for workers exposed to cumulative external dose above 50 mGy compared to non-exposed, but these associations were based only on three cases and became non-significant, although of similar magnitude, after adjustment for smoking. Associations with internal dose showed no consistent pattern. CONCLUSIONS: For the first time, a study was conducted in a French cohort of uranium workers with a complete reconstruction of internal dose. Results are preliminary and must be interpreted with caution because of the limited cohort size and significant sources of uncertainty. Future steps of this study will overcome these limitations.

Liposomal formulations of carboplatin injected by convection-enhanced delivery increases the median survival time of F98 glioma bearing rats.

BACKGROUND: Effectiveness of chemotherapy for treating glioblastoma (GBM) brain tumors is hampered by the blood-brain barrier which limits the entry into the brain of most drugs from the blood. To bypass this barrier, convection-enhanced delivery (CED) was proposed to directly inject drugs in tumor. However, the benefit of CED may be hampered when drugs diffuse outside the tumor to then induce neurotoxicity. Encapsulation of drugs into liposome aims at increasing tumor cells specificity and reduces neurotoxicity. However, the most appropriate liposomal formulation to inject drugs into brain tumor by CED still remains to be determined. In this study, four liposomal carboplatin formulations were prepared and tested in vitro on F98 glioma cells and in Fischer rats carrying F98 tumor implanted in the brain. Impact of pegylation on liposomal surface and relevance of positive or negative charge were assessed. RESULTS: The cationic non-pegylated (L1) and pegylated (L2) liposomes greatly improved the toxicity of carboplatin in vitro compared to free carboplatin, whereas only a modest improvement and even a reduction of efficiency were measured with the anionic non-pegylated (L3) and the pegylated (L4) liposomes. Conversely, only the L4 liposome significantly increased the median survival time of Fisher rats implanted with the F98 tumor, compared to free carboplatin. Neurotoxicity assays performed with the empty L4' liposome showed that the lipid components of L4 were not toxic. These results suggest that the positive charge on liposomes L1 and L2, which is known to promote binding to cell membrane, facilitates carboplatin accumulation in cancer cells explaining their higher efficacy in vitro. Conversely, negatively charged and pegylated liposome (L4) seems to diffuse over a larger distance in the tumor, and consequently significantly increased the median survival time of the animals. CONCLUSIONS: Selection of the best liposomal formulation based on in vitro studies or animal model can result in contradictory conclusions. The negatively charged and pegylated liposome (L4) which was the less efficient formulation in vitro showed the best therapeutic effect in animal model of GBM. These results support that relevant animal model of GBM must be considered to determine the optimal physicochemical properties of liposomal formulations.

First mortality analysis in the French cohort of uranium millers (F-Millers), period 1968-2013.

PURPOSE: Epidemiological studies in cohorts of uranium millers can be informative to improve knowledge of the health effects of uranium, but are very rare. The aim of this study was to analyze, for the first time, mortality in a French cohort of uranium millers. METHODS: The F-Millers cohort includes permanent contract workers employed at least 6 months at French uranium milling plants. Vital status and causes of death were obtained from national registries between 1968 and 2013, in order to perform comparisons with French national and local mortality rates by computing standardized mortality ratios (SMRs) with 95% confidence intervals (95% CI). RESULTS: The cohort includes 1291 workers. The average duration of follow-up is 32.1 years. At the end of follow-up, 448 workers were deceased and 13 lost to follow-up. We observed a significant deficit of mortality for all causes combined when the national reference was considered (SMR 0.81; 95% CI [0.74;0.89]), but no significant difference when the local reference was considered (SMR 0.97; 95% CI [0.88;1.07]). Significant excesses were observed only in a subgroup of 552 workers hired at the manufacturing unit, mainly when the local reference was considered. CONCLUSION: No significant excess of mortality was observed at the scale of the full cohort. The cause-specific excesses of mortality observed in the subgroup of workers hired at the manufacturing unit were based on small number of cases, but would warrant further investigations. Undertaking analytical studies and combined analyses of cohorts of uranium millers would help to study the influence of potential risk factors and obtain more precise results.

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors.

Glioblastoma (GBM) represents the most common and aggressive malignant primary brain tumors in adults. Response to standard treatment is transitory and the survival of clinical trial cohorts are little more than 14 months. GBM are characterized by excessive proliferation, invasiveness, and radio-/chemoresistance features; which are strongly upregulated by transforming growth factor-beta (TGF-ß). We hypothesized that TGF-ß gene expression could correlate with overall survival (OS) and serve as a prognostic biomarker. TGF-ß1 and -ß2 expression were analyzed by qPCR in 159 GBM tumor specimens. Kaplan-Meier and multivariate analyses were used to correlate expression with OS and progression-free survival (PFS). In GBM, TGF-ß1 and -ß2 levels were 33- and 11-fold higher respectively than in non-tumoral samples. Kaplan-Meier and multivariate analyses revealed that high to moderate expressions of TGF-ß1 significantly conferred a strikingly poorer OS and PFS in newly diagnosed patients. Interestingly, at relapse, neither isoforms had meaningful impact on clinical evolution. We demonstrate that TGF-ß1 is the dominant isoform in newly diagnosed GBM rather than the previously acknowledged TGF-ß2. We believe our study is the first to unveil a significant relationship between TGF-ß1 expression and OS or PFS in newly diagnosed GBM. TGF-ß1 could serve as a prognostic biomarker or target affecting treatment planning and patient follow-up.

PI3Kß Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors.

BACKGROUND/AIMS: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F1-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F1-ATPase activation. METHODS: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F1-ATPase activation by apoA-I. RESULTS: ApoA-I and HDL both induced Akt phosphorylation. F1-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F1-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y1-ADPreceptor and the PI3Kß isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. CONCLUSION: Altogether, these data highlight a key role of the P2Y1/PI3Kß axis in endothelial cell proliferation downstream of ecto-F1-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.

Mortality (1968-2008) in a French cohort of uranium enrichment workers potentially exposed to rapidly soluble uranium compounds.

OBJECTIVES: Until recently, enrichment of uranium for civil and military purposes in France was carried out by gaseous diffusion using rapidly soluble uranium compounds. We analysed the relationship between exposure to soluble uranium compounds and exposure to external γ-radiation and mortality in a cohort of 4688 French uranium enrichment workers who were employed between 1964 and 2006. METHODS: Data on individual annual exposure to radiological and non-radiological hazards were collected for workers of the AREVA NC, CEA and Eurodif uranium enrichment plants from job-exposure matrixes and external dosimetry records, differentiating between natural, enriched and depleted uranium. Cause-specific mortality was compared with the French general population via standardised mortality ratios (SMR), and was analysed via Poisson regression using log-linear and linear excess relative risk models. RESULTS: Over the period of follow-up, 131 161 person-years at risk were accrued and 21% of the subjects had died. A strong healthy worker effect was observed: all causes SMR=0.69, 95% CI 0.65 to 0.74. SMR for pleural cancer was significantly increased (2.3, 95% CI 1.06 to 4.4), but was only based on nine cases. Internal uranium and external γ-radiation exposures were not significantly associated with any cause of mortality. CONCLUSIONS: This is the first study of French uranium enrichment workers. Although limited in statistical power, further follow-up of this cohort, estimation of internal uranium doses and pooling with similar cohorts should elucidate potential risks associated with exposure to soluble uranium compounds.

Spatial variability of the effect of air pollution on term birth weight: evaluating influential factors using Bayesian hierarchical models.

BACKGROUND: Epidemiological studies suggest that air pollution is adversely associated with pregnancy outcomes. Such associations may be modified by spatially-varying factors including socio-demographic characteristics, land-use patterns and unaccounted exposures. Yet, few studies have systematically investigated the impact of these factors on spatial variability of the air pollution's effects. This study aimed to examine spatial variability of the effects of air pollution on term birth weight across Census tracts and the influence of tract-level factors on such variability. METHODS: We obtained over 900,000 birth records from 2001 to 2008 in Los Angeles County, California, USA. Air pollution exposure was modeled at individual level for nitrogen dioxide (NO2) and nitrogen oxides (NOx) using spatiotemporal models. Two-stage Bayesian hierarchical non-linear models were developed to (1) quantify the associations between air pollution exposure and term birth weight within each tract; and (2) examine the socio-demographic, land-use, and exposure-related factors contributing to the between-tract variability of the associations between air pollution and term birth weight. RESULTS: Higher air pollution exposure was associated with lower term birth weight (average posterior effects: -14.7 (95 % CI: -19.8, -9.7) g per 10 ppb increment in NO2 and -6.9 (95 % CI: -12.9, -0.9) g per 10 ppb increment in NOx). The variation of the association across Census tracts was significantly influenced by the tract-level socio-demographic, exposure-related and land-use factors. Our models captured the complex non-linear relationship between these factors and the associations between air pollution and term birth weight: we observed the thresholds from which the influence of the tract-level factors was markedly exacerbated or attenuated. Exacerbating factors might reflect additional exposure to environmental insults or lower socio-economic status with higher vulnerability, whereas attenuating factors might indicate reduced exposure or higher socioeconomic status with lower vulnerability. CONCLUSIONS: Our Bayesian models effectively combined a priori knowledge with training data to infer the posterior association of air pollution with term birth weight and to evaluate the influence of the tract-level factors on spatial variability of such association. This study contributes new findings about non-linear influences of socio-demographic factors, land-use patterns, and unaccounted exposures on spatial variability of the effects of air pollution.

Comparison of birth certificates and hospital-based birth data on pregnancy complications in Los Angeles and Orange County, California.

BACKGROUND: The incidence of both gestational diabetes mellitus and preeclampsia is on the rise; however, these pregnancy complications may not be systematically reported. This study aimed to examine differences in reporting of preeclampsia and gestational diabetes between hospital records and birth certificate data, and to determine if such differences vary by maternal socioeconomic status indicators. METHODS: We obtained over 70,000 birth records from 2001 to 2006 from the perinatal research database of the Memorial Care system, a network of four hospitals in Los Angeles and Orange Counties, California. Memorial birth records were matched to corresponding state birth certificate records and analyzed to determine differential rates of reporting of preeclampsia and diabetes. Additionally, the influence of maternal socioeconomic factors on the reported incidence of such adverse pregnancy outcomes was analyzed. Socioeconomic factors of interest included maternal education levels, race, and type of health insurance (private or public). RESULTS: It was found that the birth certificate data significantly underreported the incidence of both preeclampsia (1.38% vs. 3.13%) and diabetes (1.97% vs. 5.56%) when compared to Memorial data. For both outcomes of interest, the degree of underreporting was significantly higher among women with lower education levels, among Hispanic women compared to Non-Hispanic White women, and among women with public health insurance. CONCLUSION: The Memorial Care database is a more reliable source of information than birth certificate data for analyzing the incidence of preeclampsia and diabetes among women in Los Angeles and Orange Counties, especially for subpopulations of lower socioeconomic status.

Geographic Distribution of Healthy Resources and Adverse Pregnancy Outcomes.

Objective To determine the risk of gestational diabetes (GDM) and preeclampsia associated with various community resources. Methods An ecological study was performed in Los Angeles and Orange counties in California. Fast food restaurants, supermarkets, grocery stores, gyms, health clubs and green space were identified using Google © Maps Extractor and through the Southern California Association of Government. California Birth Certificate data was used to identify cases of GDM and preeclampsia. Unadjusted and adjusted risk ratios were calculated using negative binomial regression. Results There were 9692 cases of GDM and 6288 cases of preeclampsia corresponding to incidences of 2.5 and 1.4 % respectively. The adjusted risk of GDM was reduced in zip codes with greater concentration of grocery stores [relative risk (RR) 0.95, 95 % confidence interval (CI) 0.92-0.99] and supermarkets (RR 0.94, 95 % CI 0.90-0.98). There were no significant relationships between preeclampsia and the concentration of fast food restaurants, grocery store, supermarkets or the amount of green space. Conclusion The distribution of community resources has a significant association with the risk of developing GDM but not preeclampsia.

Adverse Reproductive Health Outcomes and Exposure to Gaseous and Particulate-Matter Air Pollution in Pregnant Women.

Introduction: There is growing epidemiologic evidence of associations between maternal exposure to ambient air pollution and adverse birth outcomes, such as preterm birth (PTB). Recently, a few studies have also reported that exposure to ambient air pollution may also increase the risk of some common pregnancy complications, such as preeclampsia and gestational diabetes mellitus (GDM). Research findings, however, have been mixed. These inconsistent results could reflect genuine differences in the study populations, the study locations, the specific pollutants considered, the designs of the study, its methods of analysis, or random variation. Dr. Jun Wu of the University of California­ Irvine, a recipient of HEI's Walter A. Rosenblith New Investigator Award, and colleagues have examined the association between air pollution and adverse birth and pregnancy outcomes in California women. In addition, they examined the effect modification by socioeconomic status (SES) and other factors. Approach: A retrospective nested case­control study was conducted using birth certificate data from about 4.4 million birth records in California from 2001 to 2008. Wu and colleagues analyzed data on low birth weight (LBW) at term (infants born between 37 and 43 weeks of gestation and weighing less than 2500 g), PTB (infants born before 37 weeks of gestation), and preeclampsia (including eclampsia) of the mother during the pregnancy. In addition, they obtained data on GDM for the years 2006­ 2008. In the analyses, all outcomes were included as binary variables. Maternal residential addresses at the time of delivery were geocoded, and a large suite of air pollution exposure metrics was considered, such as (1) regulatory monitoring data on concentrations of criteria pollutants NO2, PM2.5 (particulate matter ≤ 2.5 µm in aerodynamic diameter), and ozone (O3) estimated by empirical Bayesian kriging; (2) concentrations of primary and secondary PM2.5 and PM0.1 components and sources estimated by the University of California­Davis Chemical Transport Model; (3) traffic-related ultrafine particles and concentrations of carbon monoxide (CO) and nitrogen oxides (NOx) estimated by a modified CALINE4 air pollution dispersion model; and (4) proximity to busy roads, road length, and traffic density calculated for different buffer sizes using geographic information system tools. In total, 50 different exposure metrics were available for the analyses. The exposure of primary interest was the mean of the entire pregnancy period for each mother. For the health analyses, controls were randomly selected from the source population. PTB controls were matched on conception year. Term LBW, preeclampsia, and GDM were analyzed using generalized additive mixed models with inclusion of a random effect per hospital. PTB analyses were conducted using conditional logistic regression, with no adjustment for hospital. The main results­ adjusted for race and education as categorical variables and adjusted for maternal age and median household income at the census-block level­were derived from single-pollutant models. Main results and interpretation: In its independent review of the study, the HEI Health Review Committee concluded that Wu and colleagues had conducted a comprehensive nested case­control study of air pollution and adverse birth and pregnancy outcomes. The very large data set and the extensive exposure assessment were strengths of the study. The study documented associations between increases in various air pollution metrics and increased risks of PTB, whereas the evidence was weaker overall for term LBW; in addition, decreases in many air pollution metrics were associated with an increased risk of preeclampsia and GDM, an unexpected result. The investigators suggested that underreporting in the registry data, especially in lower-SES groups, might have caused the many negative associations found for preeclampsia and GDM. In addition, poor geocoding was listed as a potential explanation, affecting in particular the results that were based on measures of proximity to busy roads and traffic density in the smallest buffer size (50 m). However, those issues were not fully explored. In general, the Committee thought that the analysis of road traffic indicators in the 50 m buffer was hampered by the lack of contrast and that the results are therefore difficult to interpret. Some other issues with the analytical approaches should be considered when interpreting the results. Only a subset of controls was used, to reduce computational demands. Hence, some models did not converge, especially in the subgroup analyses. Most of the results in the report were based on analyses using single-pollutant models, which is a reasonable approach but ignores that people are exposed to complex mixtures of pollutants. The Committee believed that the few two-pollutant models that were run provided important insights: these models showed the strongest association for PM2.5 mass, whereas components and source-specific positive associations largely disappeared after adjusting for PM2.5 mass. This study adds to the ongoing debate about whether some particle components and sources are of greater public health concern than others.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta.

BACKGROUND: Glioblastoma (GBM), the most common and aggressive primary brain tumor, is characterized by excessive brain infiltration which prevents the complete surgical resection. These tumors also display treatment non-compliance and responses to standard therapy are invariably transient; consequently, the prognosis barely exceeds 14 months and recurrence is inevitable. Accordingly, several new treatment strategies have been studied. One such option is the use of chloroquine (CQ), a lysosomotropic weak base and renowned antimalarial drug, that has shown promising results in several pre-clinical studies. In this paper, we investigate the efficiency of CQ to hinder the malignant phenotype of GBM, namely extensive proliferation, invasion and radio-resistance. RESULTS: In cell cycle analysis, proliferation assays and immunofluorescence, CQ treatments halved proliferation of primary cultures from GBM specimens and GBM cell lines (U-373 MG et U-87 MG). Gelatin zymography and Matrigel(TM)-coated transwell invasion assays also revealed a 50 % CQ induced inhibition of MMP-2 activity and GBM invasion. Concomitant treatment with CQ and radiation also radiosensitized GBM cells as shown by an accumulation in the G2/M phase, increased cell death and reduced clonogenic formation. Moreover, radiation-induced invasion was considerably restrained by CQ. We also observe that these effects are owed to CQ-induced inhibition of TGF-ß secretion and signaling pathway, a predominant growth factor in GBM progression. CONCLUSION: These results suggest that CQ, alone or as an adjuvant therapeutic, could be used to inhibit the GBM malignant phenotype and could benefit GBM afflicted patients.

Sources and contents of air pollution affecting term low birth weight in Los Angeles County, California, 2001-2008.

BACKGROUND: Low birth weight (LBW, <2500 g) has been associated with exposure to air pollution, but it is still unclear which sources or components of air pollution might be in play. The association between ultrafine particles and LBW has never been studied. OBJECTIVES: To study the relationships between LBW in term born infants and exposure to particles by size fraction, source and chemical composition, and complementary components of air pollution in Los Angeles County (California, USA) over the period 2001-2008. METHODS: Birth certificates (n=960,945) were geocoded to maternal residence. Primary particulate matter (PM) concentrations by source and composition were modeled. Measured fine PM, nitrogen dioxide and ozone concentrations were interpolated using empirical Bayesian kriging. Traffic indices were estimated. Associations between LBW and air pollution metrics were examined using generalized additive models, adjusting for maternal age, parity, race/ethnicity, education, neighborhood income, gestational age and infant sex. RESULTS: Increased LBW risks were associated with the mass of primary fine and ultrafine PM, with several major sources (especially gasoline, wood burning and commercial meat cooking) of primary PM, and chemical species in primary PM (elemental and organic carbon, potassium, iron, chromium, nickel, and titanium but not lead or arsenic). Increased LBW risks were also associated with total fine PM mass, nitrogen dioxide and local traffic indices (especially within 50 m from home), but not with ozone. Stronger associations were observed in infants born to women with low socioeconomic status, chronic hypertension, diabetes and a high body mass index. CONCLUSIONS: This study supports previously reported associations between traffic-related pollutants and LBW and suggests other pollution sources and components, including ultrafine particles, as possible risk factors.