Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function.
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ABSTRACT:
SUBMITTER: Bettonville M
PROVIDER: S-EPMC6025959 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inconsistent findings exist regarding the potential association between polluted air and Parkinson's disease (PD), with unclear insights into the role of inherited sensitivity. This study sought to explore the potential link between various air pollutants and PD risk, investigating whether genetic susceptibility modulates these associations. The population-based study involved 312,009 initially PD-free participants with complete genotyping data. Annual mean concentrations of PM2.5, PM10, NO2, and NOx were estimated, and a polygenic risk score (PRS) was computed to assess individual genetic risks for PD. Cox proportional risk models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between ambient air pollutants, genetic risk, and incident PD. Over a median 12.07-year follow-up, 2356 PD cases (0.76%) were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs and 95% CIs of 1.247 (1.089-1.427) and 1.201 (1.052-1.373) for PD incidence, respectively. Each 10 μg/m3 increase in NO2 and PM10 yielded elevated HRs and 95% CIs for PD of 1.089 (1.026-1.155) and 1.363 (1.043-1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145-3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912-3.048). Findings suggest that exposure to air contaminants heightens PD risk, particularly in individuals genetically predisposed to high susceptibility.
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Project description:Studies that examined dietary energy requirements (DERs) of patients undergoing maintenance hemodialysis (MHD) have shown mixed results. Many studies reported normal DERs, but some described increased energy needs. DERs in MHD patients have been estimated primarily from indirect calorimetry and from nitrogen balance studies. The present study measured DERs in MHD patients on the basis of their dietary energy intake and changes in body composition.This study assessed DERs in MHD patients who received a constant energy intake while changes in their body composition were measured.Seven male and 6 female sedentary, clinically stable MHD patients received a constant mean (±SD) energy intake for 92.2 ± 7.9 d while residing in a metabolic research ward. Changes in fat and fat-free mass, measured by dual-energy X-ray absorptiometry, were converted to calorie equivalents and added to energy intake to calculate energy requirements.The average DER was 31 ± 3 kcal · kg(-1) · d(-1) calculated from energy intake and change in fat and fat-free calories, which was 28 ± 197 kcal/d over the 92 d of the study. DERs of MHD patients correlated strongly with their body weight (r = 0.81, P = 0.002) and less closely with their measured resting energy expenditure expressed as kcal/d (r = 0.69, P = 0.01). Although the average observed DER in MHD patients was similar to published estimated values for normal sedentary individuals of similar age and sex, there was wide variability in DER among individual patients (range: 26-36 kcal · kg(-1) · d(-1)).Average DERs of sedentary, clinically stable patients receiving MHD are similar to those of sedentary normal individuals. Our data do not support the theory that MHD patients have increased DERs. Due to the high variability in DERs, careful monitoring of the nutritional status of individual MHD patients is essential. This trial was registered at clinicaltrials.gov as NCT02194114.
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Project description:BackgroundRecent studies suggest that household endotoxin and allergens can modify the impact of air pollutants on development of asthma; however, epidemiological evidence is limited and conflicting.ObjectivesTo investigate whether pet ownership modified the association between ambient air pollution and asthma in children.MethodsWe conducted a population-based cross-sectional study, the Seven Northeast Cities Study in China and recruited a total of 59,754 children from 94 schools during 2012-2013. Long-term air pollutant concentrations, including airborne particulate matter with a diameter of 1 μm or less (PM1 ), PM2.5 , PM10 , and nitrogen dioxide (NO2 ) from 2009 to 2012 were estimated using a random forest model. We collected information of respiratory health in children using the Epidemiologic Standardization Project Questionnaire of the American Thoracic Society (ATS-DLD-78-A). Regression models were used to evaluate associations between pet ownership and air pollution on asthma after adjusting for potential covariates.ResultsExposure to increasing levels of air pollutants was associated with higher prevalence of asthma, but associations were significantly attenuated in children who owned pets. For example, compared to children without pets, those who owned pets did not have an increased risk of symptoms of asthma (odds ratio, 1.01, 95% confidence interval: 0.78, 1.30), wheeze (0.96, 95% confidence interval [CI]: 0.76, 1.21), and cough (1.01, 95% CI: 0.87, 1.18) for each 10 µg/m3 increase in PM1 (P-int < 0.05). Similar trends were observed for other air pollutants. Dog and bird ownership decreased the associations of asthma and cough with air pollutant exposure. The main findings were consistent with a series of sensitivity analyses.ConclusionCurrent pet ownership may reduce the adverse impact of long-term air pollution on childhood asthma. Longitudinal studies are needed to confirm this finding which could have important implications for public health.
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Project description:Adoptive T cell therapies have been transformative in the treatment of a subset of hematological malignancies. However, many patients either fail to respond or relapse, and these therapies still have had much more limited success in solid tumors. A critical challenge for increasing patient response rates and achieving durable efficacy of adoptive T cell therapies is overcoming suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints. Targeted gene editing has the potential to enhance T cell therapeutic function and improve clinical responses. Here we perform multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to nominate genes that could be targeted to prevent T cell dysfunction. These CRISPR screens converged on RASA2 as a target to confer resistance to suppressive conditions found in tumor microenvironments. We identify RASA2 as a signaling checkpoint in human T cells that is downregulated upon acute TCR stimulation but increases gradually with chronic antigen exposure. Antigen titration showed that genetic ablation of RASA2 enhances mitogen activated protein kinase (MAPK) signaling and CAR-T cell cytolytic activity in response to low antigen levels. Repeated tumor antigen stimulation in vitro revealed that RASA2-deficient TCR-T and CAR-T cells have increased activation, cytokine production, and metabolic activity compared to control cells, and show a striking advantage in persistent cancer cell killing. RASA2 KO CAR-T cells showed a competitive fitness advantage over CAR-T control cells in the bone marrow of an in vivo leukemia model. Deletion of RASA2 in multiple preclinical models of TCR- and CAR-T cell therapies prolonged survival in animals xenografted with either liquid or solid tumors. Altogether, our findings from multiple genome-wide screens and preclinical studies highlight RASA2 as a promising new target to enhance both persistence and effector function in TCR-T and CAR-T cell therapies for cancer treatment.
2022-05-29 | GSE204862 | GEO