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Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

BackgroundRemote sensing (RS) is increasingly used for exposure assessment in epidemiological and burden of disease studies, including those investigating whether chronic exposure to ambient fine particulate matter (PM2.5) is associated with mortality.ObjectivesWe compared relative risk estimates of mortality from diseases of the circulatory system for PM2.5 modeled from RS with that for PM2.5 modeled using ground-level information.MethodsWe geocoded the baseline residence of 668,629 American Cancer Society Cancer Prevention Study II (CPS-II) cohort participants followed from 1982 to 2004 and assigned PM2.5 levels to all participants using seven different exposure models. Most of the exposure models were averaged for the years 2002-2004, and one RS estimate was for a longer, contemporaneous period. We used Cox proportional hazards regression to estimate relative risks (RRs) for the association of PM2.5 with circulatory mortality and ischemic heart disease.ResultsEstimates of mortality risk differed among exposure models. The smallest relative risk was observed for the RS estimates that excluded ground-based monitors for circulatory deaths [RR = 1.02, 95% confidence interval (CI): 1.00, 1.04 per 10 μg/m3 increment in PM2.5]. The largest relative risk was observed for the land-use regression model that included traffic information (RR = 1.14, 95% CI: 1.11, 1.17 per 10 μg/m3 increment in PM2.5).ConclusionsWe found significant associations between PM2.5 and mortality in every model; however, relative risks estimated from exposure models using ground-based information were generally larger than those estimated using RS alone.

In Mediterranean regions, severe summers are becoming more common, leading to restrictions to vine productivity and yield quality, requiring sustainable practices to support this sector. We assessed the behaviour of three red grapevine varieties from the Douro Region to examine their tolerance to summer climate stress from the perspective that the less common varieties may have potential for increased use in a climate change scenario.Leaf and fruit biochemical profile, antioxidant activity and fruit colorimetric parameters were assessed at different phenological stages in Aragonez (AR), Tinto Cão (TC) and Touriga Nacional (TN) grape varieties.All three varieties exhibit significant variability in phenological timing, influenced by genetic and environmental factors. Photosynthetic pigment strategies differed among varieties. Chlorophyll content in AR was high to cope with high radiation, while TN displaying a balanced approach, and TC had lower pigment levels, with higher levels of phenolics, antioxidants, and soluble sugars, particularly during stress. The variations in berry biochemical profile highlight the distinct characteristics of the varieties. TC and TN show potential for coping with climate change, having elevated total acidity, while AR has larger and heavier berries with distinct coloration.These findings reinforce the need to study the behaviour of different varieties in each Terroir, to understand their diverse strategies to deal with summer climate stress. This will help in selecting the most suitable variety for these conditions under vineyard management in the Douro Region [ABSTRACT FROM AUTHOR]

RationaleTropospheric ozone (O3) is potentially associated with cardiovascular disease risk and premature death. Results from long-term epidemiological studies on O3 are scarce and inconclusive.ObjectivesIn this study, we examined associations between chronic ambient O3 exposure and all-cause and cause-specific mortality in a large cohort of U.S. adults.MethodsCancer Prevention Study II participants were enrolled in 1982. A total of 669,046 participants were analyzed, among whom 237,201 deaths occurred through 2004. We obtained estimates of O3 concentrations at the participant's residence from a hierarchical Bayesian space-time model. Estimates of fine particulate matter (particulate matter with an aerodynamic diameter of up to 2.5 μm [PM2.5]) and NO2 concentrations were obtained from land use regression. Cox proportional hazards regression models were used to examine mortality associations adjusted for individual- and ecological-level covariates.Measurements and main resultsIn single-pollutant models, we observed significant positive associations between O3, PM2.5, and NO2 concentrations and all-cause and cause-specific mortality. In two-pollutant models adjusted for PM2.5, significant positive associations remained between O3 and all-cause (hazard ratio [HR] per 10 ppb, 1.02; 95% confidence interval [CI], 1.01-1.04), circulatory (HR, 1.03; 95% CI, 1.01-1.05), and respiratory mortality (HR, 1.12; 95% CI, 1.08-1.16) that were unchanged with further adjustment for NO2. We also observed positive mortality associations with both PM2.5 (both near source and regional) and NO2 in multipollutant models.ConclusionsFindings derived from this large-scale prospective study suggest that long-term ambient O3 contributes to risk of respiratory and circulatory mortality. Substantial health and environmental benefits may be achieved by implementing further measures aimed at controlling O3 concentrations.

BackgroundNumerous studies have examined associations between air pollution and pregnancy outcomes, but most have been restricted to urban populations living near monitors.ObjectivesWe examined the association between pregnancy outcomes and fine particulate matter in a large national study including urban and rural areas.MethodsAnalyses were based on approximately 3 million singleton live births in Canada between 1999 and 2008. Exposures to PM2.5 (particles of median aerodynamic diameter ≤ 2.5 μm) were assigned by mapping the mother's postal code to a monthly surface based on a national land use regression model that incorporated observations from fixed-site monitoring stations and satellite-derived estimates of PM2.5. Generalized estimating equations were used to examine the association between PM2.5 and preterm birth (gestational age < 37 weeks), term low birth weight (< 2,500 g), small for gestational age (SGA; < 10th percentile of birth weight for gestational age), and term birth weight, adjusting for individual covariates and neighborhood socioeconomic status (SES).ResultsIn fully adjusted models, a 10-μg/m(3) increase in PM2.5 over the entire pregnancy was associated with SGA (odds ratio = 1.04; 95% CI 1.01, 1.07) and reduced term birth weight (-20.5 g; 95% CI -24.7, -16.4). Associations varied across subgroups based on maternal place of birth and period (1999-2003 vs. 2004-2008).ConclusionsThis study, based on approximately 3 million births across Canada and employing PM2.5 estimates from a national spatiotemporal model, provides further evidence linking PM2.5 and pregnancy outcomes.

Background and Purpose: Sepsis‐surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, an outcome mediated by the axis IL‐33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long‐term immune consequences of paediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis. Experimental Approach: Here, we compared the frequency of Tregs, the activation of the IL‐33/ILC2s axis in M2 macrophages and the DNA methylation of epithelial lung cells from post‐septic infant and adult mice. Likewise, sepsis‐surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis‐surviving patients were collected and the concentration of IL‐33 and Tregs frequency were assessed. Key Results: In contrast to 6‐week‐old mice, 2‐week‐old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL‐33 levels, Tregs expansion, and activation of ILC2s and M2‐macrophages were observed in 6‐week‐old but not 2‐week‐old post‐septic mice. Moreover, impaired IL‐33 production in 2‐week‐old post‐septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL‐33 treatment boosted the expansion of Tregs and induced immunosuppression in 2‐week‐old mice. Clinically, adults but not paediatric post‐septic patients exhibited higher counts of Tregs and seral IL‐33 levels. Conclusion and Implications: These findings demonstrate a crucial and age‐dependent role for IL‐33 in post‐sepsis immunosuppression. Thus, a better understanding of this process may lead to differential treatments for adult and paediatric sepsis. [ABSTRACT FROM AUTHOR]

We develop a novel methodology for disentangling the demand and cost drivers of firm heterogeneity when firms sort themselves into different markets, and we apply it to export status differences. Our methodology results in joint estimates of firm-level productivity and of markups in every market, without imposing functional form restrictions on demand. We find that exporters, relative to nonexporters, (i) have flatter domestic demand curves—thicker domestic markets—and (ii) have higher demand conditional on productivity. Finally, (iii) these demand advantages translate to foreign markets, thereby leading to export status differences. [ABSTRACT FROM AUTHOR]

Onshore gas-to-wire is considered for 6.5 MMSm3/d of natural gas, with 44% mol carbon dioxide coming from offshore deep-water oil and gas fields. Base-case GTW-CONV is a conventional natural gas combined cycle, with a single-pressure Rankine cycle and 100% carbon dioxide emissions. The second variant, GTW-CCS, results from GTW-CONV with the addition of post-combustion aqueous monoethanolamine carbon capture, coupled to carbon dioxide dispatch to enhance oil recovery. Despite investment and power penalties, GTW-CCS generates both environmental and economic benefits due to carbon dioxide's monetization for enhanced oil production. The third variant, GTW-CCS-EGR, adds two intensification layers over GTW-CCS, as follows: exhaust gas recycle and a triple-pressure Rankine cycle. Exhaust gas recycle is a beneficial intensification for carbon capture, bringing a 60% flue gas reduction (reduces column's diameters) and a more than 100% increase in flue gas carbon dioxide content (increases driving force, reducing column's height). GTW-CONV, GTW-CCS, and GTW-CCS-EGR were analyzed on techno-economic and environment–thermodynamic grounds. GTW-CCS-EGR's thermodynamic analysis unveils 807 MW lost work (79.8%) in the combined cycle, followed by the post-combustion capture unit with 113 MW lost work (11.2%). GTW-CCS-EGR achieved a 35.34% thermodynamic efficiency, while GTW-CONV attained a 50.5% thermodynamic efficiency and 56% greater electricity exportation. Although carbon capture and storage imposes a 35.9% energy penalty, GTW-CCS-EGR reached a superior net value of 1816 MMUSD thanks to intensification and carbon dioxide monetization, avoiding 505.8 t/h of carbon emissions (emission factor 0.084 tCO2/MWh), while GTW-CONV entails 0.642 tCO2/MWh. [ABSTRACT FROM AUTHOR]

RationaleAlthough substantial scientific evidence suggests that chronic exposure to ambient air pollution contributes to premature mortality, uncertainties exist in the size and consistency of this association. Uncertainty may arise from inaccurate exposure assessment.ObjectivesTo assess the associations of three types of air pollutants (fine particulate matter, ozone [O3], and nitrogen dioxide [NO2]) with the risk of mortality in a large cohort of California adults using individualized exposure assessments.MethodsFor fine particulate matter and NO2, we used land use regression models to derive predicted individualized exposure at the home address. For O3, we estimated exposure with an inverse distance weighting interpolation. Standard and multilevel Cox survival models were used to assess the association between air pollution and mortality.Measurements and main resultsData for 73,711 subjects who resided in California were abstracted from the American Cancer Society Cancer Prevention II Study cohort, with baseline ascertainment of individual characteristics in 1982 and follow-up of vital status through to 2000. Exposure data were derived from government monitors. Exposure to fine particulate matter, O3, and NO2 was positively associated with ischemic heart disease mortality. NO2 (a marker for traffic pollution) and fine particulate matter were also associated with mortality from all causes combined. Only NO2 had significant positive association with lung cancer mortality.ConclusionsUsing the first individualized exposure assignments in this important cohort, we found positive associations of fine particulate matter, O3, and NO2 with mortality. The positive associations of NO2 suggest that traffic pollution relates to premature death.