359 research outputs found

    Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6

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    The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.This work was supported by (J.-H.L. and J.C.) Wellcome Trust and the Royal Society (107633/Z/15/Z), European Research Council Starting Grant (679411), and the Cambridge Stem Cell Institute Core grant (07922/Z/11/Z) from Wellcome Trust and Medical Research Council; (J.-H.L.) the Hope Funds for Cancer Research; (M.P.) American Lung Association (400553); (A.R.) Howard Hughes Medical Institute, the Klarman Cell Observatory, and NCI grant 1U24CA180922; (A.R., T.T., and T.J.) the Koch Institute Core grant P30-CA14051 from the NCI; (T.T.) the National Cancer InstituteK99 CA187317, the Sigrid Juselius Foundation, the Hope Funds for Cancer Research; (T.J.) a Howard Hughes Medical Institute Investigator, a David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar; and (C.F.K.) R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402, Harvard Stem Cell Institute, Alfred and Gilda Slifka, Gail and Adam Slifka, and the CFMS Fund

    Synergistic Effects of Traffic-Related Air Pollution and Exposure to Violence on Urban Asthma Etiology

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    Background: Disproportionate life stress and consequent physiologic alteration (i.e., immune dysregulation) has been proposed as a major pathway linking socioeconomic position, environmental exposures, and health disparities. Asthma, for example, disproportionately affects lower-income urban communities, where air pollution and social stressors may be elevated. Objectives: We aimed to examine the role of exposure to violence (ETV), as a chronic stressor, in altering susceptibility to traffic-related air pollution in asthma etiology. Methods: We developed geographic information systems (GIS)–based models to retrospectively estimate residential exposures to traffic-related pollution for 413 children in a community-based pregnancy cohort, recruited in East Boston, Massachusetts, between 1987 and 1993, using monthly nitrogen dioxide measurements for 13 sites over 18 years. We merged pollution estimates with questionnaire data on lifetime ETV and examined the effects of both on childhood asthma etiology. Results: Correcting for potential confounders, we found an elevated risk of asthma with a 1-SD (4.3 ppb) increase in NO2 exposure solely among children with above-median ETV [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.14–2.33)]. Among children always living in the same community, with lesser exposure measurement error, this association was magnified (OR = 2.40; 95% CI, 1.48–3.88). Of multiple exposure periods, year-of-diagnosis NO2_2 was most predictive of asthma outcomes. Conclusions: We found an association between traffic-related air pollution and asthma solely among urban children exposed to violence. Future studies should consider socially patterned susceptibility, common spatial distributions of social and physical environmental factors, and potential synergies among these. Prospective assessment of physical and social exposures may help determine causal pathways and critical exposure periods

    Evaluation of Treatment-Related Mortality Among Paediatric Cancer Deaths: a population based analysis.

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    BACKGROUND: Objectives were to describe the proportion of deaths due to treatment-related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort. METHODS: We included children with cancer ⩽18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described. RESULTS: Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0-18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage. CONCLUSIONS: TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients

    $1.25 Trillion is Still Real Money: Some Facts About the Effects of the Federal Reserve’s Mortgage Market Investments

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    This paper measures the effects on the primary U.S. mortgage market of the large-scale asset purchase (LSAP) program in which the Federal Reserve bought $1.25 trillion of mortgagebacked securities in 2009 and 2010. We use an event-study approach and measure the movements in both prices and quantities around the initial announcement of the LSAP and subsequent changes to the program. We use a new dataset to document the changes in the menu of rates and points offered to borrowers and show that there was wide dispersion in the rate changes generated by the announcement of the LSAP program, with some borrowers seeing immediate rate reductions of up to 40 basis points and other borrowers confronting rate increases. We show that the LSAP program led to a substantial boost in market activity, with discontinuous increases in searches, applications and originations for refinance mortgages, but not purchase mortgages. Finally, we show that more creditworthy borrowers were significantly more likely to benefit from the improved credit availability

    TOWARD A COMPREHENSIVE APPROACH TO YOUTH EMPOWERMENT FOR CLIMATE ACTION

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    This brief focuses on empowering the youth to act on climate change and environmental protection by strengthening formal and informal environmental and sustainability education. Environmental education is the foundation for problem recognition and solving. The G20 is in a powerful position to exercise environmental and climate leadership by mandating sustainability and environmental education domestically, regularly tracking environmental and climate literacy internationally, investing in infrastructure and educator training for environmental education, promoting games drawing on real-world problems, developing partnerships for environmental education in local communities, and organizing an annual Youth Summit for Climate, Environment, and Sustainable Development Solutions

    Outcomes of abdominoperineal resection for management of anal cancer in HIV-positive patients: a national case review

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    BACKGROUND: The incidence of anal cancer in human immunodeficiency virus (HIV)-positive individuals is increasing, and how co-infection affects outcomes is not fully understood. This study sought to describe the current outcome disparities between anal cancer patients with and without HIV undergoing abdominoperineal resection (APR). METHODS: A retrospective review of all US patients diagnosed with anal squamous cell carcinoma, undergoing an APR, was performed. Cases were identified using a weighted derivative of the Healthcare Utilization Project’s National Inpatient Sample (2000–2011). Patients greater than 60 years old were excluded after finding a skewed population distribution between those with and without HIV infection. Multivariable logistic regression and generalized linear modeling analysis examined factors associated with postoperative outcomes and cost. Perioperative complications, in-hospital mortality, length of hospital stay, and hospital costs were compared for those undergoing APR with and without HIV infection. RESULTS: A total of 1725 patients diagnosed with anal squamous cell cancer undergoing APR were identified, of whom 308 (17.9 %) were HIV-positive. HIV-positive patients were younger than HIV-negative patients undergoing APR for anal cancer (median age 47 years old versus 51 years old, p < 0.001) and were more likely to be male (95.1 versus 30.6 %, p < 0.001). Postoperative hemorrhage was more frequent in the HIV-positive group (5.1 versus 1.5 %, p = 0.05). Mortality was low in both groups (0 % in HIV-positive versus 1.49 % in HIV-negative, p = 0.355), and length of stay (LOS) (10+ days; 75th percentile of patient data) was similar (36.9 % with HIV versus 29.8 % without HIV, p = 0.262). Greater hospitalization costs were associated with patients who experienced a complication. However, there was no difference in hospitalization costs seen between HIV-positive and HIV-negative patients (p = 0.66). CONCLUSIONS: HIV status is not associated with worse postoperative recovery after APR for anal cancer as measured by length of stay or hospitalization cost. Further study may support APRs to be used more aggressively in HIV-positive patients with anal cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12957-016-0970-x) contains supplementary material, which is available to authorized users
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