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McGrath-Morrow S.A.,Johns Hopkins University | Lee S.,Johns Hopkins University | Gibbs K.,Johns Hopkins University | Lopez A.,Johns Hopkins University | And 5 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2015

Neonates and infants have a higher morbidity and mortality associated with lower respiratory tract illnesses compared with older children. To identify age-related and longitudinal differences in the cellular immune response to acute lung injury (ALI), neonatal and juvenile mice were given Escherichia coli LPS using a novel, minimally invasive aspiration technique. Neonatal and juvenile mice received between 3.75 and 7.5 mg/kg LPS by intrapharyngeal aspiration. Airway and lung cells were isolated and characterized by flow cytometry, cytokine/chemokine mRNA expression from lung homogenates was quantified, and lung morphometry and injury scores were performed. LPS-treated neonatal mice underwent adoptive transfer with adult T regulatory cells (Tregs). After LPS aspiration, lung monocytes isolated from neonatal mice had a predominant M2 phenotype, whereas lung monocytes from juvenile mice displayed a mixed M1/M2 phenotype. At 72 hours after LPS exposure, neonatal lungs were slower to resolve inflammation and expressed lower mRNA levels of CCL2, CCL5, CXCL10, and IL-10. Juvenile, but not neonatal, mice demonstrated a significant increase in airway Tregs after LPS exposure. Adoptive transfer of adult Tregs into LPS-challenged neonatal mice resulted in reduced lung inflammation and improved weight gain. These findings underscore several vulnerabilities in the neonatal immune response to LPS-induced ALI. Most striking was the deficiency in airway Tregs after LPS aspiration. Adoptive transfer of adult Tregs mitigated LPS-induced ALI in neonatal mice, highlighting the importance of age-related differences in Tregs and their response to ALI during early postnatal development. Copyright © 2015 by the American Thoracic Society. Source


Vendrame E.,University of California at Los Angeles | Hussain S.K.,University of California at Los Angeles | Breen E.C.,University of California at Los Angeles | Magpantay L.I.,University of California at Los Angeles | And 6 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2014

Background: HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDSNHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood. Methods: In this study, serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1 to 5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV{thorn} controls from the Multicenter AIDS Cohort Study (MACS). Results: Multivariate analyses revealed that serum levels of immunoglobulin free light chains (FLC), interleukin (IL)-6, IL-10, IP-10/CXCL10, neopterin, and TNF-A were elevated in those HIV{thorn} individuals who went on to develop AIDS-NHL. In addition, the fraction of specimens with detectable IL-2 was increased and the fraction with detectable IL-4 was decreased in these subjects. Conclusions: These results suggest that long-term, chronic immune activation, possibly driven by macrophage- produced cytokines, precedes development of NHL in HIV{thorn} individuals. Impact: FLC, IL-6, IL-10, IP-10/CXCL10, neopterin, and TNF-A may serve as biomarkers for AIDS-NHL. © 2013 American Association for Cancer Research. Source


Louie K.S.,Queen Mary, University of London | Louie K.S.,London School of Hygiene and Tropical Medicine | Castellsague X.,Institute Catala dOncologia ICO | Castellsague X.,CIBER ISCIII | And 7 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2011

Background: The independent role of tobacco smoking in invasive cervical cancer (ICC) has been established. We evaluated the potential impact of passive smoking (PS). Methods: A pooled analysis of 1,919 couples enrolled in one of seven case-control studies involving cervical carcinoma in situ (CIS) or ICC was investigated. Information on smoking and sexual behavior was collected from interviews. Specimens were taken from the cervix and penis for human papillomavirus (HPV) DNAtesting. Three PS risk models were constructed with all couples, couples with monogamous women, and couples with lifetime nonsmoking monogamous women. For the third model, the analysis considered potential misclassification of smoking status and was restricted to the risk period for which the woman was exposed to both HPV, a necessary cause of ICC, and PS. Multivariable unconditional logistic regression was used to estimate associations between CIS or ICC and PS. Results: An increased risk was found among couples with both ever smoking men and women (OR = 2.26; 95% CI: 1.40-3.64). No statistically increased risk of CIS was found with PS in the models analyzed. Similar significant increased risks of ICC with PS was found among all couples (OR = 1.57; 95% CI: 1.15-2.15) and couples with monogamous women (OR = 1.55; 95% CI: 1.07-2.23) but not among lifetime nonsmoking monogamous women married to ever smoking men. Conclusion: PS could not be detected as an independent risk factor of ICC in the absence of active smoking. Impact: The combined effects of exposure to active and PS suggest its potential adverse role in cervical carcinogenesis. ©2011 AACR. Source


Herbeck J.T.,University of Washington | Gottlieb G.S.,University of Washington | Winkler C.A.,SAIC | Nelson G.W.,SAIC | And 15 more authors.
Journal of Infectious Diseases | Year: 2010

Background. A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study. Methods. The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters. Results. Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P = 6.23 × 10-7). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 × 10-6). Conclusions. This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-γ expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis. © 2010 by the Infectious Diseases Society of America. All rights reserved. Source


Beachler D.C.,Johns Hopkins Bloomberg | Viscidi R.,Molecular Microbiology and Immunology | Sugar E.A.,Johns Hopkins Bloomberg | Minkoff H.,Maimonides Medical Center | And 9 more authors.
Sexually Transmitted Diseases | Year: 2015

Individuals with human papillomavirus (HPV) infections can develop IgG antibodies to HPV proteins including the L1 capsid and E6 and E7 oncoproteins. Evidence on whether L1 antibodies reduce the risk of cervical HPV infection is mixed, but this has not been explored for oral HPV infections. Antibodies to HPV16's E6 oncoprotein have been detected in some oropharyngeal cancer cases years before cancer diagnosis, but it is unknown if these antibodies are associated with oral HPV16 DNA. METHODS: Enzyme-linked immunosorbent assays tested for serum antibodies to HPV16's L1 capsid in 463 HIV-infected and 293 HIV-uninfected adults, and for antibodies to recombinantly expressed E6 and E7 oncoproteins to HPV16 in 195 HIV-infected and 69 HIV-uninfected cancer-free participants at baseline. Oral rinse samples were collected semiannually for up to 3 years and tested for HPV DNA using PGMY 09/11 primers. Adjusted Poisson, logistic, and Wei-Lin-Weissfeld regression models were used. RESULTS: Human papillomavirus 16 L1 seroreactivity did not reduce the subsequent risk of incident oral HPV16 infection in unadjusted (hazard ratio, 1.4; 95% confidence interval, 0.59-3.3) or adjusted (adjusted hazard ratio = 1.1; 95% confidence interval, 0.41-3.0) analysis. Antibodies to HPV16 E6 and E7 oncoproteins were detected in 7.6% and 3.4% of participants, respectively, but they were not associated with baseline oral HPV16 DNA prevalence or oral HPV16 persistence (each P > 0.40). CONCLUSIONS: Naturally acquired HPV16 L1 antibodies did not reduce the risk of subsequent oral HPV16 infection. Human papillomavirus 16 E6 and E7 seropositivity was not a marker for oral HPV16 infection in this population without HPV-related cancer. Source

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