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Introduction: Increased levels of angiotensin II (Ang II) and activity of Ang II receptor type 1 (AT1R) elicit detrimental effects in cardiovascular disease. However, the role of Ang II receptor type 2 (AT2R) remains poorly defined. Mesenchymal stem cells (MSCs) replenish and repair endothelial cells in the cardiovascular system. Herein, we investigated a novel role of angiotensin signaling in enhancing vascular endothelial growth factor (VEGF)-A-mediated differentiation of MSCs into endothelial cells (ECs). Methods: Bone marrow was aspirated from the femurs of Yucatan microswine. MSCs were extracted via ficoll density centrifugation technique and were strongly immunopositive for MSC markers, CD44, CD90, and CD105, but negative for hematopoietic markers, CD14 and CD45. Subsequently, naïve MSCs were differentiated for 10 days in varying concentrations and combinations of VEGF-A, Ang II, and AT1R or AT2R antagonists. Markers specific to ECs were determined by FACS analysis. Results: AT1R and AT2R expression and cellular localization was demonstrated in MSCs stimulated with VEGF-A and Ang II via quantitative RT-PCR and immunofluorescence, respectively. Differentiation of naïve MSCs in media containing Ang II (2 ng/ml) plus low-dose VEGF-A (2 ng/ml) produced a significantly higher percentage of cells that were positive for expression of EC markers (for example, platelet endothelial cell adhesion molecule, vascular endothelial Cadherin and von Willebrand factor) compared to VEGF-A alone. Ang II alone failed to induce EC marker expression. MSCs differentiated with the combination of Ang II and VEGF-A were capable of forming capillary tubes using an in vitro angiogenesis assay. Induction of EC marker expression was greatly attenuated by co-treatment of Ang II/VEGF-A with the AT2R antagonist PD123319, but not the AT1R antagonist telmisartan. Conclusions: We report the presence of functional AT2R receptor on porcine bone marrow-derived MSCs, where it positively regulates EC differentiation. These findings have significant implications toward therapeutic approaches based on activation of AT2R, which could be a means to stimulate regeneration of damaged endothelium and prevent vascular thrombosis. © 2015 Ikhapoh et al.; licensee BioMed Central. Source

Rainwater-Lovett K.,Johns Hopkins University | Luzuriaga K.,Center for Clinical and Translational Science | Persaud D.,Johns Hopkins University
Current Opinion in HIV and AIDS

Purpose of review: A single case of sustained HIV control in the absence of antiretroviral therapy or HIV-specific immune responses ensued following 18 months of combination antiretroviral therapy initiated at 30h of age in a perinatally HIV-infected child (the Mississippi child). This case provides proof-of-concept that delay in HIV viremic rebound may ensue following very early treatment (VET) in perinatal infection, likely through marked reduction of latent replication-competent HIV reservoirs.Recent findings: The latent HIV reservoir remains the critical barrier to remission. Several studies indicate that the earlier effective combination antiretroviral therapy is initiated, the smaller the size of the HIV reservoir. The unique ability of perinatally infected neonates to initiate VET at the time of birth maximizes the potential benefits of limiting latent reservoir size and permitting reservoir decay, likely lengthening the duration of remission and limiting the capacity for re-establishment of viremia.This article covers the rationale and feasibility of VET to achieve sustained virologic remission in perinatal infection. Recent studies highlighting the effects of VET on biomarkers of HIV persistence in perinatal HIV infection are reviewed as well as implications and challenges for cure research in pediatric populations. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Guan H.-B.,Shenyang University | Wu L.,Center for Clinical and Translational Science | Wu Q.-J.,Shanghai Cancer Institute | Zhu J.,University of Minnesota | Gong T.,Shenyang University

Background: Previous epidemiologic studies have reported inconsistent results between parity and pancreatic cancer (PC) risk. To our knowledge, a comprehensive and quantitative assessment of this association has not been conducted. Methods: Relevant published studies of parity and PC were identified using MEDLINE (PubMed) and Web of Science databases until November 2013. Two authors (H-BG and LW) independently assessed eligibility and extracted data. Eleven prospective and 11 case-control studies reported relative risk (RR) estimates and 95% confidence intervals (CIs) of PC associated with parity. Fixed- and random-effects models were used to estimate the summary RR depending on the heterogeneity of effects. Results: The summary RR for PC comparing the highest versus lowest parity was 0.86 (95% CI: 0.73-1.02; Q = 50.49, P<0.001, I2 = 58.4%). Significant inverse associations were also observed in the studies that adjusted for cigarette smoking (RR = 0.81; 95% CI: 0.68-0.98), Type 2 diabetes mellitus (RR = 0.83; 95% CI: 0.75-0.93), and those that included all confounders or important risk factors (RR = 0.85; 95% CI: 0.76-0.96). Additionally, in the dose-response analysis, the summary RR for per one live birth was 0.97 (95% CI: 0.94-1.01; Q = 62.83, P<0.001, I2 = 69.8%), which also indicated a borderline statistically significant inverse effect of parity on PC risk. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses. Conclusion: In summary, these findings suggest that higher parity is associated with a decreased risk of PC. Future large consortia or pooled studies are warranted to fully adjust for potential confounders to confirm this association. © 2014 Guan et al. Source

Tabibian J.H.,Mayo Medical School | Tabibian J.H.,Center for Clinical and Translational Science | O'Hara S.P.,Mayo Medical School | Lindor K.D.,Arizona State University
Scandinavian Journal of Gastroenterology

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis. PSC generally progresses to liver cirrhosis, is a major risk factor for hepatobiliary and colonic neoplasia, and confers a median survival to death or liver transplantation of only 12 years. Although it is well recognized that approximately 75% of patients with PSC also have inflammatory bowel disease (IBD), the significance of this association remains elusive. Accumulating evidence now suggests a potentially important role for the intestinal microbiota, and enterohepatic circulation of molecules derived therefrom, as a putative mechanistic link between PSC and IBD and a central pathobiological driver of PSC. In this concise review, we provide a summary of and perspectives regarding the relevant basic, translational, and clinical data, which, taken together, encourage further investigation of the role of the microbiota and microbial metabolites in the etiopathogenesis of PSC and as a potential target for novel pharmacotherapies. © 2014 Informa Healthcare. Source

Wu L.,Center for Clinical and Translational Science | Zhu J.,University of Minnesota
Human Reproduction

STUDY QUESTION Is there an association between oral contraceptive (OC) use and thyroid cancer risk in females? SUMMARY ANSWER OC use is inversely associated with the risk of thyroid cancer in females. WHAT IS KNOWN ALREADY OC use may be relevant to the risk of thyroid cancer as suggested by some epidemiological studies. However, the findings are inconsistent regarding the effect direction and size. STUDY DESIGN, SIZE, DURATION This systematic review and meta-analysis included a total of 1906 patients from about 1.3 million individuals who had participated in 9 prospective cohort studies. The follow-up length ranged 7.5-15.9 years. PARTICIPANTS/MATERIALS, SETTING, METHODS PubMed (MEDLINE) was searched through to January 2015 for eligible studies. References of relevant review articles were also manually screened. Prospective cohort studies that evaluated the association between OC use and thyroid cancer risk were included. Study characteristics including patients' characteristics, length of the follow-up and risk estimates were extracted. The quality of the studies was also assessed. MAIN RESULTS AND THE ROLE OF CHANCE The included studies were of high methodological quality according to the Newcastle-Ottawa Quality Assessment Scale. After pooling risk estimates from all the studies, there was a significant inverse association between the longest versus shortest duration of OC use and the risk of thyroid cancer [relative risk (RR) = 0.84, 95% confidence interval (CI) 0.73-0.97], with no considerable heterogeneity (I2 = 26.1%). There was no significant publication bias. The significant association persisted in the subgroup of high-quality studies (RR = 0.84, 95% CI 0.72-0.97). By dose-response analysis, there was a linear relationship (P = 0.0001) between the duration of OC use and thyroid cancer risk. The summary RR for an increment of 1 year of OC use was 0.96 (95% CI 0.94-0.98), with no significant heterogeneity. LIMITATIONS, REASONS FOR CAUTION Individual patient data were unavailable for a more accurate estimation. WIDER IMPLICATIONS OF THE FINDINGS These results indicate that OC use may decrease the risk of thyroid cancer in females. This may have implications for women's decisions regarding the use of OC. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. Source

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