http://hdl.handle.net/10027/7337 Thu, 20 Jun 2013 01:13:46 GMT 2013-06-20T01:13:46Z http://hdl.handle.net/10027/9671 Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis Zhou, Tong; Zhang, Wei; Sweiss, Nadera J.; Chen, Edward S.; Moller, David R.; Knox, Kenneth S.; Ma, Shwu-Fan; Wade, Michael S.; Noth, Imre; Machado, Roberto F.; Garcia, Joe G. N. Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ,20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis. The original version is available through Public Library of Science at DOI: 10.1371/journal.pone.0044818. (c) 2012 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Sat, 01 Sep 2012 05:00:00 GMT http://hdl.handle.net/10027/9671 2012-09-01T05:00:00Z http://hdl.handle.net/10027/8580 Activity of Ca -activated Cl channels contributes to regulating receptor- and store-operated Ca entry in human pulmonary artery smooth muscle cells Yamamura, Aya; Yamamura, Hisao; Zeifman, Amy; Yuan, Jason X-J Intracellular Ca(2+) plays a fundamental role in regulating cell functions in pulmonary arterial smooth muscle cells (PASMCs). A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. [Ca(2+)](cyt) is increased mainly by Ca(2+) release from intracellular stores and Ca(2+) influx through plasmalemmal Ca(2+)-permeable channels. Given the high concentration of intracellular Cl(-) in PASMCs, Ca(2+)-activated Cl(-)(Cl(Ca)) channels play an important role in regulating membrane potential and cell excitability of PASMCs. In this study, we examined whether activity of Cl(Ca) channels was involved in regulating [Ca(2+)](cyt) in human PASMCs via regulating receptor- (ROCE) and store- (SOCE) operated Ca(2+) entry. The data demonstrated that an angiotensin II (100 nM)-mediated increase in [Ca(2+)](cyt) via ROCE was markedly attenuated by the Cl(Ca) channel inhibitors, niflumic acid (100 muM), flufenamic acid (100 muM), and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (100 muM). The inhibition of Cl(Ca) channels by niflumic acid and flufenamic acid significantly reduced both transient and plateau phases of SOCE that was induced by passive depletion of Ca(2+) from the sarcoplasmic reticulum by 10 muM cyclopiazonic acid. In addition, ROCE and SOCE were abolished by SKF-96365 (50 muM) and 2-aminoethyl diphenylborinate (100 muM), and were slightly decreased in the presence of diltiazem (10 muM). The electrophysiological and immunocytochemical data indicate that Cl(Ca) currents were present and TMEM16A was functionally expressed in human PASMCs. The results from this study suggest that the function of Cl(Ca) channels, potentially formed by TMEM16A proteins, contributes to regulating [Ca(2+)](cyt) by affecting ROCE and SOCE in human PASMCs. The original version is available through Medknow Publications at DOI: 10.4103/2045-8932.83447 Fri, 01 Apr 2011 05:00:00 GMT http://hdl.handle.net/10027/8580 2011-04-01T05:00:00Z http://hdl.handle.net/10027/8534 High frequency chest wall oscillation for asthma and chronic obstructive pulmonary disease exacerbations: a randomized sham-controlled clinical trial Mahajan, Amit K.; Diette, Gregory B.; Hatipoğlu, Umur; Bilderback, Andrew; Ridge, Alana; Harris, Vanessa Walker; Dalapathi, Vijay; Badlani, Sameer; Lewis, Stephanie; Charbeneau, Jeff T.; Naureckas, Edward T.; Krishnan, Jerry A. Background: High frequency chest wall oscillation (HFCWO) is used for airway mucus clearance. The objective of this study was to evaluate the use of HFCWO early in the treatment of adults hospitalized for acute asthma or chronic obstructive pulmonary disease (COPD). Methods: Randomized, multi-center, double-masked phase II clinical trial of active or sham treatment initiated within 24 hours of hospital admission for acute asthma or COPD at four academic medical centers. Patients received active or sham treatment for 15 minutes three times a day for four treatments. Medical management was standardized across groups. The primary outcomes were patient adherence to therapy after four treatments (minutes used/60 minutes prescribed) and satisfaction. Secondary outcomes included change in Borg dyspnea score (≥ 1 unit indicates a clinically significant change), spontaneously expectorated sputum volume, and forced expired volume in 1 second. Results: Fifty-two participants were randomized to active (n = 25) or sham (n = 27) treatment. Patient adherence was similarly high in both groups (91% vs. 93%; p = 0.70). Patient satisfaction was also similarly high in both groups. After four treatments, a higher proportion of patients in the active treatment group had a clinically significant improvement in dyspnea (70.8% vs. 42.3%, p = 0.04). There were no significant differences in other secondary outcomes. Conclusions: HFCWO is well tolerated in adults hospitalized for acute asthma or COPD and significantly improves dyspnea. The high levels of patient satisfaction in both treatment groups justify the need for sham controls when evaluating the use of HFCWO on patient-reported outcomes. Additional studies are needed to more fully evaluate the role of HFCWO in improving in-hospital and post-discharge outcomes in this population. © 2011 Mahajan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1186/1465-9921-12-120 Sat, 10 Sep 2011 05:00:00 GMT http://hdl.handle.net/10027/8534 2011-09-10T05:00:00Z http://hdl.handle.net/10027/8488 Survival in pulmonary arterial hypertension: A brief review of registry data Pauwaa, Sunil; F Machado, Roberto; A Desai, Ankit © 2011 by Medknow Publications, Pulmonary Circulation. DOI:10.4103/2045-8932.87314 Sat, 01 Jan 2011 06:00:00 GMT http://hdl.handle.net/10027/8488 2011-01-01T06:00:00Z