Publications

XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV-positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain was derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection.

Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.

Vitamin D and its analogs have been suggested to have palliative effects in the cardiovascular system. We have examined the effects of co-administration of the vitamin D receptor agonist, paricalcitol, on the hypertension, cardiac hypertrophy and interstitial fibrosis produced by chronic angiotensin II (AII) infusion. Administration of AII (800ng/kg/min) over a 14-day period resulted in increased blood pressure, myocyte hypertrophy, activation of the hypertrophic fetal gene program (atrial natriuretic peptide, B-type natriuretic peptide and alpha skeletal actin gene expression), increased expression of the pro-hypertrophic modulatory calcineurin inhibitor protein 1 (MCIP 1), and increased fibrosis with augmented procollagen 1 and 3 gene expression. In each case co-administration of paricalcitol (300ng/kg intraperitoneally every 48h) at least partially reversed the AII-dependent effect. These studies demonstrate that the liganded vitamin D receptor possesses potent anti-hypertrophic activity in this non-renin-dependent model of cardiac hypertrophy. The anti-hypertrophic activity appears to be at least partially intrinsic to the cardiac myocyte and may involve suppression of the MCIP 1 protein. This article is part of a Special Issue entitled 'Vitamin D Workshop'.