Evidence of key role of Cdk2 overexpression in pemphigus vulgaris

The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc

Evidence of key role of Cdk2 overexpression in pemphigus vulgaris

The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc

ESTREMO/WFXRT: Extreme phySics in the TRansient and Evolving COsmos

We present a mission designed to address two main themes of the ESA Cosmic Vision Programme: the Evolution of the Universe and its Violent phenomena. ESTREMO/WFXRT is based on innovative instrumental and observational approaches, out of the mainstream of observatories of progressively increasing area, i.e.: Observing with fast reaction transient sources, like GRB, at their brightest levels, thus allowing high resolution spectroscopy. Observing and surveying through a X-ray telescope with a wide field of view and with high sensitivity extended sources, like cluster and Warm Hot Intragalactic Medium (WHIM). ESTREMO/WFXRT will rely on two cosmological probes: GRB and large scale X-ray structures. This will allow measurements of the dark energy, of the missing baryon mass in the local universe, thought to be mostly residing in outskirts of clusters and in hot filaments (WHIM) accreting onto dark matter structures, the detection of first objects in the dark Universe, the history of metal formation. The key asset of ESTREMO/WFXRT with regard to the study of Violent Universe is the capability to observe the most extreme objects of the Universe during their bursting phases. The large flux achieved in this phase allows unprecedented measurements with high resolution spectroscopy. The mission is based on a wide field X-ray/hard X-ray monitor, covering >1/4 of the sky, to localize transients; fast (min) autonomous follow-up with X-ray telescope (2000 cm ) equipped with high resolution spectroscopy transition edge (TES) microcalorimeters (2eV resolution below 2 keV) and with a wide field (1°) for imaging with 10" resolution (CCD) extended faint structures and for cluster surveys. A low background is achieved by a 600 km equatorial orbit. The performances of the mission on GRB and their use as cosmological beacons are presented and discussed

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes