AimsPathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-b1 (TGF-b1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-b1 by inducing a conformational change in the latent complex. The mesenchymal integrins avb5 and avb3 are expressed in the heart, but their role in the activation of TGF-b1 remains elusive. Here, we test whether targeting avb5 and avb3 integrins reduces latent TGF-b1 activation by cardiac fibroblasts with the goal to prevent the formation of a-smooth muscle actin (a-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis. Methods and resultsUsing a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins avb5 and avb3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-b1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-b1 activation by cardiac fibroblast contraction and loss of a-SMA expression, which is restored by adding active TGF-b1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-b1 activation and induction of a-SMA expression. ConclusionsIntegrins avb5 and avb3 both control myofibroblast differentiation by activating latent TGF-b1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-b1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.--

These data can serve as the basis for comparison with pathologic feet for both diagnostic and therapeutic purposes.

Neonatal pulmonary vein banding in piglets recapitulates critical aspects of clinical PVS and highlights a pathologic profile consistent with EndMT, supporting the rationale for evaluating therapeutic strategies designed to exploit reversibility of upstream pulmonary vein pathology.

Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[−]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n = 20/25] versus EBV[−]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E.

Low ALC is a poor prognostic marker in patients with DLBCL and suggests patients' survival benefit from rituximab.

Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza) is a histone deacetylase inhibitor with clinical activity in cutaneous T‐cell lymphoma (CTCL). A phase I trial of oral vorinostat was conducted in Japanese patients with malignant lymphoma. Vorinostat 100 or 200 mg was administered twice daily for 14 consecutive days followed by a 1‐week rest interval. Of 10 patients enrolled, four had follicular lymphoma (FL), two mantle cell lymphoma (MCL), two diffuse large B‐cell lymphoma, and two CTCL (median age, 60 years; median number of prior regimens, 3). Vorinostat was well tolerated up to 200 mg with only one of six patients developing a dose‐limiting toxicity (DLT; Grade 3 anorexia/hypokalemia). Common Grade 3 events were reversible neutropenia (30%), thrombocytopenia, and hypermagnesemia (20% each). The median number of treatment cycles was five (range, 1–36); two patients were continuing treatment. The overall response rate was 40%, with two complete responses/unconfirmed (CRu) and one partial response among FL patients and one CRu among MCL patients. One FL patient maintained CRu for 18.0 months. The median time to achieve CRu among the three patients was 8 months. These data suggest that further investigations of vorinostat in non‐Hodgkin lymphoma, focusing on FL and MCL, are warranted. (Cancer Sci 2009)

Losartan treatment improved PVS-associated pulmonary hypertension and intimal hyperplasia and might be a beneficial prophylactic therapy for patients at high risk of developing PVS after pulmonary vein surgery.

Remote cardioprotection by IPC effluent preserves mitochondrial integrity and function in an adenosine receptor dependent mechanism, and although infarct size reduction can be mimicked by adenosine, IPC effluent contains additional factor(s) contributing to modulation of the mitochondrial response to ischemia/reperfusion injury.