Connexin and pannexin (hemi) channels in the liver

The liver was among the first organs in which connexin proteins have been identified. Hepatocytes harbor connexin32 and connexin26, while non-parenchymal liver cells typically express connexin43. Connexins give rise to hemichannels, which dock with counterparts on adjacent cells to form gap junctions. Both hemichannels and gap junctions provide pathways for communication, via paracrine signaling or direct intercellular coupling, respectively. Over the years, hepatocellular gap junctions have been shown to regulate a number of liver-specific functions and to drive liver cell growth. In the last few years, it has become clear that connexin hemichannels are involved in liver cell death, particularly in hepatocyte apoptosis. This also holds true for hemichannels composed of pannexin1, a connexin-like protein recently identified in the liver. Moreover, pannexin1 hemichannels are key players in the regulation of hepatic inflammatory processes. The current paper provides a concise overview of the features of connexins, pannexins and their channels in the liver.This work was financially supported by the grants of the Agency for Innovation by Science and Technology in Flanders (IWT), the University Hospital of the Vrije Universiteit Brussel-Belgium (Willy Gepts Fonds UZ-VUB), the Fund for Scientific Research - Flanders (FWO grants G009514N and G010214N), the European Research Council (ERC Starting Grant 335476), the University of Sao Paulo-Brazil (USP) and the Foundation for Research Support of the State of Sao Paulo (FAPESP SPEC grant 2013/50420-6)

Etude de mécanismes moléculaires associés à l effet suppresseur de tumeur des connexines 30 et 43

Les jonctions communicantes étant connues pour participer au maintien de l homéostasie tissulaire et leur absence étant une caractéristique des cellules cancéreuses, elles ont été suspectées de jouer un rôle important lors de la carcinogénèse. Cette hypothèse a été renforcée par l effet suppresseur de tumeur qui est fréquemment observé après transfection, dans des cellules tumorales, de gènes codant pour les protéines de structure des jonctions communicantes, les connexines (Cx). Le mécanisme moléculaire responsable de l effet suppresseur de tumeur des connexines n est pas encore élucidé. Nous avons tenté de cerner davantage le rôle tenu par les connexines et plus particulièrement de la connexine 43 (Cx43) dans le contrôle de la prolifération cellulaire par l utilisation de divers modèles.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Etude de mécanismes moléculaires associés à l effet suppresseur de tumeur des connexines 30 et 43

Les jonctions communicantes étant connues pour participer au maintien de l homéostasie tissulaire et leur absence étant une caractéristique des cellules cancéreuses, elles ont été suspectées de jouer un rôle important lors de la carcinogénèse. Cette hypothèse a été renforcée par l effet suppresseur de tumeur qui est fréquemment observé après transfection, dans des cellules tumorales, de gènes codant pour les protéines de structure des jonctions communicantes, les connexines (Cx). Le mécanisme moléculaire responsable de l effet suppresseur de tumeur des connexines n est pas encore élucidé. Nous avons tenté de cerner davantage le rôle tenu par les connexines et plus particulièrement de la connexine 43 (Cx43) dans le contrôle de la prolifération cellulaire par l utilisation de divers modèles.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Fibronectin expression is decreased in metastatic renal cell carcinoma following endostatin gene therapy

Tumor cells induce the disruption of homeostasis between cellular and extracellular compartments to favor tumor progression. The expression of fibronectin (FN), a matrix glycoprotein, is increased in several carcinoma cell types, including renal cell carcinoma (RCC). RCC are highly vascularized tumors and are often amenable to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the modulation of FN gene expression by ES gene therapy in a murine metastatic renal cell carcinoma (mRCC) model. Balb/C mice bearing Renca cells were treated with NIH/3T3-LXSN cells or NIH/3T3-LendSN cells. At the end of the experiment, the ES serum levels were measured, and the FN gene expression was assessed using real-time PCR. The tissue FN was evaluated by western blotting and by immunofluorescence analysis. The ES serum levels in treated mice were higher than those in the control group (P < 0.05). ES treatment led to significant decreases at the FN mRNA (P < 0.001) and protein levels (P < 0.01). Here, we demonstrate the ES antitumor effect that is mediated by down-regulation of FN expression in mRCC. (C) 2012 Elsevier Masson SAS. All rights reserved.FAPESP [2010/18969-0, 2009/12518-9]FAPES

In vitro inhibitory effect of trichostatin A on canine grade 3 mast cell tumor

Mast cell tumor (MCT) is one of the most prevalent neoplasms that affect skin and soft tissue in dogs. Because mast cell tumors present a great variety of clinical appearance and behavior, their treatment becomes a challenge. Trichostatin A (TSA), an antifungal antibiotic, has shown inhibitory effects on the proliferation and induction of apoptosis in various types of cancer cells. In order to evaluate the potential of trichostatin A as a therapeutic drug, cells of grade 3 MCT were cultured and treated with concentrations of 1 nM to 400 nM of TSA. MTT assay and trypan blue exclusion assays were performed to estimate cell growth and cell viability, and cell cycle analysis was evaluated. TSA treatment showed a reduction in numbers of viable cells and an increase of cell death by apoptosis. The cell cycle analysis showed an increase of hypodiploid cells and a reduction of G0/G1 and G2/M -phases. According to these results, trichostatin A may be an interesting potential chemotherapeutic agent for the treatment of canine MCT.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq[140451/2007-2]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP

Fibronectin expression is decreased in metastatic renal cell carcinoma following endostatin gene therapy

Tumor cells induce the disruption of homeostasis between cellular and extracellular compartments to favor tumor progression. the expression of fibronectin (FN), a matrix glycoprotein, is increased in several carcinoma cell types, including renal cell carcinoma (RCC). RCC are highly vascularized tumors and are often amenable to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. in this study, we examined the modulation of FN gene expression by ES gene therapy in a murine metastatic renal cell carcinoma (mRCC) model. Balb/C mice bearing Renca cells were treated with NIH/3T3-LXSN cells or NIH/3T3-LendSN cells. At the end of the experiment, the ES serum levels were measured, and the FN gene expression was assessed using real-time PCR. the tissue FN was evaluated by western blotting and by immunofluorescence analysis. the ES serum levels in treated mice were higher than those in the control group (P < 0.05). ES treatment led to significant decreases at the FN mRNA (P < 0.001) and protein levels (P < 0.01). Here, we demonstrate the ES antitumor effect that is mediated by down-regulation of FN expression in mRCC. (C) 2012 Elsevier Masson SAS. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilUniv São Paulo, Sch Vet Med & Anim Sci, Dept Pathol, São Paulo, BrazilUniv São Paulo, Dept Radiol, São Paulo, BrazilUniv São Paulo, IPEN CNEN, Dept Biotechnol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilFAPESP: 2010/18969-0FAPESP: 2009/12518-9Web of Scienc

Connexin and pannexin (hemi) channels in the liver

The liver was among the first organs in which connexin proteins have been identified. Hepatocytes harbor connexin32 and connexin26, while non-parenchymal liver cells typically express connexin43. Connexins give rise to hemichannels, which dock with counterparts on adjacent cells to form gap junctions. Both hemichannels and gap junctions provide pathways for communication, via paracrine signaling or direct intercellular coupling, respectively. Over the years, hepatocellular gap junctions have been shown to regulate a number of liver-specific functions and to drive liver cell growth. In the last few years, it has become clear that connexin hemichannels are involved in liver cell death, particularly in hepatocyte apoptosis. This also holds true for hemichannels composed of pannexin1, a connexin-like protein recently identified in the liver. Moreover, pannexin1 hemichannels are key players in the regulation of hepatic inflammatory processes. The current paper provides a concise overview of the features of connexins, pannexins and their channels in the liver.status: publishe

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial

Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials. gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14.5%, 95% CI 8.7-22.2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3 . 3 months (IQR 2.2-4.8), and median duration of response was not reached (95% CI 8 . 31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6 . 0 months, 95% CI 4.7-10.9). 20 (17%) of 117 patients reported grade 3-4 treatmentrelated adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment