Role of Fas and granule exocytosis pathways in tumor-infiltrating T lymphocyte-induced apoptosis of autologous human lung-carcinoma cells

We have isolated a cytotoxic T lymphocyte (CTL) clone, Heu161, that reacts specifically with the human autologous lung carcinoma cell line IGR-Heu. We first demonstrated that IGR-Heu lacked Fas-receptor expression and was resistant to CD95-induced apoptosis. To further elucidate the role of Fas in tumor immune surveillance, we have stably transfected IGR-Heu with a Fas-expression vector and isolated CD95-sensitive and -resistant clones. Our data indicated that the resistance of 2 selected Fas-transfected clones to CD95-mediated lysis correlated with down-regulation of caspase-8 or its lack of cleavage and subsequent activation. All Fas transfectants, either sensitive or resistant to anti-Fas agonistic antibody, were as efficiently lysed by the CTL clone as the parental cell line. In addition, neither anti-Fas-blocking antibody nor Fas-Fc molecule inhibited T-cell lysis of Fas-sensitive tumor clone. This cytotoxicity was extracellular Ca(2+)-dependent and abolished in the presence of EGTA, indicating that it was mainly granzyme-mediated. Interestingly, although the caspase inhibitor z-VAD-fmk had no effect on tumor-cell lysis, it efficiently blocked target DNA damage triggered by autologous CTLs via the granule exocytosis pathway, indicating that the latter event was caspase-dependent. The present results suggest that lung carcinoma-specific CTLs use mainly a granule exocytosis-dependent pathway to lyse autologous target cells and that these effectors are able to circumvent alteration of the Fas-triggered intracellular signalling pathway via activation of a caspase-independent cytoplasmic death mechanism.     

Fistules artérioveineuse post-traumatiques des membres : expérience de 26 cas

Introduction

Posttraumatic arteriovenous fistulas are not a rare event in military facilities during periods of armed conflicts, but are seldom seen in the civilian health care system.

Patients and method

We report our approach to the management of 26 cases of posttraumatic limb arteriovenous fistulas colligated from 1996 to 2006.

Results

The main cause of our posttraumatic arteriovenous fistulas is the penetrating traumatism. Arteriography was the mostly used imaging exploration. The treatment was surgical for 24 patients. One case of thrombosis was reported.

Conclusion

Our series of posttraumatic fistulas is characterized by a particularly high rate of penetrating trauma, in which case intervention is the rule. Our study shows that, in our experience, surgical treatment is still a safe and efficient therapeutic attitude.     

Epidemiological and evolutionary characteristics of heart failure in patients with left bundle branch block – A Moroccan center-based study

Background

In patients with heart failure, left bundle branch block (LBBB) seems to be associated with an increased risk of cardiovascular mortality.

Purpose

The purpose of this study is to determine the in-hospital outcome of congestive heart failure patients with LBBB versus those without.

Methods

We conducted a prospective observational study at the Department of Intensive Care and Rhythmology at the Mohammed V Military Hospital of Rabat, where 330 patients were admitted for heart failure between January 2008 and September 2012. Screening out patients with missing data yielded a cohort of 274 patients. Among the 274 patients, only 110 had LBBB and a left ventricular ejection fraction lower than 50%. We randomly selected a subset of 110 patients diagnosed as non-LBBB to ensure a significant statistical comparison between LBBB and non-LBBB patients. We therefore considered two groups in our analysis: 110 heart failure (HF) patients with LBBB and 110 HF patients without LBBB. Patients with incomplete records were excluded.

Results

Male gender was dominant in both groups (82.7% vs. 66.7%, p = 0.005). Patients with LBBB had a higher prevalence of idiopathic dilated cardiomyopathy (39.1% vs. 4.8%, p < 0.001); and a higher prevalence of previous hospitalization for heart failure (64.5% vs. 23.3%, p < 0.001). The left ventricular ejection fraction was significantly lower in the group with LBBB (25.49% vs. 39.53%, p < 0.001). Age, cardiovascular risk factors, rhythmic and thromboembolic complications did not significantly differ. In patients with LBBB, 61.8% received cardiac resynchronization therapy performed both during the index hospital stay (50.9%) and previously (10.9%). Hospital outcome was marked by 20 in-hospital deaths in the group with LBBB and eight deaths in the group without LBBB (p = 0.008).

Conclusion

Our analysis emphasizes increased in-hospital mortality and higher disease severity, over a short period of stay, in heart failure patients with left bundle branch block.     

Diverticulite solitaire du c?lon droit

Diverticula of the right colon are a rare clinical entity. Diverticulitis can occur with these lesions, but the diagnosis is frequently missed as the presentation is similar to that of acute appendicitis and can mimic other acute intraabdominal infections such as cholecystitis. The authors report a case of solitary diverticulitis of the right colon in a young woman, an incidental discovery during surgery for suspected appendicitis, with emphasis on the diagnostic and therapeutic modalities.     

Crosstalk between extrinsic and intrinsic cell death pathways in pancreatic cancer: synergistic action of estrogen metabolite and ligands of death receptor family

2-Methoxyestradiol is a physiologic metabolite of 17beta-estradiol. This orally active compound can inhibit tumor growth or metastasis in tumor models without inducing any clinical sign of toxicity. Our previous studies indicated that 2-methoxyestradiol-mediated apoptosis involves the disappearance of intact 21-kDa Bid protein, cytochrome c release, and predominant procaspase-3 cleavage. Here, using MIA PaCa-2 cells as a model, we investigated whether this estrogen metabolite induces apoptosis by converging two major pathways: the death receptor-mediated extrinsic and the mitochondrial intrinsic pathway. Exogenous expression of dominant-negative caspase-8 or dominant-negative FADD reverts the effect of 2-methoxyestradiol-mediated cell death. In parallel with this observation, Z-IETD-FMK, a cell permeable irreversible inhibitor of caspase-8, can render significant protection against 2-methoxyestradiol-induced apoptosis. RNase protection assay and cell surface receptor analysis by flow cytometry show the up-regulation of members of death receptor family in 2-methoxyestradiol-exposed pancreatic cancer cells. Our mechanistic studies also implicate that oxidative stress precedes 2-methoxyestradiol-mediated c-Jun NH2-terminal kinase activation, leading to elevated Fas level. Because 2-methoxyestradiol is able to trigger death receptor signaling, we were interested in examining the effects of 2-methoxyestradiol and Fas ligand (FasL)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) together on pancreatic cancer cell death. Interestingly, the endogenous angiogenesis inhibitor 2-methoxyestradiol augments FasL/TRAIL-induced apoptosis in these cells. Moreover, the combination of 2-methoxyestradiol and TRAIL reduces the tumor burden in vivo in MIA PaCa-2 tumor xenograft model by caspase-3 activation.