Inhibitors of glioma growth that reveal the tumour to the immune system

Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 ?M or higher.At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step

Clinical nephrology-epidemiology-clinical trials: Determinants of outcome in ANCA-associated glomerulonephritis: A prospective clinico-histopathological analysis of 96 patients

Background. The predictive value of clinical and renal histological features for renal outcome in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis was investigated in a prospective analysis of 96 patients with ANCA-associated vasculitis, and moderate renal involvement (creatinine <500 \uce\ubcmol/L). Methods. The extent of 39 histological features in 96 biopsies (performed at entry in a clinical trial) was scored by two independent observers, according to a standardized protocol. Age, gender, diagnosis, glomerular filtration rate at entry (GFR0), ANCA-specificity, proteinuria, and treatment of these 96 patients were also taken into account. Treatment was standardized and started after the biopsy was performed. Endpoints included renal function at 18 months (GFR18), GFR18 corrected for GFR0 (CORGFR18), and the occurrence of relapse or death. Results. Parameters that most strongly correlated with GFR18 were GFR0 (r = 0.67), interstitial fibrosis (r = -0.45), glomerulosclerosis (r = -0.37), and tubular atrophy (r = -0.36). Parameters that most strongly correlated with CORGFR18 were segmental (r = 0.45) and cellular (r = 0.30) crescents, and fibrinoid necrosis (r = 0.46). None of the clinical and histological features predicted the occurrence of relapse or death. By applying a stepwise linear multiple regression analysis, we designed a formula for the estimation of renal function at 18 months: GFR18 (mL/min) = 17 + 0.71 \uc3\u97 GFR0 (mL/min) + 0.34 \uc3\u97 fibrinoid necrosis (%) + 0.33 \uc3\u97 segmental crescents (%), (r2 = 0.60; standard deviation = 19 mL/min). Our results were independent of diagnosis, ANCA-specificity, and treatment limb. Conclusions. These data suggest that in ANCA-associated glomerulonephritis, GFR0 and predominantly chronic renal lesions are potent predictors of GFR18. Active lesions are associated with renal function recovery and may be reversible. The formula for the estimation of GFR18 shows that a combination of GFR0 and renal histology is a better predictor for GFR18 than GFR0 only