GLI inhibitors overcome Erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin

Inhibition of hedgehog (Hh) signalling pathway, including its end effector GLI1, can reverse epithelial-to-mesenchymal transition (EMT) which plays an important role in drug resistance of pancreatic cancer cells to Erlotinib (ETB). This study investigated the effect of GLI inhibitors Forskolin (FSK), GANT-61 (GNT), and Arsenic trioxide (ATX) on suppressing the resistance of pancreatic cancer cells to ETB. The effect of GLI inhibitors was evaluated by measuring mRNA expression levels of EMT factors using quantitative RT-PCR. Immunocytochemistry and flow cytometry were used to assess E-cadherin (E-Cad) and GLI1 protein levels. MTT and apoptosis assays were used to evaluate the synergistic effects for the combination treatment of each GLI inhibitor with ETB. Pancreatic cancer cells PANC-1 treated by GNT showed the highest significant reduction in mRNA levels of GLI1 and other EMT pathway genes. Moreover, GNT was able to upregulate E-Cad and downregulate GLI1 proteins, more than FSK, while ATX had no effect. Apoptosis levels of PANC-1 cells following treatment with LD30 concentrations of FSK, GNT, or ATX, showed 57%, 62% and 67%, respectively, in comparison to ETB (～48%). Importantly, combination treatments of ETB with either FSK, GNT, or ATX demonstrated a significant increase in apoptotic cells reaching 61% (ETB?+?FSK), 80% (ETB?+?GNT) or 88% (ETB?+?ATX). FSK did not have much effect on the drug resistance of PANC-1 cells to ETB. However, GNT, but more effectively ATX, were able to reduce the drug resistance of this cell line to ETB.     

Safety and efficacy of drug-eluting stents and bare metal stents in acute coronary syndrome

Compared with medical therapy, percutaneous coronary intervention has been shown to reduce the rates of death and recurrent ischemia in patients presenting with acute coronary syndromes (ACS). In the current interventional era, both drug-eluting stents (DES) and bare-metal stents (BMS) have been widely used, despite the fact that the use of DES in the context of ACS was initially an “off-label” indication and that ACS has been associated with stent thrombosis (ST). In contrast to the wealth of data available for the use of DES in patients with ST-elevation myocardial infarction, data regarding the performance of DES in non–ST-elevation ACS is restricted to a handful of registries with conflicting data. The aim of this review was to summarize the safety and efficacy of DES in the entire spectrum of ACS.     

Defective T-cell Proliferation and IL-2 Production in a Subgroup of Patients with Coronary Artery Disease

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by innate and adaptive immune responses to a variety of microbial and self-antigens. Given the crucial role of adaptive immunity in the pathogenesis of atherosclerosis, this study was performed to investigate the proliferative response of peripheral blood mononuclear cells (PBMC) and interleukin (IL)-2 production in patients with coronary artery disease (CAD). In this study, 25 patients with chronic stable CAD and 25 healthy individuals were investigated. The PBMCs were separated and stimulated with phytohaemagglutinin (PHA). MTT assay was performed to measure cell viability and proliferation. IL-2 concentrations in cell culture supernatants were determined by Enzyme-Linked Immunosorbent Assay. PHA-stimulated cells revealed a significantly increased optical density (OD) in both groups of patients (p=0.004) and controls (p<0.001). However, the patient group showed a significantly lower Stimulation index (SI) (p=0.001). Upon in vitro stimulation with PHA, IL-2 levels were significantly increased in both groups of patients and controls (p<0.001). However, IL-2 concentrations were significantly lower in the patient group (p=0.018). Six patients showed defective IL-2 production, whereas similar finding was not observed in the normal control subjects (p=0.022). PBMCs from patients with coronary artery disease showed defective PHA-induced mitogenesis and IL-2 production. Considering the autoimmune nature of atherosclerosis, decreased IL-2 production may potentially enhance the atherogenic process, leading to spontaneous activation of autoreactive T lymphocytes.     

HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis

Liver steatosis is a main histopathological feature of Hepatitis C (HCV) infection because of genotype 3. Steatosis and/or mechanisms underlying steatogenesis can contribute to hepatocarcinogenesis. The aim of this retrospective study was to assess the impact of infection with HCV genotype 3 on hepatocellular carcinoma (HCC) occurrence in patients with ongoing HCV cirrhosis. Three hundred and fifty-three consecutive patients (193 men, mean age 58 ± 13 years), with histologically proven HCV cirrhosis and persistent viral replication prospectively followed and screened for HCC between 1994 and 2007. Log-rank test and Cox model were used to compare the actuarial incidence of HCC between genotype subgroups. The patients infected with a genotype 3 (n = 25) as compared with those infected with other genotypes (n = 328) had a lower prothrombin activity [78 (interquartile range 60-85) vs 84 (71-195) %, P = 0.03] and higher rate of alcohol abuse (48%vs 29%, P = 0.046). During a median follow-up of 5.54 years [2.9-8.6], 11/25 patients (44%) and 87/328 patients (26%) with a genotype 3 and non-3 genotype, respectively, develop a HCC. HCC incidences were significantly different among the genotype subgroups (P = 0.001). The 5-year occurrence rate of HCC was 34% (95% CI, 1.3-6.3) and 17% (95% CI, 5.7-9.2) in genotype 3 and non-3 genotype groups, respectively (P = 0.002). In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of HCC occurrence [hazard ratio 3.54 (95% CI, 1.84-6.81), P = 0.0002], even after adjustment for prothrombin activity and alcohol abuse [3.58 (1.80-7.13); P = 0.003]. For patients with HCV cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of HCC development.     

The Canadian off-pump coronary artery bypass graft registry: a one-year prospective comparison with on-pump coronary artery bypass grafting

BACKGROUND: The authors sought to examine in-hospital and one-year outcomes of off-pump coronary artery bypass grafting (CABG) and to determine the subgroups of patients most likely to benefit from the off-pump procedure in a regular surgical practice. METHODS: From March 2001 to December 2002, 1657 consecutive patients were treated with off-pump CABG and 1693 consecutive patients were treated with on-pump CABG. Propensity score modelling was performed to control for treatment and selection bias. A propensity-matched analysis was performed to identify factors associated with survival benefit from the off-pump procedure. RESULTS: The mortality was similar postoperatively and at one year after surgery. The rate of stroke was decreased in the off-pump group postoperatively (OR=0.49, 95% CI 0.23 to 1.06) and significantly at one year after surgery (OR=0.49, 95% CI 0.27 to 0.90). A significant reduction in acute renal dialysis and a significant increase in myocardial infarction rates were seen in off-pump patients during the initial hospitalization but these differences disappeared during the follow-up period. The number of grafts completed was significantly lower in off-pump CABG than in on-pump CABG (2.62+/-1.00 versus 3.36+/-0.92, respectively; P<0.001). Hospital length of stay and the percentage of patients who required mechanical ventilation were significantly lower in the off-pump group than in the on-pump group. At one year after surgery, the adjusted rate of coronary angiogram and revascularization was similar between the two groups, and the adjusted rate of self-reported angina and memory status was significantly better in the off-pump CABG group. Almost all subgroups of patients had a neutral effect or a survival benefit with the off-pump technique. CONCLUSIONS: The results from a Canada-wide multicentre registry showed the safety and effectiveness of off-pump CABG in most subgroups of patients in a regular surgical practice.     

Recurrence rates of basal cell carcinoma of the periocular skin: what to do with patients who have positive margins after resection

ObjectiveTo determine the recurrence rates of basal cell carcinoma of the periocular skin in patients who were in the following 3 groups after pathologic analysis: Mohs frozen sections (negative margins); permanent sections with positive tumor margins; and permanent sections with negative tumor margins at the time of primary surgical removal.DesignThe study is a retrospective chart review.ParticipantsWe identified 385 patients who underwent surgery for basal cell carcinoma. The surgery was performed by a single surgeon between January 1, 1995 and January 1, 2005.MethodsThe patients were divided into 3 groups: (i) Mohs frozen sections with margins negative for tumor; (ii) permanent sections with margins negative for tumor; (iii) permanent sections with margins positive for tumor. The recurrence rates of basal cell carcinoma were compared.ResultsThe recurrence-free rate was 92% for the group that had had Mohs frozen-section, 87% for the group that had had permanent sections with negative margins, and 80% for the group that had had permanent sections with positive margins at 170 months follow-up time. We found that the only predictor of recurrence rate was younger age (hazards ratio (HR) = 0.97 95%; CI 0.94, 0.99; p = 0.021).ConclusionsThe results showed a statistically significant difference in the recurrence-free rate in the 3 groups. A minimum of a 3-year follow-up is recommended in patients who have had basal cell carcinomas removed; the average time to recurrence was approximately 3 years.