Pegylated IFN-α sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1-mediated signaling

Pegylated interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed against melanoma. Interferon regulatory factor-1 (IRF-1) has an important role in the transcriptional regulation of the IFN response, cell cycle and apoptosis. We have studied pIFN-α-induced responses when combined with the chemotherapy agent, vinblastine (VBL), in tumor and endothelial cell lines and the connection to IRF-1 signaling. Levels of IRF-1/IRF-2 protein expression were found to be decreased in tumor versus normal tissues. pIFN-α induced IRF-1 signaling in human melanoma (M14) and endothelial (EA.hy926) cells and enhanced cell death when combined with VBL. Upon combined IFN-α and VBL treatment, p21 expression, poly (ADP-ribose) polymerase cleavage and activated Bak levels were increased in M14 cells. An increase in p21 and cyclin D1 expression occurred in EA.hy926 cells after 6 h of treatment with pIFN-α, which dissipated by 24 h. This biphasic response, characteristic of cellular senescence, was more pronounced upon combined treatment. Exposure of the EA.hy926 cells to pIFN-α was associated with an enlarged, multinucleated, β-galactosidase-positive senescent phenotype. The overall therapeutic mechanism of IFN-α combined with chemotherapy may be due to both direct tumor cell death via IRF-1 signaling and by premature senescence of endothelial cells and subsequent effects on angiogenesis in the tumor microenvironment

Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment

Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome

Attrition in Web-Based Treatment for Problem Drinkers

Background: Web-based interventions for problem drinking are effective but characterized by high rates of attrition. There is a need to better understand attrition rates in order to improve the completion rates and the success of Web-based treatment programs.\ud \ud Objective: The objectives of our study were to (1) examine attrition prevalence and pretreatment predictors of attrition in a sample of open-access users of a Web-based program for problem drinkers, and (2) to further explore attrition data from our randomized controlled trial (RCT) of the Web-based program.Methods\ud Attrition data from two groups of Dutch-speaking problem drinkers were collected: (1) open-access participants enrolled in the program in 2009 (n = 885), and (2) RCT participants (n = 156). Participants were classified as noncompleters if they did not complete all 12 treatment sessions (9 assignments and 3 assessments). In both samples we assessed prevalence of attrition and pretreatment predictors of treatment completion. Logistic regression analysis was used to explore predictors of treatment completion. In the RCT sample, we additionally measured reasons for noncompletion and participants’ suggestions to enhance treatment adherence. The qualitative data were analyzed using thematic analysis.\ud \ud Results: The open-access and RCT group differed significantly in the percentage of treatment completers (273/780, 35.0% vs 65/144, 45%, χ2 1 = 5.4, P = .02). Logistic regression analysis revealed a significant contribution of treatment readiness, gender, education level, age, baseline alcohol consumption, and readiness to change to predict treatment completion. The key reasons for noncompletion were personal reasons, dissatisfaction with the intervention, and satisfaction with their own improvement. The main suggestions for boosting strategies involved email notification and more flexibility in the intervention.\ud \ud Conclusions: The challenge of Web-based alcohol treatment programs no longer seems to be their effectiveness but keeping participants involved until the end of the treatment program. Further research should investigate whether the suggested strategies to improve adherence decrease attrition rates in Web-based interventions. If we can succeed in improving attrition rates, the success of Web-based alcohol interventions will also improve and, as a consequence, their public health impact will increase

A population-based study of fish allergy in the Philippines, Singapore and Thailand

10.1159/000338940International Archives of Allergy and Immunology1594384-390IAAI