IL-6 signaling by STAT3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells

BACKGROUND: STAT3 phosphorylation is associated with the neoplastic state in many types of cancer, including prostate cancer. We investigated the role of IL-6 signaling and phosphorylation of STAT3 in 2 rat prostatic epithelial lines. NRP-152 and NRP-154 cells were derived from the same rat prostate, yet the NRP-152 cells are not tumorigenic while the NRP-154 cells are tumorigenic. These lines are believed to represent 2 of the stages in the development of prostate cancer, hyperplasia and neoplasia. Differences in signaling pathways should play a role in the 2 phenotypes, hyperplastic and neoplastic. METHODS: We looked at the phosphorylation state of STAT3 by intracellular flow cytometry, using phospho-specific antibodies to STAT3. We used the same method to examine IL-6 production by the cell lines. We also measured apoptosis by binding of fluorescent annexin V to the cells. RESULTS: Although both cells lines made IL-6 constitutively, phosphorylated-STAT3 was present in untreated NRP-154 cells, but not in NRP-152 cells. Treatment with dexamethasone inhibited the IL-6 production of NRP-152 cells, but enhanced that of NRP-154 cells. Treatment with the JAK2 inhibitor AG490 induced apoptosis in NRP-152, but not NRP-154 cells. CONCLUSIONS: We conclude from these experiments that STAT3 activity plays a role in the phenotype of NRP-154 cell, but not NRP-152 cells. The significance of alternative IL-6 signaling pathways in the different phenotypes of the 2 cell lines is discussed

Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum.

Item does not contain fulltextTopical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated

Multi-drug resistance 1 genetic polymorphism and prediction of chemotherapy response in Hodgkin's Lymphoma

<p>Abstract</p> <p>Background</p> <p>The human multi-drug resistance gene (<it>MDR1</it>), which encodes the major trans-membrane transporter P-glycoprotein (P-gp), was found to be associated with susceptibility to cancer and response to chemotherapy. The C3435T Polymorphism of <it>MDR1 </it>gene was correlated with expression levels and functions of P-gp. Here, we studied the association between <it>MDR1 </it>C3435T polymorphism and susceptibility to Hodgkin lymphoma (HL) and patient's response to ABVD chemotherapy regimen.</p> <p>Methods</p> <p>a total of 130 paraffin embedded tissue samples collected from HL patients were analyzed to identify the C3435T polymorphism. As a control group, 120 healthy subjects were enrolled in the study. The C3435T Polymorphism was genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism.</p> <p>Results</p> <p>these studies revealed that the frequency of T allele was significantly higher in HL patients compared to the controls (P < 0.05). In addition, the frequency of CT and TT genotypes were also significantly higher in HL patients compared to the controls (P < 0.05). No association between C3435T polymorphism and response to ABVD was detected among HL patients (P > 0.05).</p> <p>Conclusions</p> <p>these results suggest that <it>MDR1 </it>C3435T polymorphism might play a role in HL occurrence; however this polymorphism is not correlated with the clinical response to ABVD.</p

Exposure-response relationships and drug interactions of sirolimus

Sirolimus (rapamycin, RAPAMUNE, RAPA) is an immunosuppressive agent used for the prophylaxis of renal allograft rejection and exhibits an immunosuppressive mechanism that is distinct from that for cyclosporine and tacrolimus. The purpose of this manuscript is to discuss the exposure-response relationships and drug interactiosn of sirolimus. The various factors affecting sirolimus whole blood exposure included first-pass extraction, formulation, food, demographics, liver disease, assay method, and interacting drugs. Clinically significant effects caused by food, pediatric age, hepatic impairment, and interacting drugs require recommendations for the safe and efficacious use of sirolimus in renal allograft patients. An exposure-response model based on multivariate logistic regression was developed using the interstudy data from 1832 renal allograft patients. The analysis revealed an increased probability of acute rejection for sirolimus troughs <5 ng/mL, cyclosporine troughs <150 ng/mL, human leukocyte antigen (HLA) mismatches ≥4, and females. The outcomes suggested that individualization of sirolimus doses immediately after transplantation, based on HLA mismatch and sex, would likely decrease the probability of acute rejections in renal allograft recipients who receive concomitant sirolimus, cyclosporine (full-dose), and corticosteroid therapy. Sirolimus is a substrate for both Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) and undergoes extensive first-pass extraction. Drugs that are known to inhibit or induce these proteins may potentially affect sirolimus whole blood exposure. In healthy volunteers, cyclosporine, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampin significantly decreased sirolimus exposure. However, sirolimus whole blood exposure was not affected by acyclovir, atorvastatin, digoxin, ethinyl estradiol/norgestrel, glyburide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and S-(−)verapamil