Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men

Background: Catechol-estrogen metabolites can induce carcinogenesis by acting as endogenous tumor initiators. Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme, is a main metabolic pathway of estrogen detoxification in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphisms and prostate cancer risk. Patients and methods: 129 patients with prostate cancer and 260 healthy controls were included in our study. A(TA)TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. Results: No significant differences were observed between the cancer group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes (P > 0.05). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype (TA(7)/TA(7) vs TA(6)/TA(7) + TA(6)/TA(6)) (P = 0.18). In addition, no association was revealed between UGT1A1 genotype distribution and Gleason score (P = 0.55). Conclusion: Our data suggest that the TA repeat polymorphism of UGT1A1 gene does not seem to alter prostate cancer risk susceptibility in Caucasian men.     

Neuronal differentiation of PC12 cells abolishes the expression of membrane androgen receptors

Sex steroids affect adrenal chromaffin cell function. In the present work, we have examined the expression and functional significance of membrane androgen receptor sites in normal rat adrenal chromaffin cells and in the PC12 rat pheochromocytoma cell line which can differentiate to either a neuronal or to an epithelial phenotype and expresses membrane estrogen receptor sites. Our data are as follows: (a) no cytosolic androgen receptors were found in both normal chromaffin and PC12 cells; (b) both types of chromaffin cells expressed high affinity membrane testosterone binding sites; (c) activation of these sites increased cytosolic Ca²⁺, decreased catecholamine secretion and induced apoptosis; (d) NGF-induced neuronal differentiation of PC12 cells resulted in the suppression of the number of membrane testosterone sites. In conclusion, our data provide evidence for the existence of specific membrane testosterone receptors on adrenal chromaffin cells via which androgens, (some of them originating in the cortex) modulate their function. Neuronal differentiation of chromaffin cells results in a significant attenuation of these effects, via suppression of the expression of membrane androgen receptors suggesting, that the latter are specific for epithelioid chromaffin cells.     

A New Mathematical Model for the Interpretation of Translational Research Evaluating Six CTLA-4 Polymorphisms in High-Risk Melanoma Patients Receiving Adjuvant Interferon

Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP). Previous analyses found no significant differences between the distributions of CTLA-4 polymorphisms in the melanoma population vs. controls, no significant difference in relapse free and overall survivals among patients and no correlation between autoimmunity and specific alleles. We report new analysis of these CTLA-4 genetic profiles, using Network Phenotyping Strategy (NPS). It is graph-theory based method, analyzing the SNP patterns. Application of NPS on CTLA-4 polymorphism captures allele relationship pattern for every patient into 6-partite mathematical graph P. Graphs P are combined into weighted 6-partite graph S, which subsequently decomposed into reference relationship profiles (RRP). Finally, every individual CTLA-4 genotype pattern is characterized by the graph distances of P from eight identified RRP''s. RRP''s are subgraphs of S, collecting equally frequent binary allele co-occurrences in all studied loci. If S topology represents the genetic “dominant model”, the RRP''s and their characteristic frequencies are identical to expectation-maximization derived haplotypes and maximal likelihood estimates of their frequencies. The graph-representation allows showing that patient CTLA-4 haplotypes are uniquely different from the controls by absence of specific SNP combinations. New function-related insight is derived when the 6-partite graph reflects allelic state of CTLA-4. We found that we can use differences between individual P and specific RRPs to identify patient subpopulations with clearly different polymorphic patterns relatively to controls as well as to identify patients with significantly different survival.     

Adherence to Internet-Based and Face-to-Face Cognitive Behavioural Therapy for Depression: A Meta-Analysis

Background

Internet-based cognitive behavioural therapy (iCBT) is an effective and acceptable treatment for depression, especially when it includes guidance, but its treatment adherence has not yet been systematically studied. We conducted a meta-analysis, comparing the adherence to guided iCBT with the adherence to individual face-to-face CBT.

Methods

Studies were selected from a database of trials that investigate treatment for adult depression (see www.evidencebasedpsychotherapies.org), updated to January 2013. We identified 24 studies describing 26 treatment conditions (14 face-to-face CBT, 12 guided iCBT), by means of these inclusion criteria: targeting depressed adults, no comorbid somatic disorder or substance abuse, community recruitment, published in the year 2000 or later. The main outcome measure was the percentage of completed sessions. We also coded the percentage of treatment completers (separately coding for 100% or at least 80% of treatment completed).

Results

We did not find studies that compared guided iCBT and face-to-face CBT in a single trial that met our inclusion criteria. Face-to-face CBT treatments ranged from 12 to 28 sessions, guided iCBT interventions consisted of 5 to 9 sessions. Participants in face-to-face CBT completed on average 83.9% of their treatment, which did not differ significantly from participants in guided iCBT (80.8%, P  =  .59). The percentage of completers (total intervention) was significantly higher in face-to-face CBT (84.7%) than in guided iCBT (65.1%, P < .001), as was the percentage of completers of 80% or more of the intervention (face-to-face CBT: 85.2%, guided iCBT: 67.5%, P  =  .003). Non-completers of face-to-face CBT completed on average 24.5% of their treatment, while non-completers of guided iCBT completed on average 42.1% of their treatment.

Conclusion

We did not find studies that compared guided iCBT and face-to-face CBT in a single trial. Adherence to guided iCBT appears to be adequate and could be equal to adherence to face-to-face CBT.     

Markers of Epithelial to Mesenchymal Transition in Association with Survival in Head and Neck Squamous Cell Carcinoma (HNSCC)

Background

Elucidating the molecular phenotype of cancers with high metastatic potential will facilitate the development of novel therapeutic approaches to the disease. Gene expression profiles link epithelial to mesenchymal transition (EMT) phenotype with high-risk HNSCC. We sought to determine the role of protein biomarkers of EMT in head and neck squamous carcinoma (HNSC) prognosis.

Methods

Protein expression analysis of EGFR, β-catenin and E-cadherin was performed on a cohort of 102 patients with HNSCC recruited between 1992 and 2005 using automated quantitative protein analysis (AQUA). We evaluated associations with clinicopathological parameters and prognosis.

Results

There were 67 patients with primary squamous cell carcinoma of the head and neck in this cohort who met inclusion criteria and for whom we had complete E-cadherin, beta-catenin and EGFR expression data. High E-cadherin expressers had longer 5-year progression-free survival (PFS) compared to those with low E-cadherin (59.7% versus 40.6%, p = 0.04) and overall survival (OS) (69.6% versus 44.3%, p  = 0.05). Kaplan-Meier analysis showed that patients with low beta-catenin-expressing tumors trended toward worse 5-year PFS (p = 0.057). High EGFR expressers had inferior OS compared to low EGFR expressers (27.7% vs. 54%, p = 0.029). In the multivariable analysis context, E-cadherin remained an independent predictor of improved OS (HR = 0.204, 95% CI 0.043 to 0.972, p = 0.046) while EGFR trended towards significance for OS.

Conclusions

The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis.     

Psychotherapies for depression: a network meta‐analysis covering efficacy,acceptability and long‐term outcomes of all main treatment types

The effects of psychotherapies for depression have been examined in several hundreds of randomized trials, but no recent network meta‐analysis (NMA) has integrated the results of these studies. We conducted an NMA of trials comparing cognitive behavioural, interpersonal, psychodynamic, problem‐solving, behavioural activation, life‐review and “third wave” therapies and non‐directive supportive counseling with each other and with care‐as‐usual, waiting list and pill placebo control conditions. Response (50% reduction in symptoms) was the primary outcome, but we also assessed remission, standardized mean difference, and acceptability (all‐cause dropout rate). Random‐effects pairwise and network meta‐analyses were conducted on 331 randomized trials with 34,285 patients. All therapies were more efficacious than care‐as‐usual and waiting list control conditions, and all therapies – except non‐directive supportive counseling and psychodynamic therapy – were more efficacious than pill placebo. Standardized mean differences compared with care‐as‐usual ranged from –0.81 for life‐review therapy to –0.32 for non‐directive supportive counseling. Individual psychotherapies did not differ significantly from each other, with the only exception of non‐directive supportive counseling, which was less efficacious than all other therapies. The results were similar when only studies with low risk of bias were included. Most therapies still had significant effects at 12‐month follow‐up compared to care‐as‐usual, and problem‐solving therapy was found to have a somewhat higher long‐term efficacy than some other therapies. No consistent differences in acceptability were found. Our conclusion is that the most important types of psychotherapy are efficacious and acceptable in the acute treatment of adult depression, with few significant differences between them. Patient preference and availability of each treatment type may play a larger role in the choice between types of psychotherapy, although it is possible that a more detailed characterization of patients with a diagnosis of depression may lead to a more precise matching between individual patients and individual psychotherapies.     

Macaques infected with a CCR5-tropic simian/human immunodeficiency virus (SHIV) develop broadly reactive anti-HIV neutralizing antibodies

The development of anti-human immunodeficiency virus (anti-HIV) neutralizing antibodies and the evolution of the viral envelope glycoprotein were monitored in rhesus macaques infected with a CCR5-tropic simian/human immunodeficiency virus (SHIV), SHIVSF162P4. Homologous neutralizing antibodies developed within the first month of infection in the majority of animals, and their titers were independent of the extent and duration of viral replication during chronic infection. The appearance of homologous neutralizing antibody responses was preceded by the appearance of amino acid changes in specific variable and conserved regions of gp120. Amino acid changes first appeared in the V1, V2, C2, and V3 regions and subsequently in the C3, V4, and V5 regions. Heterologous neutralizing antibody responses developed over time only in animals with sustained plasma viremia. Within 2 years postinfection the breadth of these responses was as broad as that observed in certain patients infected with HIV type 1 (HIV-1) for over a decade. Despite the development of broad anti-HIV-1 neutralizing antibody responses, viral replication persisted in these animals due to viral escape. Our studies indicate that cross-reactive neutralizing antibodies are elicited in a subset of SHIVSF162P4 infected macaques and that their development requires continuous viral replication for extended periods of time. More importantly, their late appearance does not prevent progression to disease. The availability of an animal model where cross-reactive anti-HIV neutralizing antibodies are developed may facilitate the identification of virologic and immunologic factors conducive to the development of such antibodies.