p21Waf1 expression is regulated by nuclear intermediate filament vimentin in neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Human neuroblastoma (NB) cell lines may present with either one of the so-called S-and N-subtypes. We have previously reported a strong correlation between protein expression levels of vimentin, an S-subtype marker, and the p21^Waf1cyclin-dependent kinase inhibitor. We here investigated whether this correlation extend to the mRNA level in NB cell lines as well as in patients' tumors. We also further explored the relationship between expression of vimentin and p21, by asking whether vimentin could regulate p21 expression.</p> <p>Methods</p> <p>Vimentin and p21 mRNA levels in NB cell lines as well as in patients' tumors (<it>n </it>= 77) were quantified using Q-PCR. Q-PCR data obtained from tumors of high risk NB patients (<it>n </it>= 40) were analyzed in relation with the overall survival using the Log-rank Kaplan-Meier estimation. siRNA-mediated depletion or overexpression of vimentin in highly or low expressing vimentin cell lines, respectively, followed by protein expression and promoter activation assays were used to assess the role of vimentin in modulating p21 expression.</p> <p>Results</p> <p>We extend the significant correlation between vimentin and p21 expression to the mRNA level in NB cell lines as well as in patients' tumors. Overall survival analysis from Q-PCR data obtained from tumors of high risk patients suggests that lower levels of p21 expression could be associated with a poorer outcome. Our data additionally indicate that the correlation observed between p21 and vimentin expression levels results from p21 transcriptional activity being regulated by vimentin. Indeed, downregulating vimentin resulted in a significant decrease in p21 mRNA and protein expression as well as in p21 promoter activity. Conversely, overexpressing vimentin triggered an increase in p21 promoter activity in cells with a nuclear expression of vimentin.</p> <p>Conclusion</p> <p>Our results suggest that p21 mRNA tumor expression level could represent a refined prognostic factor for high risk NB patients. Our data also show that vimentin regulates p21 transcription; this is the first demonstration of a gene regulating function for this type III-intermediate filament.</p

Особенности промышленного развития монофункциональных городов Донецкой области

Рассмотрены особенности промышленности моноотраслевых городов Донецкой области. Предлагаются мероприятия по решению проблем их социально-экономического развития.Розглянуто особливості промисловості моногалузевих міст Донецької області. Пропонуються заходи щодо вирішення проблем їх соціально-економічного розвитку.The paper describes the features of the industry in mono-branch cities of Donetsk region. The measures are offered to solve the problems concerning their socio-economic development

European Consensus Statement on Expert Colposcopy

Peer reviewedPublisher PD

The Problematization of Sexuality among Women Living with HIV and a New Feminist Approach for Understanding and Enhancing Women’s Sexual Lives

In the context of HIV, women’s sexual rights and sexual autonomy are important but frequently overlooked and violated. Guided by community voices, feminist theories, and qualitative empirical research, we reviewed two decades of global quantitative research on sexuality among women living with HIV. In the 32 studies we found, conducted in 25 countries and composed mostly of cis-gender heterosexual women, sexuality was narrowly constructed as sexual behaviours involving risk (namely, penetration) and physiological dysfunctions relating to HIV illness, with far less attention given to the fullness of sexual lives in context, including more&nbsp;positive and rewarding experiences such as satisfaction and pleasure. Findings suggest that women experience declines in sexual activity, function, satisfaction, and pleasure following HIV diagnosis, at least for some period. The extent of such declines, however, is varied, with numerous contextual forces shaping women’s sexual well-being. Clinical markers of HIV (e.g., viral load, CD4 cell count) poorly predicted sexual outcomes, interrupting widely held assumptions about sexuality for women with HIV. Instead, the effects of HIV-related stigma intersecting with inequities related to trauma, violence, intimate relations, substance use, poverty, aging, and other social and cultural conditions primarily influenced the ways in which women experienced and enacted their sexuality. However, studies framed through a medical lens tended to pathologize outcomes as individual “problems,” whereas others driven by a public health agenda remained primarily preoccupied with protecting the public from HIV. In light of these findings, we present a new feminist approach for research, policy, and practice toward understanding and enhancing women’s sexual lives—one that affirms sexual diversity; engages deeply with society, politics, and history; and is grounded in women’s sexual rights

Sex in the shadow of HIV:A systematic review of prevalence, risk factors, and interventions to reduce sexual risk-taking among HIVpositive adolescents and youth in sub-Saharan Africa

Background Evidence on sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa is urgently needed. This systematic review synthesizes the extant research on prevalence, factors associated with, and interventions to reduce sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa. Methods Studies were located through electronic databases, grey literature, reference harvesting, and contact with researchers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Quantitative studies that reported on HIV-positive participants (10-24 year olds), included data on at least one of eight outcomes (early sexual debut, inconsistent condom use, older partner, transactional sex, multiple sexual partners, sex while intoxicated, sexually transmitted infections, and pregnancy), and were conducted in sub-Saharan Africa were included. Two authors piloted all processes, screened studies, extracted data independently, and resolved any discrepancies. Due to variance in reported rates and factors associated with sexual risk-taking, meta-analyses were not conducted. Results 610 potentially relevant titles/abstracts resulted in the full text review of 251 records. Forty-two records (n=35 studies) reported one or multiple sexual practices for 13,536 HIV-positive adolescents/youth from 13 sub-Saharan African countries. Seventeen cross-sectional studies reported on individual, relationship, family, structural, and HIV-related factors associated with sexual risk-taking. However, the majority of the findings were inconsistent across studies, and most studies scored Conclusions Sexual risk-taking among HIV-positive adolescents and youth is high, with inconclusive evidence on potential determinants. Few known studies test secondary HIV-prevention interventions for HIV-positive youth. Effective and feasible low-cost interventions to reduce risk are urgently needed for this group.</p

Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II

Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m2 14C-vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168 h after injection or until recovered radioactivity over 24 h was less than 1% of the administered dose (whichever was earlier). Total radioactivity (TRA), vosaroxin and metabolites were studied in all matrices. Results Unchanged vosaroxin was the major species identified in plasma, urine, and feces. N-desmethylvosaroxin was the only circulating metabolite detected in plasma, accounting for <3% of the administered dose. However, in plasma, the combined vosaroxin + N-desmethylvosaroxin AUC0-∞was 21% lower than the TRA AUC0-∞, suggesting the possible formation of protein bound metabolites after 48 h when the concentration-time profiles diverged. The mean recovery of TRA in excreta was 81.3% of the total administered dose; 53.1% was excreted through feces and 28.2% through urine. Conclusions Unchanged vosaroxin was the major compound found in the excreta, although 10 minor metabolites were detected. The biotransformation reactions were demethylation, hydrogenation, decarboxylation and phase II conjugation including glucuronidation

[Cervical screening: toward a new paradigm?]

International audienceOBJECTIVES: Analysis of the trials which compare the virologic testing (HPV testing) and the cytology in the cervical screening. MATERIAL AND METHODS: The MedLine database was consulted using the Keywords: "cervical screening", "pap smear", "liquid based cytology", "HPV testing", "adults", "adolescents", "cervical intraepithelial neoplasia (CIN)", "uterine cervix cancer". Articles were selected according their concern about the debate of the uterine cervix cancer screening in France. RESULTS: The HPV testing seems interesting allowing a decreasing delay in the diagnosis of CIN (more diagnosis of CIN2+ in the first round and less during the second one). But, when the two rounds are added, the number of CIN2+ are identical in the two arms (cytology and HPV testing) in all the trials (except the Italian NTCC trial). A negative HPV testing protects the women much longer than cytology can do: a delay of five years between two rounds seems ideal. The HPV testing alone increases the detection rate of cervical lesions, which could regress spontaneously and may induce an overtreatment, especially in the youngest population: a triage is necessary and the cytology appears to be the best way to select the candidates for colposcopy in case of positive HPV testing and cytology. The HPV infection presents some particularities in adolescent females: for this reason, the HPV testing should not be used in this special population. In vaccinated women, a consensus for the screening is necessary. CONCLUSION: The health care providers in France have to understand the characteristics of the HPV testing: its advantages compared to the cytologic screening are only evident in case of an organization of the screening in France and even in Europe