Functional assays to determine the significance of two common XPC 3'UTR variants found in bladder cancer patients

<p>Abstract</p> <p>Background</p> <p><it>XPC </it>is involved in the nucleotide excision repair of DNA damaged by carcinogens known to cause bladder cancer. Individuals homozygous for the variant allele of <it>XPC </it>c.1496C > T (p.Ala499Val) were shown in a large pooled analysis to have an increased bladder cancer risk, and we found two 3'UTR variants, *611T > A and c.*618A > G, to be in strong linkage disequilibrium with c.1496T. Here we determined if these two 3'UTR variants can affect mRNA stability and assessed the impact of all three variants on mRNA and protein expression.</p> <p>Methods</p> <p><it>In vitro </it>mRNA stability assays were performed and mRNA and protein expression measured both in plasmid-based assays and in lymphocytes and lymphoblastoid cell lines from bladder and breast cancer patients.</p> <p>Results</p> <p>The two 3'UTR variants were associated with reduced protein and mRNA expression in plasmid-based assays, suggesting an effect on mRNA stability and/or transcription/translation. A near-significant reduction in XPC protein expression (p = 0.058) was detected in lymphoblastoid cell lines homozygous for these alleles but no differences in mRNA stability in these lines was found or in mRNA or protein levels in lymphocytes heterozygous for these alleles.</p> <p>Conclusion</p> <p>The two 3'UTR variants may be the variants underlying the association of c.1496C > T and bladder cancer risk acting via a mechanism modulating protein expression.</p

In vitro functional effects of XPC gene rare variants from bladder cancer patients

The XPC gene is involved in repair of bulky DNA adducts formed by carcinogenic metabolites and oxidative DNA damage, both known bladder cancer risk factors. Single nucleotide polymorphisms (SNPs) in XPC have been associated with increased bladder cancer risk. Recently, rarer genetic variants have been identified but it is difficult to ascertain which are of functional importance. During a mutation screen of XPC in DNA from 33 bladder tumour samples and matched blood samples, we identified five novel variants in the patients’ germ line DNA. In a case–control study of 771 bladder cancer cases and 800 controls, c.905T>C (Phe302Ser), c.1177C>T (Arg393Trp), c.*156G>A [3′ untranslated region (UTR)] and c.2251-37C>A (in an intronic C>G SNP site) were found to be rare variants, with a combined odds ratio of 3.1 (95% confidence interval 1.0–9.8, P = 0.048) for carriage of one variant. The fifth variant was a 2% minor allele frequency SNP not associated with bladder cancer. The two non-synonymous coding variants were predicted to have functional effects using analytical algorithms; a reduced recruitment of GFP-tagged XPC plasmids containing either c.905T>C or c.1177C>T to sites of 408 nm wavelength laser-induced oxidative DNA damage was found in vitro. c.*156G>A appeared to be associated with reduced messenger RNA stability in an in vitro plasmid-based assay. Although the laser microbeam assay is relevant to a range of DNA repair genes, our 3′ UTR assay based on Green fluorescent protein(GFP) has widespread applicability and could be used to assess any gene. These assays may be useful in determining which rare variants are functional, prior to large genotyping efforts

A Collaborative Filtering Approach for Protein-Protein Docking Scoring Functions

A protein-protein docking procedure traditionally consists in two successive tasks: a search algorithm generates a large number of candidate conformations mimicking the complex existing in vivo between two proteins, and a scoring function is used to rank them in order to extract a native-like one. We have already shown that using Voronoi constructions and a well chosen set of parameters, an accurate scoring function could be designed and optimized. However to be able to perform large-scale in silico exploration of the interactome, a near-native solution has to be found in the ten best-ranked solutions. This cannot yet be guaranteed by any of the existing scoring functions

An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma

: Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered

Security Policies of India, Brazil and South Africa – Regional Security Contexts as Constraints for a Common Agenda

In the course of the last decade, the IBSA states (India, Brazil, South Africa) have increased their weight in the shifting global order, particularly in economic affairs. Can the same be said about the IBSA states' position in the international security hierarchy? After locating the IBSA coalition in the shifting world order, we analyze its member states' willingness and capacity to coordinate their security policies and build a common global security agenda. In addition, we explore the state of and perspectives on bi- and trilateral collaboration initiatives on defense and armaments between India, Brazil and South Africa. A key reason for the mostly modest results of global security agenda coordination and cross-regional defense collaboration is that the prevailing security concerns of each country are located at the regional level. Therefore, the starting point of an assessment of the prospects of IBSA's security cooperation and its potential impact on the strategic global landscape has to be a comparative evaluation of the regional security environments, focusing on overlaps and potential synergies between the national security policies of the three state actors.Im Verlauf der letzten Dekade konnten die IBSA-Staaten (Indien, Brasilien, Südafrika) ihre Position in der sich verschiebenden Weltordnung erheblich verbessern; das gilt insbesondere für ihren Einfluss auf globale Handelsfragen. Lässt sich ein ähnlicher Aufstieg der IBSA-Staaten in der internationalen Sicherheitsordnung konstatieren? Die Autoren verorten die IBSA-Koalition in der sich verschiebenden Weltordnung und analysieren die Bereitschaft und Fähigkeit der drei Staaten, ihre Sicherheitsstrategien zu koordinieren und eine gemeinsame Sicherheitsagenda zu entwerfen. Ferner werden die Bedingungen und Perspektiven biund trilateraler Verteidigungs- und Rüstungszusammenarbeit untersucht. Im Ergebnis zeichnen sich bisher allenfalls anfängliche Bemühungen bei der Zusammenarbeit im Verteidigungssektor und bei der Entwicklung einer globalen Sicherheitsagenda ab. Ausschlaggebend dafür sind die primär auf der regionalen Ebene liegenden Sicherheitsprioritäten der IBSA-Staaten. Die perspektivische Bewertung des potenziellen Einflusses der Staatenkoalition auf globale Sicherheitsfragen erfolgt demnach vor dem Hintergrund der regionalen Sicherheitsstrategien Indiens, Brasiliens und Südafrikas. Dabei stehen mögliche Überschneidungen und Synergien zwischen den regionalen Sicherheitsstrategien im Zentrum des Interesses

The Responsiveness of Married Women's Labor Force Participation to Income and Wages: Recent Changes and Possible Explanations

One contributor to the twentieth century rise in married women's labor force participation was declining responsiveness to husbands' wages and other family income. Now that the rapid rise in married women's participation has slowed and even begun to reverse, this paper asks whether married women's cross-wage elasticities have continued to fall. Using the outgoing rotation group of the monthly Current Population Survey (CPS) and estimating coefficients separately for each year from 1994 through 2006, we find that the decline in responsiveness to husbands' wages has come to an endat least for the time beingand even find evidence of rising responsiveness to husbands' wages. This increase in the cross-wage elasticity of participation occurs largely between 1997 and 2002 and is concentrated among younger women and women with children. We also explore a number of possible explanations for this development. We conclude that declining divorce rates, rising child care costs, and the increasing prevalence of high work hours for high payall of which were more pronounced at the high end of the income distributionalong with rising income inequality may have played a role. Also possible is that some of the decline is an artifact of changes in the tax system and the way income is measured. In addition, we observe some backsliding in attitudes supportive of gender equality in the market and at home, and perhaps a change in lifecycle timing among Generation X women

Window shopping: cinema and the postmodern

Departing from those who define postmodernism in film merely as a visual style or set of narrative conventions, Anne Friedberg develops the first sustained account of the cinema's role in postmodern culture. She explores the ways in which nineteenth-century visual experiences - photography, urban strolling, panorama and diorama entertainments - anticipate contemporary pleasures provided by cinema, video, shopping malls, and emerging "virtual reality" technologies.Comparing the visual practices of shopping, tourism, and film-viewing, Friedberg identifies the experience of "virtual" mobility through time and space as a key determinant of postmodern cultural identity. Evaluating the theories of Jameson, Lyotard, Baudrillard, and others, she adds critical insights about the role of gender and gender mobility in the configurations of consumer culture.A strikingly original work, Window Shopping challenges many of the existing assumptions about what exactly post modern is. This book marks the emergence of a compelling new voice in the study of contemporary culture