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

“I would rather be told than not know” - A qualitative study exploring parental views on identifying the future risk of childhood overweight and obesity during infancy

BACKGROUND: Risk assessment tools provide an opportunity to prevent childhood overweight and obesity through early identification and intervention to influence infant feeding practices. Engaging parents of infants is paramount for success however; the literature suggests there is uncertainty surrounding the use of such tools with concerns about stigmatisation, labelling and expressions of parental guilt. This study explores parents' views on identifying future risk of childhood overweight and obesity during infancy and communicating risk to parents. METHODS: Semi-structured qualitative interviews were conducted with 23 parents and inductive, interpretive and thematic analysis performed. RESULTS: Three main themes emerged from the data: 1) Identification of infant overweight and obesity risk. Parents were hesitant about health professionals identifying infant overweight as believed they would recognise this for themselves, in addition parents feared judgement from health professionals. Identification of future obesity risk during infancy was viewed positively however the use of a non-judgemental communication style was viewed as imperative. 2) Consequences of infant overweight. Parents expressed immediate anxieties about the impact of excess weight on infant ability to start walking. Parents were aware of the progressive nature of childhood obesity however, did not view overweight as a significant problem until the infant could walk as viewed this as a point when any excess weight would be lost due to increased energy expenditure. 3) Parental attributions of causality, responsibility, and control. Parents articulated a high level of personal responsibility for preventing and controlling overweight during infancy, which translated into self-blame. Parents attributed infant overweight to overfeeding however articulated a reluctance to modify infant feeding practices prior to weaning. CONCLUSION: This is the first study to explore the use of obesity risk tools in clinical practice, the findings suggest that identification, and communication of future overweight and obesity risk is acceptable to parents of infants. Despite this positive response, findings suggest that parents' acceptance to identification of risk and implementation of behaviour change is time specific. The apparent level of parental responsibility, fear of judgement and self-blame also highlights the importance of health professionals approach to personalised risk communication so feelings of self-blame are negated and stigmatisation avoided

The ChatGPT Artificial Intelligence Chatbot: How Well Does It Answer Accounting Assessment Questions?

ChatGPT, a language-learning model chatbot, has garnered considerable attention for its ability to respond to users’ questions. Using data from 14 countries and 186 institutions, we compare ChatGPT and student performance for 28,085 questions from accounting assessments and textbook test banks. As of January 2023, ChatGPT provides correct answers for 56.5 percent of questions and partially correct answers for an additional 9.4 percent of questions. When considering point values for questions, students significantly outperform ChatGPT with a 76.7 percent average on assessments compared to 47.5 percent for ChatGPT if no partial credit is awarded and 56.5 percent if partial credit is awarded. Still, ChatGPT performs better than the student average for 15.8 percent of assessments when we include partial credit. We provide evidence of how ChatGPT performs on different question types, accounting topics, class levels, open/closed assessments, and test bank questions. We also discuss implications for accounting education and research

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

Parental beliefs on the early identification of future overweight risk and the development of a scale to assess parental engagement in prevention

Parents play a crucial role in the prevention of child obesity but to date, little is understood regarding their beliefs about overweight and obesity in early childhood and how these may influence receptiveness to engage in preventative interventions. The primary aim of this research project was to identify factors influencing engagement and to develop a new psychometric scale to measure parental engagement in obesity prevention. To address the research aims, a two-phase mixed methods design was employed. In study one, 20 parents of infants under one were individually interviewed, using an inductive and interpretive qualitative approach. Thematic analysis resulted in three themes: 1) the identification of infant overweight and future risk, 2) the consequences of infant overweight status, and 3) parental attributions of causality, responsibility, and control. Study one findings, along with existing research and theory, informed the development of salient constructs for inclusion within a new scale: The Parental Engagement in Obesity Prevention (PEOP) scale. Exploratory factor analysis was performed within a sample of 282 mothers and a stable four-factor solution was identified. Confirmatory factor analysis in a new sample of 446 mothers confirmed the structure and demonstrated acceptable levels of reliability. The PEOP has 19-items and measures four conceptually unique factors influencing parental engagement: fear of judgement about infant weight; perceived consequences of infant overweight; maternal drive to feed; and self-efficacy in identifying infant overweight. The absolute scores from the four subscales indicate that mothers within this study sample did not fear judgement about their infants’ weight and felt confident in recognising if their own infant was or was becoming overweight. However, potential negative influences on engagement included a strong drive to feed their infant and a poor perception of the health consequences and implications of infant overweight. The study provides new insight and a valid and reliable measure of parental engagement. Use of the scale in practice will support identification of parents less likely to engage in prevention so that perceived barriers can be minimised

Asked & Answered: Student Edition Video_April 15, 2020

Video of University of Maine President Joan Ferrini-Mundy\u27s informal virtual town hall session for UMaine and UMM students. Joining President Ferrini-Mundy were Interim Provost Faye Gilbert; Head of Campus Daniel Qualls; Vice Presidents Robert Dana and Kody Varahramyan; UMaine Athletic Director Ken Ralph; Senior Associate Provost Jeff St. John; Associate Vice President for Graduate Studies and Senior Associate Dean Scott Delcourt; UMM Dean of Students and Admissions Marnie Kaler; and UMaine and UMM Student Government Leaders: Bentley Simpson, President UMSG, Inc, Avery Davis, President UMM Student Government, and UMaine Graduate Student Association President Lacey Darling. Also, includes screenshot of webpage regarding the town hall

MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer

Radical radiotherapy and surgery achieve similar cure rates in muscle invasive bladder cancer, but the choice of which treatment would be most beneficial cannot currently be predicted for individual patients. The primary aim of this study was to assess whether expression of any of a panel of DNA damage signalling proteins in tumour samples taken before irradiation could be used as a predictive marker of radiotherapy response, or rather was prognostic. Protein expression of MRE11, RAD50, NBS1, ATM and H2AX was studied by immunohistochemistry in pre-treatment tumour specimens from two cohorts of bladder cancer patients (validation cohort prospectively acquired) treated with radical radiotherapy and one cohort of cystectomy patients. In the radiotherapy test cohort (n=86), low tumour MRE11 expression was associated with worse cancer-specific survival compared with high expression (43.1% versus 68.7% 3 year cause-specific survival, p=0.012) by Kaplan Meier analysis. This was confirmed in the radiotherapy validation cohort (n=93) (43.0% versus 71.2%, p=0.020). However, in the cystectomy cohort (n=88), MRE11 expression was not associated with cancer-specific survival, commensurate with MRE11 being a predictive marker. High MRE11 expression in the combined radiotherapy cohort had a significantly better cancer-specific survival compared with the high expression cystectomy cohort (69.9% vs 53.8% 3 year cause-specific survival, p=0.021). In this validated immunohistochemistry study, MRE11 protein expression was demonstrated and confirmed as a predictive factor associated with survival following bladder cancer radiotherapy, justifying its inclusion in subsequent trial design. MRE11 expression may ultimately allow patient selection for radiotherapy or cystectomy, thus improving overall cure rates