Lymphocyte radiosensitivity in BRCA1 and BRCA2 mutation carriers and implications for breast cancer susceptibility

There is conflicting evidence as to whether individuals who are heterozygous for germ-line BRCA1 or BRCA2 mutations have an altered phenotypic cellular response to irradiation. To investigate this, chromosome breakage and apoptotic response were measured after irradiation in peripheral blood lymphocytes from 26 BRCA1 and 18 BRCA2 mutation carriers without diagnosed breast cancer, and 38 unaffected age, ethnically and sex-matched controls. To assess the role of BRCA1 and BRCA2 in homologous recombination, an S phase enrichment chromosome breakage assay was used. BrdUrd incorporation studies allowed verification of the correct experimental settings. We found that BRCA1 mutation carriers without cancer had increased chromosome breaks as well as breaks and gaps per cell post irradiation using the classical G2 assay (p = 0.01 and 0.004, respectively) and the S phase enrichment assay (p = 0.01 and 0.01, respectively) compared to age-matched unaffected controls. BRCA2 mutation carriers without cancer had increased breaks as well as breaks and gaps per cell post irradiation using the S phase enrichment assay (p = 0.045 and 0.012, respectively). No difference was detected using the G2 assay (p = 0.88 and 0.40 respectively). BRCA1 and BRCA2 mutation carriers had normal cell cycle kinetics and apoptotic response to irradiation compared to age-matched controls. Our results show a demonstrable impairment in irradiation induced DNA repair in women with heterozygous germline BRCA1 and BRCA2 mutations prior to being diagnosed with breast cancer.     

What do we know about partnership with service users and carers in social work education and how robust is the evidence base?

Partnership work with service users and carers in social work education is a policy requirement, and it is also central to the anti-oppressive and rights-based values of social work. This paper reports research findings which are drawn from an educational context, but are also relevant to the wider field of health and social care. The research team undertook a systematic knowledge review using the Evidence for Policy and Practice Information and Coordinating Centre system, which had been used in health and education, but which had not previously been used in social care and social work. This involved an extensive search of electronic databases and rigorous screening to identify studies which had sufficient relevance to be subjected to detailed analysis. The research team also undertook a practice survey of the teaching, learning and assessment of partnership in prequalifying programmes in England, Wales and Northern Ireland. This involved three stages: a document search; telephone interviews; and focus groups held with students, academic staff, and service users and carers. Throughout the research process, the interdisciplinary team was advised and supported by a stakeholder group which consisted of service users and carers, students, and employer representatives. In the second part of the paper, subsequent discussion explores key findings from the research, including the disputed nature of the concept of partnership, models of partnership work within social work education and the dearth of research on partnership outcomes. Five related questions are identified as a means of interrogating the robustness of the research process and findings. The paper concludes by arguing for work to be done to theorise partnership, and to develop effective strategies for improving the quality of partnership working in education, and health and social care practice.     

SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention.     

Dacomitinib‐induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats

Dacomitinib—an irreversible pan‐ErbB tyrosine kinase inhibitor (TKI)—causes diarrhoea in 75% of patients. Dacomitinib‐induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in‐vitro and in‐vivo model of dacomitinib‐induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1‐4 μM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays. Rats were treated with 7.5 mg/kg dacomitinib daily via oral gavage for 7 or 21 days (n = 6/group). Weights, and diarrhoea incidence were recorded daily. Rats were administered FITC‐dextran 2 hr before cull, and serum levels of FITC‐dextran were measured and serum biochemistry analysis was conducted. Detailed histopathological analysis was conducted throughout the gastrointestinal tract. Gastrointestinal expression of ErbB1, ErbB2 and ErbB4 was analysed using RT‐PCR. The ileum and the colon were analysed using multiplex for expression of various cytokines. T84 cells treated with dacomitinib showed no alteration in TEER or cell viability. Rats treated with dacomitinib developed severe diarrhoea, and had significantly lower weight gain. Further, dacomitinib treatment led to severe histopathological injury localised to the ileum. This damage coincided with increased levels of MCP1 in the ileum, and preferential expression of ErbB1 in this region compared to all other regions. This study showed dacomitinib induces severe ileal damage accompanied by increased MCP1 expression, and gastrointestinal permeability in rats. The histological changes were most pronounced in the ileum, which was also the region with the highest relative expression of ErbB1.     

Computer use and carpal tunnel syndrome: a 1-year follow-up study

Context  Computer use is increasingly common among many working populations, and concern exists about possible adverse effects of computer use, such as carpal tunnel syndrome (CTS). Objectives  To estimate the prevalence and incidence of possible CTS and to evaluate the contribution of use of mouse devices and keyboards to the risk of possible CTS. Design and Setting  A 1-year follow-up study with questionnaires conducted in 2000 and 2001 at 3500 workplaces in Denmark, followed on each of the 2 occasions by a clinical interview on symptom distribution and frequency. Participants  The questionnaire was sent to 9480 members of a trade union, with an initial response rate of 73% (n = 6943), and 82% (n = 5658) at follow-up. Main Outcome Measures  At baseline, there were 3 outcome measures: tingling/numbness in the right hand once a week or more as reported in the questionnaire; tingling, numbness, and pain in the median nerve in the right hand confirmed by clinical interview; and tingling, numbness, and pain in the median nerve in the right hand at night confirmed by clinical interview. At 1 year of follow-up the main outcome of interest was onset of symptoms among participants who had no or minor symptoms at baseline. Results  The overall self-reported prevalence of tingling/numbness in the right hand at baseline was 10.9%. The interview confirmed that prevalence of tingling/numbness in the median nerve was 4.8%, of which about one third, corresponding to a prevalence of 1.4%, experienced symptoms at night. Onset of new symptoms in the 1-year follow-up was 5.5%. In the cross-sectional comparisons and in the follow-up analyses, there was an association between use of a mouse device for more than 20 h/wk and risk of possible CTS but no statistically significant association with keyboard use. Conclusions  The occurrence of possible CTS in the right hand was low. The study emphasizes that computer use does not pose a severe occupational hazard for developing symptoms of CTS.