A mutational signature in gastric cancer suggests therapeutic strategies

published_or_final_versio

Measuring the impact and costs of a universal group based parenting programme : protocol and implementation of a trial

Background Sub-optimal parenting is a common risk factor for a wide range of negative health, social and educational outcomes. Most parenting programmes have been developed in the USA in the context of delinquency prevention for targeted or indicated groups and the main theoretical underpinning for these programmes is behaviour management. The Family Links Nurturing Programme (FLNP) focuses on family relationships as well as behaviour management and is offered on a universal basis. As a result it may be better placed to improve health and educational outcomes. Developed in the UK voluntary sector, FLNP is popular with practitioners, has impressed policy makers throughout the UK, has been found to be effective in before/after and qualitative studies, but lacks a randomised controlled trial (RCT) evidence base. Methods/Design A multi-centre, investigator blind, randomised controlled trial of the FLNP with a target sample of 288 south Wales families who have a child aged 2-4 yrs living in or near to Flying Start/Sure Start areas. Changes in parenting, parent child relations and parent and child wellbeing are assessed with validated measures immediately and at 6 months post intervention. Economic components include cost consequences and cost utility analyses based on parental ranking of states of quality of life. Attendance and completion rates and fidelity to the FLNP course delivery are assessed. A nested qualitative study will assess reasons for participation and non-participation and the perceived value of the programme to families. By the end of May 2010, 287 families have been recruited into the trial across four areas of south Wales. Recruitment has not met the planned timescales with barriers including professional anxiety about families entering the control arm of the trial, family concern about video and audio recording, programme facilitator concern about the recording of FLNP sessions for fidelity purposes and delays due to the new UK research governance procedures. Discussion Whilst there are strong theoretical arguments to support universal provision of parenting programmes, few universal programmes have been subjected to randomised controlled trials. In this paper we describe a RCT protocol with quantitative and qualitative outcome measures and an economic evaluation designed to provide clear evidence with regard to effectiveness and costs. We describe challenges implementing the protocol and how we are addressing these

Intramucosal leiomyosarcoma of the stomach following hereditary retinoblastoma in childhood – a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Leiomyosarcomas of the stomach are very rare. At the time of primary diagnosis the tumors are most often in advanced stage and the patients complain of abdominal pain due to large tumor size. Endosonographically, the tumors impress as submucous mass with suspicion to malignancy. Sarcomas following hereditary retinoblastoma in childhood are in generally located in the soft tissue. Structural alterations of the <it>retinoblastoma </it>gene (<it>RB1</it>) seem to be involved in the pathogenesis.</p> <p>Case presentation</p> <p>A 37-year-old german male suffered from reflux disorder. In endoscopic examination a small polypous tumor was detected in the stomach. The resection specimen revealed an intramucosal leiomyosarcoma. At the age of one year, the patient had a retinoblastoma.</p> <p>Conclusion</p> <p>This is the unique report of an intramucosal gastric leiomyosarcoma and the first account of a gastric leiomyosarcoma after retinoblastoma in childhood. A careful clinical follow-up is advised because of increased risk of developing further metachronous malignancies.</p

Sustained Effects of Incredible Years as a Preventive Intervention in Preschool Children with Conduct Problems

The present study evaluated preventive effects of the Incredible Years program for parents of preschool children who were at risk for a chronic pattern of conduct problems, in the Netherlands. In a matched control design, 72 parents of children with conduct problems received the Incredible Years program. These families (intervention group) were compared with 72 families who received care as usual (control group). Two years after termination of the intervention, it appeared that observed and selfrated parenting skills were significantly improved in the intervention group. Likewise, in this group, observed child conduct problems showed sustained intervention effects. The decrease in observed critical parenting mediated the decrease in observed child conduct problems over time. In addition, it appeared that parental influence increased over time

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Experimental infection of dogs with a feline endogenous retrovirus RD-114

<p>Abstract</p> <p>Background</p> <p>The feline endogenous retrovirus RD114 is contained in the genome of cats. The virus may contaminate live canine vaccines based on cultured feline cells. The <it>in vivo </it>infectivity, acute and subacute pathogenicity, and viral proliferation of the RD114 virus were evaluated by experimental infection of dogs.</p> <p>Methods</p> <p>Nine specific pathogen free dogs were divided into three groups, with each group consisting of one female and two male dogs. Dogs were subcutaneously inoculated in the neck with either 1 ml RD114 stock virus (group A), inactivated RD114 virus suspension (group B), or cell culture medium (group C) as a negative control. To assess blood cell counts and biochemical properties, blood samples from each group were collected 5 days before inoculation, just prior to inoculation, and 1, 3, 7 and 10 days post-inoculation.</p> <p>Result</p> <p>During the experimental period of 51 days, none of the dogs inoculated with RD114 virus showed any clinical signs, significant increases in rectal temperature or abnormal blood biochemical characteristics including C-reactive protein when compared with the negative controls. We were not able to re-isolate the RD114 virus from buffy coat cells of group A dogs. Additionally, we could not detect RD114 provirus in the genomic DNA isolated from peripheral blood leukocytes, lymph node, spleen and sternal bone marrow cells.</p> <p>Conclusions</p> <p>Signs of RD114 virus proliferation were not found after subcutaneous infection of dogs. Although the potential risk caused by infection with RD114 virus in dogs could not be assessed in this study, we suspect that RD114 virus has little or no virulence in dogs.</p