FGFR2 amplification in colorectal adenocarcinoma

FGFR2 is recurrently amplified in 5% of gastric cancers and 1%–4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.</jats:p

Victimization and Perpetration Experiences of Adults with Autism

This study aimed to describe the self-reported experiences of childhood and adult victimization and perpetration in adults with autism spectrum conditions (ASC) compared to a matched sample, and how victimization and perpetration are associated with autism-related difficulties. Forty-five adults with ASC and 42 adults without ASC completed questionnaires regarding violence victimization and perpetration, emotion regulation, and sociocommunicative competence. Participants with ASC reported experiencing, as children, more overall victimization; specifically, more property crime, maltreatment, teasing/emotional bullying, and sexual assault by peers, compared to participants without ASC. Participants with ASC also reported experiencing more teasing/emotional bullying in adulthood and greater sexual contact victimization. No significant differences were found between groups on perpetration. Sociocommunicative ability and emotion regulation deficits did not explain the heightened risk for victimization. Individuals with ASC have an increased vulnerability to violence victimization, which speaks to the need for interventions, and proactive prevention strategies.JW was funded by the Chair in ASD Treatment and Care Research, funded by the Canadian Institutes of Health Research in partnership with Kids Brain Health Foundation, Sinneave Family Foundation, CASDA, Autism Speaks Canada and Health Canada, while MF was funded by the Canadian Institutes of Health Research Frederick Banding and Charles Best Canada Graduate Scholarship

Measurement of the Neutron Radius of 208Pb Through Parity-Violation in Electron Scattering

We report the first measurement of the parity-violating asymmetry A_PV in the elastic scattering of polarized electrons from 208Pb. A_PV is sensitive to the radius of the neutron distribution (Rn). The result A_PV = 0.656 \pm 0.060 (stat) \pm 0.014 (syst) ppm corresponds to a difference between the radii of the neutron and proton distributions Rn - Rp = 0.33 +0.16 -0.18 fm and provides the first electroweak observation of the neutron skin which is expected in a heavy, neutron-rich nucleus.Comment: 6 pages, 1 figur

One-year molecular survey of astrovirus infection in turkeys in Poland

The presence of turkey astrovirus (TAstV) was monitored in meat-type turkey flocks in Poland in 2008. Clinical samples (10 individual faecal swabs/flock) from 77 flocks aged 1-19 weeks were collected from different regions of the country. RT-PCR experiments were performed for detection and molecular characterization of TAstV using four sets of primers within the RdRp gene (ORF1b). The prevalence of astrovirus was 34/77 (44.15%) in the flocks tested. TAstV type 2 was associated with 30 of 77 infections (38.9%), either alone or in mixed infections; TAstV type 1 was detected in 9 of 77 flocks (11.6%), either alone or in mixed infections; ANV was detected only in one flock (1.29%) by sequence analysis during this study. Phylogenetic analysis revealed genetic variability in the TAstV strains that were isolated. Some of Polish TAstV-2 strains were genetically related to the North American isolates; however, most of them formed a distinct subgroup of “European” isolates, suggesting their separate origin or evolution. Additionally, due to the high variability of the TAstV sequences, the most suitable method for TAstV typing seems to be sequencing

LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1 -Rac1 pathway

Leucine-rich repeat-containing G protein–coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts, and is highly up-regulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro; however, deletion of LGR5 in stem cells has little or no effect on Wnt/β-catenin signaling or cell proliferation in vivo. Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell–cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell–cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell–cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1–Rac1 pathway to strengthen cell–cell adhesion in normal adult crypt stem cells and colon cancer cells

Making Boards Effective: An Empirical Examination of Board Task Performance

Despite the increasing attention of management scholars to boards of directors, there is still scant evidence on the antecedents of board task performance. The lack of significant results seems to be due to some theoretical and methodological choices followed by scholars, i.e. the almost exclusive reliance on agency theory and the use of demographic data. Following the call for dismantling the fortresses dominating past studies, this paper contributes to opening the \u2018black box\u2019 of boards of directors, developing a conceptual model that considers the impact of board members\u2019 diversity, commitment and critical debate on board task effectiveness in performing its service and control tasks. We collected primary data through a questionnaire survey, and we tested the model controlling for board, firm and industry characteristics. Our findings suggest that (i) the predictors we identified, and particularly the board members\u2019 commitment, are far more important than board demographics to predict board task performance; (ii) firm and industry contexts exert a significant influence on board task performance; (iii) predictors have a different impact on specific sets of tasks. Thus, our findings support the idea that several board characteristics and contingencies at both industry and firm level must be acknowledged in board design

Interaction between non-executive and executive directors in English National Health Service trust boards: an observational study

Research funded by Burdett FoundationBackground National Health Service (NHS) trusts, which provide the majority of hospital and community health services to the English NHS, are increasingly adopting a ‘public firm’ model with a board consisting of executive directors who are trust employees and external non-executives chosen for their experience in a range of areas such as finance, health care and management. In this paper we compare the non-executive directors’ roles and interests in, and contributions to, NHS trust boards’ governance activities with those of executive directors; and examine non-executive directors’ approach to their role in board meetings. Methods Non-participant observations of three successive trust board meetings in eight NHS trusts (primary care trusts, foundation trusts and self-governing (non-foundation) trusts) in England in 2008–9. The observational data were analysed inductively to yield categories of behaviour reflecting the perlocutionary types of intervention which non-executive directors made in trust meetings. Results The observational data revealed six main perlocutionary types of questioning tactic used by non-executive directors to executive directors: supportive; lesson-seeking; diagnostic; options assessment; strategy seeking; and requesting further work. Non-executive board members’ behaviours in holding the executive team to account at board meetings were variable. Non-executive directors were likely to contribute to finance-related discussions which suggests that they did see financial challenge as a key component of their role. Conclusions The pattern of behaviours was more indicative of an active, strategic approach to governance than of passive monitoring or ‘rubber-stamping’. Nevertheless, additional means of maintaining public accountability of NHS trusts may also be required

Transforming Community Health Services for Children and Young People who are Ill : A quasi-experimental evaluation

Background: Children’s community nursing (CCN) services support children with acute, chronic, complex and end-of-life care needs in the community. Objectives: This research examined the impact of introducing and expanding CCN services on quality, acute care and costs. Methods: A longitudinal, mixed-methods, case study design in three parts. The case studies were in five localities introducing or expanding services. Part 1: an interrupted time series (ITS) analysis of Hospital Episode Statistics on acute hospital admission for common childhood illness, and bed-days and length of stay for all conditions, including a subset for complex conditions. The ITS used between 60 and 84 time points (monthly data) depending on the case site. Part 2: a cost–consequence analysis using activity data from CCN services and resource-use data from a subset of families (n = 32). Part 3: in-depth interviews with 31 parents of children with complex conditions using services in the case sites and a process evaluation of service change with 41 NHS commissioners, managers and practitioners, using longitudinal in-depth interviews, focus groups and documentary data. Findings: Part 1: the ITS analysis showed a mixed pattern of impact on acute activity, with the greatest reductions in areas that had rates above the national average before CCN services were introduced and significant reductions in some teams in acute activity for children with complex conditions. Some models of CCN appear to have more potential for impact than others. Part 2: the cost–consequence analysis covered only part of the CCN teams’ activity. It showed some potential savings from reduced admissions and bed-days, but none that was greater than the total cost of the services. Part 3: three localities implemented services as planned, one achieved partial service change and one was not able to achieve any service change. Organisational stability, finance, medical stakeholder support, competition, integration with primary care and visibility influenced the planning and implementation of new and expanded CCN services. Feeling supported to manage their ill child at home was a key outcome of using services for parents. Various service features contributed to this and were important in different ways at different times. Other outcomes included being able to avoid hospital care, enabling the child to stay in school, and getting respite. Although parents judged that care was of high quality when teams enabled them to feel supported, reassured and secure in managing their ill child at home, this did not depend on a constant level of contact from teams. Limitations: Delays in service reconfigurations required adaptation of research activity across sites. Use of administrative data, such as Hospital Episode Statistics, for research purposes is technically difficult and imposed some limitations on both the ITS and the cost–consequence analyses. Conclusions: Large, generic CCN teams that integrate acute admission avoidance for all children with support for children with complex conditions and highly targeted teams for children with complex conditions offer the possibility of supporting children more appropriately at home while also making some difference to acute activity. This possibility remains to be tested further. Future work: Further work should refine the evidence on outcomes of services by looking at outcomes in promising models, value for money and measuring quality-based outcomes. Funding: The National Institute for Health Research Health Services and Delivery Research Programme

Beyond gender diversity: How specific attributes of female directors affect earnings management

We apply the system GMM regression estimation approach to a matched sample of French firms listed on Euronext Paris during the period 2001–2010 in order to investigate the relationship between female directors and earnings management by considering their specific (statutory and demographic) attributes. We first find that the presence of female directors deters managers from managing earnings. However, this finding does not hold when the statutory and demographic attributes of female directors are taken into account, thus showing that the detection and the correction of earnings management require particular competencies and skills. Interestingly, we find that business expertise and audit committee membership are key attributes of female directors that promote the effective monitoring of earnings management. An important implication of our findings is that the decision to appoint women on corporate boards should be based more on their statutory and demographic attributes than on blind implementation of gender quotas. Finally, our supplementary analysis reveals that female CEOs and CFOs are strongly inclined to reduce earnings management