Mechanostimulation of integrin αvβ6 and fibronectin in DCISmyoepithelial cells

PhDAlterations to the tumour microenvironment is a common feature of many cancers, including breast cancer, and there is increasing evidence that alterations to the microenvironment, including; increased integrin expression, ECM deposition and protease activity, promote cancer progression. Most invasive breast cancers arise from a preinvasive stage, ductal carcinoma in situ (DCIS). Previous work in our laboratory has shown the microenvironment of DCIS is altered, such that myoepithelial cells (MECs) switch to a tumour-promoting phenotype, associated with upregulation of integrin αvβ6 and fibronectin (FN) expression. Mechanisms by which integrin αvβ6 and FN expression are regulated is unclear. We show DCIS progression into invasion is accompanied by an increase in MEC expression of integrin αvβ6 and periductal FN deposition, and their expression were associated in DCIS. These findings were modelled in isolated primary DCIS-MECs, primary normal MECs and MEC lines, with and without integrin αvβ6 expression, where integrin αvβ6-positive MECs upregulating FN expression. We identified integrin αvβ6-positive DCIS ducts were larger than integrin αvβ6-negative DCIS ducts, and mechanical stretching of primary normal MECs and a normal MEC line led to upregulation of integrin αvβ6 expression and FN deposition in a TGFβ-dependent manner. We further show upregulation of integrin αvβ6 and FN by MECs mediate TGFβ-dependent upregulation of MMP13 which promotes breast cancer cell invasion in vitro. These data show altered tissue mechanics in DCIS and MEC expression of integrin αvβ6 and FN deposition are linked, and implicate TGFβ in their activation. These findings suggest integrin αvβ6 and FN may be used as markers to stratify DCIS patients

Evidence for Past Subduction Earthquakes at a Plate Boundary with Widespread Upper Plate Faulting: Southern Hikurangi Margin, New Zealand

At the southern Hikurangi margin, New Zealand, we use salt marsh stratigraphy, sedimentology, micropaleontology, and radiocarbon dating to document evidence of two earthquakes producing coseismic subsidence and (in one case) a tsunami over the past 1000 yrs. The earthquake at 520-470 yrs before present (B.P.) produced 0.25 +/- 0.1 m of subsidence at Big Lagoon. The earthquake at 880-800 yrs B.P. produced 0.45 +/- 0.1 m of subsidence at Big Lagoon and was accompanied by a tsunami that inundated >= 360 m inland with a probable height of >= 3.3 m. Distinguishing the effects of upper plate faulting from plate interface earthquakes is a significant challenge at this margin. We use correlation with regional upper plate paleoearthquake chronologies and elastic dislocation modeling to determine that the most likely cause of the subsidence and tsunami events is subduction interface rupture, although the older event may have been a synchronous subduction interface and upper plate fault rupture. The southern Hikurangi margin has had no significant (M > 6.5) documented subduction interface earthquakes in historic times, and previous assumptions that this margin segment is prone to rupture in large to great earthquakes were based on seismic and geodetic evidence of strong contemporary plate coupling. This is the first geologic evidence to confirm that the southern Hikurangi margin ruptures in large earthquakes. The relatively short-time interval between the two subduction earthquakes (similar to 350 yrs) is shorter than in current seismic-hazard models.GNSEQC Biennial ProjectNew Zealand Natural Hazards Research Platform and Foundation for Research Science and TechnologyInstitute for Geophysic

Increasing access to CBT for psychosis patients: a feasibility, randomised controlled trial evaluating brief, targeted CBT for distressing voices delivered by assistant psychologists (GiVE2)

Background: The National Institute for Health and Care Excellence (NICE) recommends that Cognitive Behaviour Therapy for psychosis (CBTp) is offered to all patients with a psychosis diagnosis. However, only a minority of psychosis patients in England and Wales are offered CBTp. This is attributable, in part, to the resource-intensive nature of CBTp. One response to this problem has been the development of CBTp in brief formats that are targeted at a single symptom and the mechanisms that maintain distress. We have developed a brief form of CBTp for distressing voices and reported preliminary evidence for its effectiveness when delivered by highly trained therapists (clinical psychologists). This study will investigate the delivery of this intervention by a cost-effective workforce of assistant psychologists following a brief training and evaluate the acceptability and feasibility of conducting a future, definitive, randomised controlled trial (RCT). Methods: This is a feasibility study for a pragmatic, three-arm, parallel-group, superiority 1:1:1 RCT comparing a Guided self-help CBT intervention for voices and treatment as usual (GiVE) to Supportive Counselling and treatment as usual (SC) to treatment as usual alone (TAU), recruiting across two sites, with blinded post-treatment and follow-up assessments. A process evaluation will quantitatively and qualitatively explore stakeholder experience. Discussion: Expected outcomes will include an assessment of the feasibility of conducting a definitive RCT, and data to inform the calculation of its sample size. If evidence from a subsequent, fully powered RCT suggests that GiVE is clinically and cost-effective when delivered by briefly trained assistant psychologists, CBTp offered in these less resource-intensive forms has the potential to generate benefits for individual patients (reduced distress, enhanced recovery and enhanced quality of life), service-level patient benefit (increased access to evidence-based psychological therapies) and economic benefits to the NHS (in terms of the reduced use of mental health inpatient services). Trial registration: Current Controlled Trials, ISRCTN registration number: 16166070. Registered on 5 February 2019

Developing vocational rehabilitation services for people with long-term neurological conditions : identifying facilitators and barriers to service provision

Purpose: This study aimed to understand existing vocational rehabilitation (VR) service provision in one locality in London (population 3.74 million), identify any gaps and explore reasons for this, to support service development. Method: Using Soft Systems Methodology to guide the research process, semi - structured interviews were completed with nine participants, who were clinicians and managers providing VR within NHS services. Data were analysed thematically to build a ‘rich picture’ and develop a conceptual model of VR service delivery. Findings were then ratified with participants at an engagement event. Results: The findings indicate a spectrum of VR service provision for long - term neurological conditions with differing levels of funding in place. VR often takes place ‘under the radar’ and therefore the true VR needs of this population, and the extent of service provision is not known. There is inconsistency of understanding across the services as to what constitutes VR and outcomes are not routinely measured. Conclusion: For VR services to develop they require appropriate funding, driven by Government policy to commissioners. Clear definitions of VR, collecting and sharing outcome data and effective communication across services are needed at a local level. This is expressed in a conceptual model of VR service delivery

Strongholds of Ostrea edulis populations in estuaries in Essex, SE England and their association with traditional oyster aquaculture: evidence to support a MPA designation

The flat oyster Ostrea edulis has declined significantly in European waters since the 1850s as a result of anthropogenic activity. Ostrea edulis was designated a UK Biodiversity Action Plan Species and Habitat in 1995, and as a Feature of Conservation Importance (FOCI) within the UK Marine & Coastal Access Act 2009. To promote the recovery of oyster beds, a greater understanding of its abundance and distribution is required. Distribution of O. edulis across the proposed Blackwater, Crouch, Roach and Colne MCZ in Essex was determined between 2008 and 2012. Ostrea edulis were present in four estuary zones; with highest sample abundance in the Blackwater and Ray Sand zones. Size structure of populations varied, with the Ray Sand and Colne zones showing a significant lack of individuals with shell height <39 mm. Ostrea edulis occurred in highest number on shell substratum, followed by silty sediments. There were no significant associations between O. edulis abundance or size structure with water column Chl a, suspended solids, oxygen, nitrate or ammonium concentrations, temperature or pH. Highest abundance and most equitable population shell-size distribution for O. edulis were located within, or adjacent to, actively managed aquaculture zones. This suggests that traditional seabed management contributed to the maintenance or recovery of the species of conservation concern. Demonstration that the Essex estuaries were a stronghold for Ostrea edulis in the southern North sea area led to the designation of the Blackwater, Crouch, Roach and Colne estuaries Marine Conservation Zone in 2013

Systematic review of health-related work outcome measures and quality criteria-based evaluations of their psychometric properties

Objective To examine the state of psychometric validation in the health-related work outcome literature. Data Sources We searched PubMed, PubMed Central, CINAHL, Embase (plus Embase Classic), and PsycINFO from inception to January 2016 using the following search terms: stroke, multiple sclerosis, epilepsy, spinal cord injury, brain injury, musculoskeletal disease, work, absenteeism, presenteeism, occupation, employment, job, outcome measure, assessment, work capacity evaluation, scale, and questionnaire. Study Selection From the 22,676 retrieved abstracts, 597 outcome measures were identified. Inclusion was based on content analysis. There were 95 health-related work outcome measures retained; of these, 2 were treated as outliers and therefore are discussed separately. All 6 authors individually organized the 93 remaining scales based on their content. Data Extraction A follow-up search using the same sources, and time period, with the name of the outcome measures and the terms psychometric, reliability, validity, and responsiveness, identified 263 unique classical test theory psychometric property datasets for the 93 tools. An assessment criterion for psychometric properties was applied to each article, and where consensus was not achieved, the rating delivered by most of the assessors was reported. Data Synthesis Of the articles reported, 18 reporting psychometric data were not accessible and therefore could not be assessed. There were 39 that scored 80%. The 3 outcome measures associated with the highest scoring datasets were the Sheehan Disability Scale, the Fear Avoidance Beliefs Questionnaire, and the assessment of the Subjective Handicap of Epilepsy. Finally, only 2 psychometric validation datasets reported the complete set of baseline psychometric properties. Conclusions This systematic review highlights the current limitations of the health-related work outcome measure literature, including the limited number of robust tools available

Similarities and Differences in Theory of Mind Responses of Patients With Anorexia Nervosa With and Without Autistic Features

Theory of Mind (ToM) is the ability to understand and represent mental states of others, a skill that plays a key role in how we interact with people around us. Difficulties with ToM have been posited as an underlying mechanism for autism and implicated in difficulties faced by those with anorexia nervosa (AN). This study examined, both quantitatively and qualitatively, the responses of women between the ages of 14 and 25 years on the Frith-Happé Triangle Animations, a well-validated test of ToM. Participants were split into healthy controls (HCs), AN patients (AN), and AN patients with high levels of autistic features (AN+ASF). We found no significant quantitative differences between groups in performance on the task. Qualitatively, there were differences between groups such that AN patients, especially those in the AN+ASF group, were more focused on describing the videos than creating narratives, were more negative in their interpretations, and were much more anxious about their performance. These qualitative differences have clinical implications, including that not all AN patients with autistic features should be assumed to have difficulties with ToM

Trends in long-term opioid prescribing in primary care patients with musculoskeletal conditions: an observational database study

Long-term opioids may benefit patients with chronic pain but have also been linked to harmful outcomes. In the United Kingdom, the predominant source of opioids is primary care prescription. The objective was to examine changes in the incidence, length, and opioid potency of long-term prescribing episodes for musculoskeletal conditions in UK primary care (2002-2013). This was an observational database study (Clinical Practice Research Datalink, 190 practices). Participants (=18 years) were prescribed an opioid for a musculoskeletal condition (no opioid prescribed in previous 6 months), and issued =2 opioid prescriptions within 90 days (long-term episode). Opioids were divided into short- and long-acting noncontrolled and controlled drugs. Annual incidence of long-term opioid episodes was determined, and for those still in a long-term episode, the percentage of patients prescribed each type 1 to 2 years, and >2 years after initiation. Annual denominator population varied from 1.25 to 1.38 m. A total of 76,416 patients started 1 long-term episode. Annual long-term episode incidence increased (2002-2009) by 38% (42.4-58.3 per 10,000 person-years), remaining stable to 2011, then decreasing slightly to 55.8/10,000 (2013). Patients prescribed long-acting controlled opioids within the first 90 days of long-term use increased from 2002 to 2013 (2.3%-9.9%). In those still in a long-term opioid episode (>2 years), long-acting controlled opioid prescribing increased from 3.5% to 22.6%. This study has uniquely shown an increase in prescribing long-term opioids to 2009, gradually decreasing from 2011 in the United Kingdom. The trend was towards increased prescribing of controlled long-acting opioids and earlier use. Further research into the risks and benefits of opioids is required

Collateral-resistance to estrogen and HER-activated growth is associated with modified AKT, ERα and cell-cycle signaling in a breast cancer model

These studies were supported by grants from Cancer Research UK (C503/A5010 and C1938/A6769).Aim : A model of progressively endocrine-resistant breast cancer was investigated to identify changes that can occur in signaling pathways after endocrine manipulation. Methods : The MCF7 breast cancer model is sensitive to estrogens and anti-estrogens while variant lines previously derived from wild-type MCF7 are either relatively 17β-estradiol (E2)-insensitive (LCC1) or fully resistant to estrogen and anti-estrogens (LCC9). Results : In LCC1 and LCC9 cell lines, loss of estrogen sensitivity was accompanied by loss of growth response to transforming growth factor alpha (TGFα), heregulin-beta and pertuzumab. LCC1 and LCC9 cells had enhanced AKT phosphorylation relative to MCF7 which was reflected in downstream activation of phospho-mechanistic target of rapamycin (mTOR), phospho-S6, and phospho-estrogen receptor alpha Ser167 [ERα(Ser167)]. Both AKT2 and AKT3 were phosphorylated in the resistant cell lines, but siRNA knockdown suggested that all three AKT isoforms contributed to growth response. ERα(Ser118) phosphorylation was increased by E2 and TGFα in MCF7, by E2 only in LCC1, but by neither in LCC9 cells. Multiple alterations in E2-mediated cell cycle control were identified in the endocrine-resistant cell lines including increased expression of MYC, cyclin A1, cyclin D1, cyclin-dependent kinase 1 (CDK1), CDK2, and hyperphosphorylated retinoblastoma protein (ppRb), whereas p21 and p27 were reduced. Estrogen modulated expression of these regulators in MCF7 and LCC1 cells but not in LCC9 cells. Seliciclib inhibited CDK2 activation in MCF7 cells but not in resistant variants; in all lines, it reduced ppRb, increased p53 associated responses including p21, p53 up-regulated modulator of apoptosis (PUMA), and p53 apoptosis-inducing protein 1 (p53AIP1), inhibited growth, and produced G2/M block and apoptosis. Conclusions : Multiple changes occur with progression of endocrine resistance in this model with AKT activation contributing to E2 insensitivity and loss of ERα(Ser118) phosphorylation being associated with full resistance. Cell cycle regulation is modified in endocrine-resistant breast cancer cells, and seliciclib is effective in both endocrine-sensitive and resistant diseases.Publisher PDFPeer reviewe

Toward a comprehensive understanding of intergroup contact: descriptions and mediators of positive and negative contact among majority and minority groups

Positive contact predicts reduced prejudice, but negative contact may increase prejudice at a stronger rate. The current project builds on this work in four ways: establishing an understanding of contact that is grounded in subjective experience, examining the affective mediators involved in the negative contact–prejudice relationship, extending research on the effects of positive and negative contact to minority groups, and examining the contact asymmetry experimentally. Study 1 introduced anger as a mediator of the relationships between positive and negative contact and prejudice among White Americans (N = 371), using a contact measure that reflected the frequency and intensity of a wide range of experiences. Study 2 found a contact asymmetry among Black and Hispanic Americans (N = 365). Study 3 found initial experimental evidence of a contact asymmetry (N = 309). We conclude by calling for a more nuanced understanding of intergroup contact that recognizes its multifaceted and subjective nature