Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic

Rooting and vegetative growth of hardwood cuttings of 12 pomegranate (\u3ci\u3ePunica granatum\u3c/i\u3e L.) cultivars

Commercial pomegranate production area has increased substantially in the western hemisphere due to increased consumer interest in the fruit. Low nursery inventory has caused many growers to propagate vegetatively their own trees and the availability of only a few cultivars is believed to have played a role in a lack of diversity in the developing market. ‘Wonderful,’ the industry standard for pomegranate in several countries, has been propagated in the United States for over 100 years, yet there is limited scientific information regarding how to most effectively propagate ‘Wonderful’ and other important cultivars. This research included two experiments. Experiment 1 evaluated rooting percentages and vegetative growth attributes of hardwood cuttings of twelve cultivars (‘Ambrosia,’ ‘Desertnyi,’ ‘Eversweet,’ ‘Golden Globe,’ ‘Green Globe,’ ‘Haku Botan,’ ‘Ki Zakuro,’ ‘Loffani,’ ‘Nochi Shibori,’ ‘Parfianka,’ ‘Phoenicia,’ and ‘Wonderful’) utilizing a basal dip in a gel formulation of 3 g·L−1 indole-3-butyric acid (IBA). Experiment 2 evaluated auxin treatments which consisted of basal dip in water only (control) or a gel formulation of IBA (1.5 g L−1 or 3 g L−1) for hardwood cuttings of ‘Wonderful’ and two cultivars that rooted poorly in Experiment 1: ‘Ambrosia’ and ‘Green Globe.’ Measured response attributes included rooting success percentages, dry root mass, leaf area, plant height, number of shoots, apical shoot growth, total shoot length, branching, stem diameter, and relative chlorophyll content (SPAD value). ‘Wonderful’ and nine other cultivars rooted over 84% of the time using cuttings treated with 3 g L−1 IBA. Differences in plant height and branching could be detected early in production. The effect of IBA concentration on rooting percentage and growth attributes varied among cultivars. Cuttings of ‘Ambrosia’ rooted best with 3 g L−1 IBA versus 0 and 1.5 g L−1 IBA, whereas rooting of cuttings of ‘Green Globe’ was similar among IBA rates. Plants of ‘Wonderful’ had significantly greater leaf area compared to those of ‘Ambrosia’ and ‘Green Globe.’ Stem diameter had no effect on rooting on any cultivar in either experiment. There were significant differences among cultivars in terms of chlorophyll content, with ‘Haku Botan’ and ‘Loffani’ having greener leaves than ‘Eversweet,’ ‘Ambrosia,’ and ‘Desertnyi.

Community pharmacists' views on providing a reproductive health service to women receiving opioid substitution treatment:A qualitative study using the TDF and COM-B

BACKGROUND: The absence of menstruation is common in women who use drugs. This can give a belief that conception is unlikely. When stabilised on Opioid Substitution Treatment (OST), fertility often returns, initially without realisation as ovulation precedes menstruation. This leaves women vulnerable to unplanned pregnancies. Community pharmacists (CPs) are frequently in contact with this patient group through the Supervised Consumption of OST service. This provides a timely opportunity to provide reproductive health (RH) advice. The aim of this study was to investigate pharmacists' views on providing a RH service to women receiving OST. METHODS: Twenty semi-structured interviews based on the Capability-Opportunity-Motivation to Behaviour (COM-B) model and the Theoretical Domains Framework (TDF) were conducted between 2016 and 2017. Data analysis involved deductive coding using the TDF domains. The TDF domains were mapped onto the elements of the COM-B and used in the second step to create the framework and chart the data. The third step involved re-reading and clustering the codes, and inductive themes were generated to explain the data in depth. RESULTS: Nine of the 14 TDF domains, mapped into five elements of the COM-B, were identified. Five inductive themes were generated: 1) The pharmacists' experience and knowledge of reproductive health (RH) needs of women receiving OST, 2) The pharmacists' approach to providing advice, 3) The pharmacists' perception of the relationship with women receiving OST, 4) Social influences, and 5) Environmental factors. Community pharmacists feared causing offense to women receiving OST and described requiring cues as to when the service was needed. Pharmacists' highlighted a power imbalance in the relationship with women receiving OST. This could influence how receptive this patient group would be to pharmacy RH interventions. CONCLUSIONS: CPs' concerns of providing RH service could hinder a proactive service provision. Supporting good rapport and providing a structured consultation would increase the accessibility of such a service

Role-model, reoffer, reward: A thematic analysis and TDF mapping of influences on families’ use of evidence-based vegetable feeding practices

Children's vegetable intake is low, despite benefits for immediate and long-term health. Repeatedly reoffering vegetables, role-modelling consumption, and offering non-food rewards effectively increase children's vegetable acceptance and intake. However, a number of barriers prevent families from reoffering previously-rejected vegetables. This study used the Theoretical Domains Framework (TDF) and the COM-B model of behaviour to explore barriers and enablers to reoffering, role-modelling and offering non-food rewards among parents of 2-4-year-old children. Twenty-five semi-structured interviews were conducted, from which eleven core inductive themes were generated: ‘Child factors’, ‘Eating beliefs’, ‘Effectiveness beliefs’, ‘Past experience’, ‘Current family behaviours’, ‘Harms’, ‘Knowledge’, ‘Need for change’, ‘Parent effort’, ‘Parent values’ and ‘Practical issues’. The codes underpinning these themes were inductively mapped to 11 of the 14 TDF domains, and five of the six COM-B components. Previously-reported influences on families' vegetable feeding practices were confirmed, including concerns about child rejection of foods/meals, cost of vegetables, and food waste. Novel findings included some parents' perceptions that these practices are pressurising, and that certain beliefs/knowledge about children's eating behaviour can provide a “protective mindset” that supports families' perseverance with reoffering over time. Future interventions should be tailored to better reflect the diversity of needs and previous experiences of feeding that families have, with some families likely to find that troubleshooting and further signposting is appropriate for their needs while others might benefit from more persuasive and educational approaches. The mapping of codes to the TDF and COM-B will facilitate the identification of appropriate intervention functions and behaviour change techniques when designing new interventions to support families with increasing their children's vegetable intake

Factors influencing the prescribing behaviour of independent prescriber optometrists:a qualitative study using the Theoretical Domains Framework

Purpose Whilst the number of independent prescriber (IP) optometrists in the United Kingdom is increasing, there is limited evidence describing the experiences of these individuals. The Theoretical Domains Framework (TDF) provides an evidence‐based approach to understand determinants of behaviour. This conceptual framework can enable mapping to the COM‐B behaviour change model and the wider Behaviour Change Wheel to develop interventions to optimise behaviour‐change and healthcare processes more systematically. The study aimed to use the TDF to identify the factors that influence independent prescribing behaviour, and to map these findings to the COM‐B system to elucidate the relevant intervention functions, in order to identify the support required by optometrist prescribers. Methods Using a qualitative design, semi‐structured interviews based on the TDF were undertaken with independent prescriber optometrists. Thematic analysis was used to identify themes inductively, which were then deductively mapped to the TDF and linked to the COM‐B. Results Sixteen participants (9 male, 7 female; median age 45 years, range 28–65 years), based in community (n = 10) and hospital (n = 6) settings, were interviewed. Eleven of the TDF domains were found to influence prescribing behaviour. Findings highlighted the need for good communication with patients (TDF domain: Skills, COM‐B: Capability); confidence (TDF domain: Beliefs about capabilities, COM‐B: Motivation); good networks and relationships with other healthcare professionals, e.g., general practitioners (TDF domain: Social influences, COM‐B: Opportunity; TDF domain: Social/professional role and identity, COM‐B: Motivation); the need for appropriate structure for remuneration (TDF domain: Reinforcement, COM‐B: Motivation; TDF domain: Social/professional role and identity, COM‐B: Motivation) and the provision of professional guidelines (TDF domain: Knowledge, COM‐B: Capability; TDF domain: Environmental context and resources, COM‐B Opportunity). Conclusions Having identified theory‐derived influencers on prescribing decisions by optometrists, the findings can be used to develop a structured intervention, such as a support package to help optimise prescribing by optometrists, with the ultimate goal of eye care quality improvement

Academic performance of third-year medical students learning in rural settings

Investigate the academic performance of medical students in rural and remote discipline rotations by rurality of placement.A retrospective cohort study.Rural and remote clinical placement locations in Queensland, Australia.University of Queensland third-year medical students.In this study, student results for a range of assessments are the main outcome measures with rural area of student placement locations as categorised by the Australian Standard Geographical Classification - Remoteness Areas system the independent variable of interest.There was a significant effect of Australian Standard Geographical Classification - Remoteness Areas of placement on the health project, clinical case presentation, clinical participation assessment and overall grade, after controlling for the potential confounding impact of sex, age, students who attended the rural clinical school, cohort year, rotation during the year and type of health service where students were placed. No significant effect of rural placement level was identified for the written examination, poster or journal of achievement assessments.Medical students' academic achievement is associated with many factors, but this study shows that being placed in remote areas is one factor that either does not impede or can positively influence the learning and academic performance of medical students