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BackgroundThe DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer.MethodsThis feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /−taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures.ResultsDDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13–15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression.ConclusionsThis study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, “cold” tumours may be effective for immune priming.Trial registrationNot applicable (non-interventional study). CRUK Internal Database Number 14232.

Background Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RAS MT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RAS MT advanced CRC patients. Methods In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RAS MT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. Results Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1–21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RAS MT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RAS MT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET -amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline  RAS MT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline  KRAS MT allele frequency. Conclusions Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RAS MT advanced CRC patients. EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

Background/purpose – Cocurricular offerings should appropriately align with academic learning goals to ensure undergraduate students’ development of professional dispositions that lead to civic and career success. This study provides a framework for implementing high impact practices into cocurricular instruction, as well as steps on how to align this instruction to the general educational goals of institutions.Materials/methods – Case study methodology was used to examine university students’ perceptions of the effect a course-embedded service-learning activity had on their development of professional dispositions.Results – University students reported a perceived positive impact of the service-learning activity on their attainment of general education goals. Specifically, they reported positive growth in collaboration skills, community connections, and an understanding of the relevance of these skills as professional dispositions.Conclusion – Leveraging high-impact practices such as service-learning and the first-year experience course to meet the general education goals of an institution is an effective use of cocurricular curriculum design.

Background Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RAS MT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials. Methods In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. Results Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1–21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%). Conclusions PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1–21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RAS MT CRC patients. EudraCT-Number 2014-000463-40

The purpose of this research was to understand faculty mentors’ perspectives on the impact of CPED-aligned methodology courses on doctoral students’ development as scholarly practitioners. This study was a pilot study and exploratory in nature. Methods included distribution of a survey which included Likert items, as well as open-ended questions. The study presents descriptive statistics and thematic analysis of the survey results. Additionally, exemplar DiPs were analyzed to demonstrate alignment with CPED principles. Findings indicated that faculty mentors perceive that the CPED-aligned methods coursework is having a positive impact on students’ learning and development as scholar practitioners. However, areas for growth and continuous improvement were identified. Implications of the research indicate a need for ongoing program assessment and evaluation of the impact of methodological coursework as the institution moves forward in program redesign and improvement. This study also serves as a model for incorporating faculty mentor perspectives in course and program assessment.

The purpose of this research was to understand faculty mentors’ perspectives on the impact of CPED-aligned methodology courses on doctoral students’ development as scholarly practitioners. This study was a pilot study and exploratory in nature. Methods included distribution of a survey which included Likert items, as well as open-ended questions. The study presents descriptive statistics and thematic analysis of the survey results. Additionally, exemplar DiPs were analyzed to demonstrate alignment with CPED principles. Findings indicated that faculty mentors perceive that the CPED-aligned methods coursework is having a positive impact on students’ learning and development as scholar practitioners. However, areas for growth and continuous improvement were identified. Implications of the research indicate a need for ongoing program assessment and evaluation of the impact of methodological coursework as the institution moves forward in program redesign and improvement. This study also serves as a model for incorporating faculty mentor perspectives in course and program assessment.

IntroductionBRCA1 mutation carriers have a significant lifetime risk of breast cancer, with their primary risk-reduction option being bilateral mastectomy. Preclinical work from our laboratory demonstrated that in BRCA1-deficient breast cells, oestrogen and its metabolites are capable of driving DNA damage and subsequent genomic instability, which are well-defined early events in BRCA1-related cancers. Based on this, we hypothesise that a chemopreventive approach which reduces circulating oestrogen levels may reduce DNA damage and genomic instability, thereby providing an alternative to risk-reducing surgery.Methods and analysis12 premenopausal women with pathogenic BRCA1 mutations and no previous risk-reducing surgery will be recruited from family history clinics. Participants will be allocated 1:1 to two arms. All will undergo baseline breast biopsies, blood and urine sampling, and quality of life questionnaires. Group A will receive goserelin 3.6 mg/28 days by subcutaneous injection, plus oral anastrozole 1 mg/day, for 12 weeks. Group B will receive oral tamoxifen 20 mg/day for 12 weeks. Following treatment, both groups will provide repeat biopsies, blood and urine samples, and questionnaires. Following a 1-month washout period, the groups will cross over, group A receiving tamoxifen and group B goserelin and anastrozole for a further 12 weeks. After treatment, biopsies, blood and urine samples, and questionnaires will be repeated. DNA damage will be assessed in core biopsies, while blood and urine samples will be used to measure oestrogen metabolite and DNA adduct levels.Ethics and disseminationThis study has ethical approval from the Office for Research Ethics Committees Northern Ireland (16/NI/0055) and the Medicines and Healthcare products Regulatory Agency (MHRA) (reference: 32485/0032/001–0001). The investigational medicinal products used in this trial are licensed and in common use, with well-documented safety information. Dissemination of results will be via high-impact journals and relevant national/international conferences. A copy of the results will be offered to the participants and be made available to patient support groups.Trial registration numberEudraCT: 2016-001087-11; Pre-results.

This study explored the experience of transitioning from common education to higher education for a group of Cheyenne and Arapaho students. Additional features of resilience were examined as well, which included their persistence in pursuit of a baccalaureate degree. A phenomenological approach was used in order to explore the lived experiences of the purposeful sample of seven Cheyenne and Arapaho tribal members, all students at a public regional university. Data were acquired by qualitative inquiry based on in-depth interviews. Participants ascribed meaning to what they experienced through textural themes, including a sense of belonging and affectional ties. Furthermore, participants spoke of how they experienced the phenomenon, resulting in structural descriptors of determination, autonomy, self-discipline, and spirituality. Implications for school personnel and teacher preparatory programs are presented, as well as suggestions for future research.

Solvents are ubiquitous in chemistry. They can drastically impact the outcome of a process or reaction, and are usually the largest material component, greatly affecting environmental impact. Choosing the best solvent usually means optimizing for the best yields, but as safety standards and environmental regulations increase there is increasing need to optimize for these as well. There have been many advances in green chemistry, including the identification of alternative solvents. This thesis discusses the application of two CO2-switchable solvents. Switchable polarity solvents (SPS) were studied to control the lifetime of a photoswitchable dye. The dyes used are spiropyrans, a class of dyes that change from colourless to coloured upon irradiation by ultraviolet (UV) light, and spontaneously revert to their colourless form. The rate of this reversion is dependent on the solvent polarity, where the coloured form is stabilized by polar solvents. To control this reversion, solvents with switchable polarity have been investigated; amidine- (or guanidine-) alcohol mixture, where the introduction of CO2 causes an ionic liquid to form, raising its polarity. DBU/alcohol has been used in particular in this research. Switchable hydrophilicity solvents (SHS) were investigated for the extraction of bio-oils from microalgae. Microalgae have been identified as a potential source of biofuel. They have several benefits compared to terrestrial crops, including increased oil production. Current methods employ highly volatile solvents to ensure low energy solvent removal, however, this also leads to increased safety demands and risk of exposure. SHS have the unique ability to change their behaviour toward water with the addition of CO2 at atmospheric pressures. In the absence of CO2 the solvent is poorly miscible with water, and with the addition of CO2 becomes miscible with water in all proportions. This property allows for easy separation of extracted material. In the hydrophobic form the solvent is excellent for the extraction of non-polar materials, and can be easily separated from those materials with the addition of carbonated water.