By utilizing the strategies outlined above, it may be possible to exploit differences between tumor and somatic cell DRR pathways, specifically their DSB repair mechanisms, to improve the therapeutic ratio of IR.

In recent years, there have been multiple breakthroughs in our understanding of lung cancer biology. Despite significant advances in molecular targeted therapies DNA-damaging cytotoxic therapies will remain the mainstay of lung cancer management for the foreseeable future. Similar to the concept of personalized targeted therapies there is mounting evidence that perturbations in DNA repair pathways are common in lung cancers, altering the resistance of the affected tumors to many chemotherapeutics as well as radiation. Defects in DNA repair may be due to a multitude of mechanisms including gene mutations, epigenetic events, and alterations in signal transduction pathways such as EGFR and PI3K/AKT. Functional biomarkers that assess the subcellular localization of central repair proteins in response to DNA damage may prove useful for individualization of cytotoxic therapies including PARP inhibitors. A better mechanistic understanding of cellular sensitivity and resistance to DNA damaging agents should facilitate the development of novel, individualized treatment approaches. Absolute resistance to radiation therapy, however, does not exist. To some extent, radiation therapy will always have to remain unselective and indiscriminant to eradicate persistent, drug-resistant tumor stem cell pools.

ContextProfessional identity formation (PIF) involves the development of professional values, actions and aspirations and is central to medical education. Current understanding of PIF is informed by psychological and sociological theories. One ideal of medicine is responsibility to the patient; the development of this ideal is related to learner autonomy. The purpose of this study was to further theorise the relationships between the individual and contextual aspects of PIF through exploring the associations amongst autonomy, making decisions and responsibility for patients during residency training.MethodsUsing constructivist grounded theory, we conducted 23 semi‐structured interviews with internal medicine residents at an academic medical centre. Interview transcripts were de‐identified and processed through open coding and analytic memo writing. During data collection and analysis, we identified social cognitive theory (SCT), specifically reciprocal determinism, or the triadic and reciprocal relationship between context, person and behaviour, as a useful theoretical lens through which to illuminate the relationship between autonomy and PIF. Using SCT to guide analysis, we organised themes, identified relationships amongst themes, and refined them through group discussion and constant comparison with new data.ResultsResidents discussed three main themes: autonomy; making decisions, and responsibility for patient care. Autonomy allowed residents to feel personally responsible for patient care, and build confidence and trust. Autonomy allowed residents to feel engaged in making ‘real decisions’ for patient care. By displaying confidence in their decision making, residents were granted more autonomy. Lack of autonomy led to disengagement and lack of ownership over patient care.ConclusionsThis study highlighted the role of autonomy in the PIF of learners. Exploring the tension between autonomy and supervision through the lens of SCT highlighted the interconnectedness of context, behaviour and identity in PIF. To ensure optimal learning environments for PIF, educators should weigh the need for autonomy against the demands for supervision and patient safety.

Introduction Medical education is moving to conceptualise feedback as a bidirectional learning conversation. Within this conversation, learners experience a tension between assessment and feedback. That perceived tension affects learners’ outward performances. In this study, we aimed to characterise residents’ experiences with this tension and its effect on learner authenticity within feedback conversations. Methods In this constructivist grounded theory study, the authors were informed by Goffman's theory of impression management. During data analysis, Dweck's theory of mindset was adopted. The authors conducted semi‐structured interviews with 15 internal medicine residents. Data collection and analysis were conducted iteratively, using constant comparison to identify themes coinciding with impression management and mindset, ultimately developing a theoretical model to help explain residents’ responses to tensions within feedback conversations. Results Residents constantly felt ‘scrutinized’, and this affected their engagement in feedback conversations. They staged a performance within those conversations, linked to their underlying mindset: growth or fixed. Growth mindset was characterised by a focus on development as a physician and was associated with asking questions and seeking opportunities for growth. Fixed mindset was characterised by a focus on achieving a favourable evaluation and was associated with a hesitation to ask questions when faced with uncertainty and admit opportunities for growth, because they were concerned about impression management. Context influenced mindset and impression management. Residents adopted a fixed mindset and managed impressions when they perceived the permanence or consequences of evaluations within feedback. Residents adopted a growth mindset when they trusted the supervisor. Discussion Residents assess the context of feedback conversations, altering the authenticity of their behaviours. Context, including the perceptions of formal assessment and relationships with supervisors, affected residents’ mindset and impression management. Providing space for relationship‐building and clarifying the purpose and structure of assessment may be helpful in supporting effective learning conversations in graduate medical education.

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Primary brain tumors, in particular, glioblastoma multiforme (GBM), continue to have dismal survivability despite advances in treating other neoplasms. The goal of new anti-glioma therapy development is to increase their therapeutic ratios by enhancing tumor control and/or decreasing the severity and incidence of side effects. Because radiotherapy and most chemotherapy agents rely on DNA damage, the cell’s DNA damage repair and response (DRR) pathways may hold the key to new therapeutic strategies. DNA double-strand breaks (DSBs) generated by ionizing radiation and chemotherapeutic agents are the most lethal form of damage, and are repaired via either homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways. Understanding and exploitation of the differences in the use of these repair pathways between tumor and normal brain cells will allow for an increase in tumor cell killing and decreased normal tissue damage. A literature review and discussion on new strategies which can improve the anti-glioma therapeutic ratio by differentially targeting HR and NHEJ function in tumor and normal neuronal tissues is the focus of this article.

Background:Although BRCA1 has been extensively studied for its role as a tumour-suppressor protein, the role of BRCA1 subcellular localisation in oncogenesis and tumour progression has remained unclear. This study explores the impact of BRCA1 mislocalisation on clinical outcomes in breast cancer.Methods:Tissue microarrays assembled from a cohort of patients with all stages of breast cancer were analysed for BRCA1 localisation and correlated with patient survival. Tissue microarrays of patients who had breast cancer that had metastasised to the lung were assembled from an independent cohort of patients. These were analysed for BRCA1 subcellular expression. In vitro studies using cultured human breast cancer cells were conducted to examine the effect of cytosolic BRCA1 on cell migration and efficiency of invasion.Results:An inverse association was found between cytosolic BRCA1 expression and metastasis-free survival in patients aged >40 years. Further analysis of BRCA1 subcellular expression in a cohort of breast cancer patients with metastatic disease revealed that the cytosolic BRCA1 content of breast tumours that had metastasised to the lung was 36.0% (95% CI=(31.7%, 40.3%), which was markedly higher than what is reported in the literature (8.2–14.8%). Intriguingly, these lung metastases and their corresponding primary breast tumours demonstrated similarly high cytosolic BRCA1 distributions in both paired and unpaired analyses. Finally, in vitro studies using human breast cancer cells demonstrated that genetically induced BRCA1 cytosolic sequestration (achieved using the cytosol-sequestering BRCA1 5382insC mutation) increased cell invasion efficiency.Conclusions:Results from this study suggest a model where BRCA1 cytosolic mislocalisation promotes breast cancer metastasis, making it a potential biomarker of metastatic disease.

Introduction Professional identity formation (PIF) is the internalization of characteristics, values, and norms of the medical profession. An individual’s identity formation has both psychological and sociological influences. Social psychology may be useful to explore the interactions between the psychological and sociological aspects of PIF. In this study, we explored how resident physicians navigated tensions between professional ideals and the reality of medical practice to characterize PIF during residency training. Methods Using constructivist grounded theory, the authors conducted 23 semi-structured interviews with internal medicine residents. Interview transcripts were processed through open coding and analytic memo writing. During data gathering and analysis, the authors utilized Social Cognitive Theory, specifically the bidirectional influence between person, behavior, and context, to analyze relationships among themes. Theoretical insights were refined through group discussion and constant comparison with newly collected data. Results Residents described tensions experienced during residency between pre-existing ideals of “a good doctor” and the realities of medical practice, often challenging residents to reframe their ideals. The authors provide evidence for the presence of dynamic, bidirectional influences between identity (person), behavior, and environment (context), and demonstrate how PIF is informed by a complex interplay between these elements. The authors present two examples to demonstrate how residents reframed their ideals during residency training. Discussion The complex bidirectional influences between person, behavior, and context, informed by SCT, helps illuminate the process of PIF in residency training. This study highlights the effects of the context of residency training on the development of residents’ professional identities.