Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.

SBCDDB: Sleeping Beauty Cancer Driver Database for gene discovery in mouse models of human cancers.

Large-scale oncogenomic studies have identified few frequently mutated cancer drivers and hundreds of infrequently mutated drivers. Defining the biological context for rare driving events is fundamentally important to increasing our understanding of the druggable pathways in cancer. Sleeping Beauty (SB) insertional mutagenesis is a powerful gene discovery tool used to model human cancers in mice. Our lab and others have published a number of studies that identify cancer drivers from these models using various statistical and computational approaches. Here, we have integrated SB data from primary tumor models into an analysis and reporting framework, the Sleeping Beauty Cancer Driver DataBase (SBCDDB, http://sbcddb.moffitt.org), which identifies drivers in individual tumors or tumor populations. Unique to this effort, the SBCDDB utilizes a single, scalable, statistical analysis method that enables data to be grouped by different biological properties. This allows for SB drivers to be evaluated (and re-evaluated) under different contexts. The SBCDDB provides visual representations highlighting the spatial attributes of transposon mutagenesis and couples this functionality with analysis of gene sets, enabling users to interrogate relationships between drivers. The SBCDDB is a powerful resource for comparative oncogenomic analyses with human cancer genomics datasets for driver prioritization.

SB Driver Analysis: a Sleeping Beauty cancer driver analysis framework for identifying and prioritizing experimentally actionable oncogenes and tumor suppressors.

Cancer driver prioritization for functional analysis of potential actionable therapeutic targets is a significant challenge. Meta-analyses of mutated genes across different human cancer types for driver prioritization has reaffirmed the role of major players in cancer, including KRAS, TP53 and EGFR, but has had limited success in prioritizing genes with non-recurrent mutations in specific cancer types. Sleeping Beauty (SB) insertional mutagenesis is a powerful experimental gene discovery framework to define driver genes in mouse models of human cancers. Meta-analyses of SB datasets across multiple tumor types is a potentially informative approach to prioritize drivers, and complements efforts in human cancers. Here, we report the development of SB Driver Analysis, an in-silico method for defining cancer driver genes that positively contribute to tumor initiation and progression from population-level SB insertion data sets. We demonstrate that SB Driver Analysis computationally prioritizes drivers and defines distinct driver classes from end-stage tumors that predict their putative functions during tumorigenesis. SB Driver Analysis greatly enhances our ability to analyze, interpret and prioritize drivers from SB cancer datasets and will continue to substantially increase our understanding of the genetic basis of cancer.

Obstetric and gynecologic ultrasound curriculum and competency assessment in residency training programs: consensus report.

Ultrasound imaging has become integral to the practice of obstetrics and gynecology. With increasing educational demands and limited hours in residency programs, dedicated time for training and achieving competency in ultrasound has diminished substantially. The American Institute of Ultrasound in Medicine assembled a multisociety task force to develop a consensus-based, standardized curriculum and competency assessment tools for obstetric and gynecologic ultrasound training in residency programs. The curriculum and competency assessment tools were developed based on existing national and international guidelines for the performance of obstetric and gynecologic ultrasound examinations and thus are intended to represent the minimum requirement for such training. By expert consensus, the curriculum was developed for each year of training, criteria for each competency assessment image were generated, the pass score was established at, or close to, 75% for each, and obtaining a set of 5 ultrasound images with pass score in each was deemed necessary for attaining each competency. Given the current lack of substantial data on competency assessment in ultrasound training, the task force expects that the criteria set forth in this document will evolve with time. The task force also encourages use of ultrasound simulation in residency training and expects that simulation will play a significant part in the curriculum and the competency assessment process. Incorporating this training curriculum and the competency assessment tools may promote consistency in training and competency assessment, thus enhancing the performance and diagnostic accuracy of ultrasound examination in obstetrics and gynecology.

Obstetric and Gynecologic Ultrasound Curriculum and Competency Assessment in Residency Training Programs: Consensus Report.

Ultrasound imaging has become integral to the practice of obstetrics and gynecology. With increasing educational demands and limited hours in residency programs, dedicated time for training and achieving competency in ultrasound has diminished substantially. The American Institute of Ultrasound in Medicine assembled a multisociety task force to develop a consensus-based, standardized curriculum and competency assessment tools for obstetric and gynecologic ultrasound training in residency programs. The curriculum and competency assessment tools were developed based on existing national and international guidelines for the performance of obstetric and gynecologic ultrasound examinations and thus are intended to represent the minimum requirement for such training. By expert consensus, the curriculum was developed for each year of training, criteria for each competency assessment image were generated, the pass score was established at, or close to, 75% for each, and obtaining a set of 5 ultrasound images with pass score in each was deemed necessary for attaining each competency. Given the current lack of substantial data on competency assessment in ultrasound training, the task force expects that the criteria set forth in this document will evolve with time. The task force also encourages use of ultrasound simulation in residency training and expects that simulation will play a significant part in the curriculum and the competency assessment process. Incorporating this training curriculum and the competency assessment tools may promote consistency in training and competency assessment, thus enhancing the performance and diagnostic accuracy of ultrasound examination in obstetrics and gynecology.

The invisible work of distributed medical education: exploring the contributions of audiovisual professionals, administrative professionals and faculty teachers.

Distributed medical education (DME) is becoming increasingly prevalent. Much of the published literature on DME has focused on the experiences of learners in distributed programs; however, our empirical work leads us to believe that DME changes the context significantly, not only for learners, but also for other important members of the educational community including audiovisual professionals, administrative professionals and faculty teachers. Based on a three-year ethnographic study, we provide a detailed account of how alliances between various workers involved in DME develop to produce and deliver an undergraduate medical curriculum across geographically separate campuses. We explore the question 'What is the work involved in the delivery of a DME program?' and cast a critical gaze on the essential but invisible, and therefore potentially unrecognized and underappreciated, contributions of AV professionals, administrative professionals, and faculty teachers. Our goal is to make visible the complexity of DME, including the essential contributions of these workers. The study was theoretically framed in sociomateriality and conceptually framed in Star and Strauss' notion of articulation work.

Uncovering the unknown: A grounded theory study exploring the impact of self-awareness on the culture of feedback in residency education.

AIM: Self-assessment and reflection are essential for meaningful feedback. We aimed to explore whether the well-known Johari window model of self-awareness could guide feedback conversations between faculty and residents and enhance the institutional feedback culture. METHODS: We had previously explored perceptions of residents and faculty regarding sociocultural factors impacting feedback. We re-analyzed data targeting themes related to self-assessment, reflection, feedback seeking and acceptance, aiming to generate individual and institutional feedback strategies applicable to each quadrant of the window. RESULTS: We identified the following themes for each quadrant: (1) Behaviors known to self and others - Validating the known; (2) Behaviors unknown to self but known to others - Accepting the blind; (3) Behaviors known to self and unknown to others - Disclosure of hidden; and (4) Behaviors unknown to self and others - Uncovering the unknown. Normalizing self-disclosure of limitations, encouraging feedback seeking, training in nonjudgmental feedback and providing opportunities for longitudinal relationships could promote self-awareness, ultimately expanding the "open" quadrant of the Johari window. CONCLUSIONS: The Johari window, a model of self-awareness in interpersonal communications, could provide a robust framework for individuals to improve their feedback conversations and institutions to design feedback initiatives that enhance its quality and impact.

"It's Just Not the Culture": A Qualitative Study Exploring Residents' Perceptions of the Impact of Institutional Culture on Feedback.

Phenomenon: Competency-based medical education requires ongoing performance-based feedback for professional growth. In several studies, medical trainees report that the quality of faculty feedback is inadequate. Sociocultural barriers to feedback exchanges are further amplified in graduate and postgraduate medical education settings, where trainees serve as frontline providers of patient care. Factors that affect institutional feedback culture, enhance feedback seeking, acceptance, and bidirectional feedback warrant further exploration in these settings. APPROACH: Using a constructivist grounded theory approach, we sought to examine residents' perspectives on institutional factors that affect the quality of feedback, factors that influence receptivity to feedback, and quality and impact of faculty feedback. Four focus group discussions were conducted, with two investigators present at each. One facilitated the discussion, and the other observed the interactions and took field notes. We audiotaped and transcribed the discussions, and performed a thematic analysis. Measures to ensure rigor included thick descriptions, independent coding by two investigators, and attention to reflexivity. FINDINGS: We identified five key themes, dominated by resident perceptions regarding the influence of institutional feedback culture. The theme labels are taken from direct participant quotes: (a) the cultural norm lacks clear expectations and messages around feedback, (b) the prevailing culture of niceness does not facilitate honest feedback, (c) bidirectional feedback is not part of the culture, (d) faculty-resident relationships impact credibility and receptivity to feedback, and (e) there is a need to establish a culture of longitudinal professional growth. Insights: Institutional culture could play a key role in influencing the quality, credibility, and acceptability of feedback. A polite culture promotes a positive learning environment but can be a barrier to honest feedback. Feedback initiatives focusing solely on techniques of feedback giving may not enhance meaningful feedback. Further research on factors that promote feedback seeking, receptivity to constructive feedback, and bidirectional feedback would provide valuable insights.

Genetic heterogeneity of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.

Introducing medical educators to qualitative study design: Twelve tips from inception to completion.

Many research questions posed by medical educators could be answered more effectively by the application of carefully selected qualitative research design than traditional quantitative research methods. Indeed, in many cases using mixed methods research would expand the scope of a study and yield meaningful qualitative data in addition to quantitative data. Qualitative research seeks to understand people's experiences, the meanings they assign to those experiences, the psychosocial aspects of and language used in interpersonal interactions, and the factors that influence perspectives and interactions. This understanding is vital in exploring learning and teaching styles, learners' experiences and perceptions, implementing and studying the impact of educational interventions and faculty development. This article aims to advance medical educators' understanding and application of qualitative research principles in educational scholarship by summarising and consolidating the fundamental principles of research in medical education described in recent AMEE guides. The 12 tips below offer a systematic, yet practical approach to designing a qualitative research study, particularly targeting educators new to this arena.

Residents as teachers: Near peer learning in clinical work settings: AMEE Guide No. 106.

This AMEE Guide provides a framework to guide medical educators engaged in the design and implementation of "Resident as Teacher" programs. The suggested approaches are based on established models of program development: the Program Logic model to guide program design, the Dundee three-circle model to inform a systematic approach to planning educational content and the Kirkpatrick pyramid, which forms the backbone of program evaluation. The Guide provides an overview of Resident as Teacher curricula, their benefits and impact, from existing literature supplemented by insights from the authors' own experiences, all of whom are engaged in teaching initiatives at their own institutions. A conceptual description of the Program Logic model is provided, a model that highlights an outcomes-based curricular design. Examples of activities under each step of this model are described, which would allow educational leaders to structure their own program based on the scope, context, institutional needs and resources available. Emphasis is placed on a modular curricular format to not only enhance the teaching skills of residents, but also enable development of future career educators, scholars and leaders. Application of the Dundee three-circle model is illustrated to allow for a flexible curricular design that can cater to varying levels of educational needs and interests. In addition, practical advice is provided on robust assessment of outcomes, both assessment of participants and program evaluation. Finally, the authors highlight the need for congruence between the formal and hidden curriculum through explicit recognition of the value of teaching by institutions, support for development of teaching programs, encouragement of evidence-based approach to education and rewards for all levels of teachers.

Coming in From the Cold-Physician Professional Development as Deepening Participation in the Healthcare Community.

This Conversation Starters article presents a selected research abstract from the 2016 Association of American Medical Colleges Southern Region Group on Educational Affairs annual spring meeting. The abstract is paired with the integrative commentary of three experts who shared their thoughts stimulated by the pilot study. These thoughts probe the concept of patient "ownership" and suggest an alternative way of conceptualizing physicians' total dedication to patient care.

A systematic review of faculty development initiatives designed to enhance teaching effectiveness: A 10-year update: BEME Guide No. 40.

BACKGROUND: This review, which focused on faculty development initiatives designed to improve teaching effectiveness, synthesized findings related to intervention types, study characteristics, individual and organizational outcomes, key features, and community building. METHODS: This review included 111 studies (between 2002 and 2012) that met the review criteria. FINDINGS: Overall satisfaction with faculty development programs was high. Participants reported increased confidence, enthusiasm, and awareness of effective educational practices. Gains in knowledge and skills, and self-reported changes in teaching behaviors, were frequently noted. Observed behavior changes included enhanced teaching practices, new educational initiatives, new leadership positions, and increased academic output. Organizational changes were infrequently explored. Key features included evidence-informed educational design, relevant content, experiential learning, feedback and reflection, educational projects, intentional community building, longitudinal program design, and institutional support. CONCLUSION: This review holds implications for practice and research. Moving forward, we should build on current success, broaden the focus beyond individual teaching effectiveness, develop programs that extend over time, promote workplace learning, foster community development, and secure institutional support. We should also embed studies in a theoretical framework, conduct more qualitative and mixed methods studies, assess behavioral and organizational change, evaluate transfer to practice, analyse key features, and explore the role of faculty development within the larger organizational context.

Investigating the feasibility and acceptability of health psychology-informed obesity training for medical students.

Health psychologists have succeeded in identifying theory-congruent behaviour change techniques (BCTs) to prevent and reduce lifestyle-related illnesses, such as cardiovascular disease, cancers and diabetes. Obesity management discussions between doctors and patients can be challenging and are often avoided. Despite a clear training need, it is unknown how best to tailor BCT research findings to inform obesity-management training for future healthcare professionals. The primary objective of this descriptive study was to gather information on the feasibility and acceptability of delivering and evaluating health psychology-informed obesity training to UK medical students. Medical students (n = 41) attended an obesity management session delivered by GP tutors. Sessions were audio-recorded to enable fidelity checks. Acceptability of training was explored qualitatively. Tutors consistently delivered training according to the intervention protocol; and students and tutors found the training highly acceptable. This psychology-informed training can be delivered successfully by GP tutors and further research is warranted to explore its efficacy.

Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway.

Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.

Using targeted transgenic reporter mice to study promoter-specific p53 transcriptional activity.

The p53 transcription factor modulates gene expression programs that induce cell cycle arrest, senescence, or apoptosis, thereby preventing tumorigenesis. However, the mechanisms by which these fates are selected are unclear. Our objective is to understand p53 target gene selection and, thus, enable its optimal manipulation for cancer therapy. We have generated targeted transgenic reporter mice in which EGFP expression is driven by p53 transcriptional activity at a response element from either the p21 or Puma promoter, which induces cell cycle arrest/senescence and apoptosis, respectively. We demonstrate that we could monitor p53 activity in vitro and in vivo and detect variations in p53 activity depending on the response element, tissue type, and stimulus, thereby validating our reporter system and illustrating its utility for preclinical drug studies. Our results also show that the sequence of the p53 response element itself is sufficient to strongly influence p53 target gene selection. Finally, we use our reporter system to provide evidence for p53 transcriptional activity during early embryogenesis, showing that p53 is active as early as embryonic day 3.5 and that p53 activity becomes restricted to embryonic tissue by embryonic day 6.5. The data from this study demonstrate that these reporter mice could serve as powerful tools to answer questions related to basic biology of the p53 pathway, as well as cancer therapy and drug discovery.

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.

Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.

How and what do medical students learn in clerkships? Experience based learning (ExBL).

Clerkship education has been called a 'black box' because so little is known about what, how, and under which conditions students learn. Our aim was to develop a blueprint for education in ambulatory and inpatient settings, and in single encounters, traditional rotations, or longitudinal experiences. We identified 548 causal links between conditions, processes, and outcomes of clerkship education in 168 empirical papers published over 7 years and synthesised a theory of how students learn. They do so when they are given affective, pedagogic, and organisational support. Affective support comes from doctors' and many other health workers' interactions with students. Pedagogic support comes from informal interactions and modelling as well as doctors' teaching, supervision, and precepting. Organisational support comes from every tier of a curriculum. Core learning processes of observing, rehearsing, and contributing to authentic clinical activities take place within triadic relationships between students, patients, and practitioners. The phrase 'supported participation in practice' best describes the educational process. Much of the learning that results is too tacit, complex, contextualised, and individual to be defined as a set of competencies. We conclude that clerkship education takes place within relationships between students, patients, and doctors, supported by informal, individual, contextualised, and affective elements of the learned curriculum, alongside formal, standardised elements of the taught and assessed curriculum. This research provides a blueprint for designing and evaluating clerkship curricula as well as helping patients, students, and practitioners collaborate in educating tomorrow's doctors.

Faculty development through international exchange: the IMEX initiative.

BACKGROUND: Faculty development is often local and international experiences are usually limited to conferences and courses. In 2006, five schools across the globe decided to enhance international faculty experiences through an exciting new collaboration: the International Medical Educators Exchange (IMEX) initiative. METHOD: Twice a year, one of the five schools in the Netherlands, Canada, Sweden and the UK organizes a week of faculty development activities for experienced medical educators from each school, including group discussions, short presentations, observations and active engagement in local education, one-on-one meetings with local faculty members, and many opportunities for in-depth discussion. We administered a survey to evaluate the impact of this international exchange. RESULTS: By August 2013, 31 IMEX scholars had attended at least one of the 14 site visits held; most of them (29) had attended 3-5 site visits. Responding IMEX alumni (55%, N = 16) felt that their experiences impacted their personal competence and international orientation, and to some extent their career, their daily work and their institution. Most features of the IMEX program were valued as highly important and highly successful. DISCUSSION: IMEX has established itself as an important additional faculty development opportunity for those medical educators who wish to develop and pursue a career in education.

Understanding, teaching and assessing the elements of the CanMEDS Professional Role: canadian program directors' views.

BACKGROUND: Physicians are required to maintain and sustain professional roles during their careers, making the Professional Role an important component of postgraduate education. Despite this, this role remains difficult to define, teach and assess. OBJECTIVE: To (a) understand what program directors felt were key elements of the CanMEDS Professional Role and (b) identify the teaching and assessment methods they used. METHODS: A two-step sequential mixed method design using a survey and semi-structured interviews with Canadian program directors. RESULTS: Forty-six program directors (48% response rate) completed the questionnaire and 10 participated in interviews. Participants rated integrity and honesty as the most important elements of the Role (96%) but most difficult to teach. There was a lack of congruence between elements perceived to be most important and most frequently taught. Role modeling was the most common way of informally teaching professionalism (98%). Assessments were most often through direct feedback from faculty (98%) and feedback from other health professionals and residents (61%). Portfolios (24%) were the least used form of assessment, but they allowed residents to reflect and stimulated self-assessment. CONCLUSION: Program directors believe elements of the Role are difficult to teach and assess. Providing faculty with skills for teaching/assessing the Role and evaluating effectiveness in changing attitudes/behaviors should be a priority in postgraduate programs.