MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia.

We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules-but not their wild-type counterparts-rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.

Making sense of how physician preceptors interact with medical students: discourses of dialogue, good medical practice, and relationship trajectories.

Work based learning and teaching in health care settings are complex and dynamic. Sociocultural theory addresses this complexity by focusing on interaction between learners, teachers, and their environment as learners develop their professional identity. Although social interaction between doctors and students plays a crucial role in this developmental process, socio-cultural research from the perspective of doctors is scarce. We performed discourse analysis on seven general practitioners' audio diaries during a 10-week general practice clerkship to study how they gave shape to their interaction with their students. Examination of 61 diary-entries revealed trajectories of developing relationships. These trajectories were initiated by the way respondents established a point of departure, based on their first impression of the students. It continued through the development of dialogue with their student and through conceptualizations of good medical practice. Such conceptualizations about what was normal in medical and educational practice enabled respondents to recognize qualities in the student and to indirectly determine students' desired learning trajectory. Towards the end, discursive turns in respondents' narratives signaled development within the relationship. This became evident in division of roles and positions in the context of daily practice. Although respondents held power in the relationships, we found that their actions depended strongly on what the students afforded them socially. Our findings address a gap in literature and could further inform theory and practice, for example by finding out how to foster constructive dialogue between doctors and students, or by exploring different discourses among learners and teachers in other contexts.

Workplace learning from a socio-cultural perspective: creating developmental space during the general practice clerkship.

Workplace learning in undergraduate medical education has predominantly been studied from a cognitive perspective, despite its complex contextual characteristics, which influence medical students' learning experiences in such a way that explanation in terms of knowledge, skills, attitudes and single determinants of instructiveness is unlikely to suffice. There is also a paucity of research which, from a perspective other than the cognitive or descriptive one, investigates student learning in general practice settings, which are often characterised as powerful learning environments. In this study we took a socio-cultural perspective to clarify how students learn during a general practice clerkship and to construct a conceptual framework that captures this type of learning. Our analysis of group interviews with 44 fifth-year undergraduate medical students about their learning experiences in general practice showed that students needed developmental space to be able to learn and develop their professional identity. This space results from the intertwinement of workplace context, personal and professional interactions and emotions such as feeling respected and self-confident. These forces framed students' participation in patient consultations, conversations with supervisors about consultations and students' observation of supervisors, thereby determining the opportunities afforded to students to mind their learning. These findings resonate with other conceptual frameworks and learning theories. In order to refine our interpretation, we recommend that further research from a socio-cultural perspective should also explore other aspects of workplace learning in medical education.

Workplace learning in general practice: supervision, patient mix and independence emerge from the black box once again.

BACKGROUND: Medical students increasingly participate in rotations in primary care settings, such as general practices. Although general practices can differ markedly from hospital settings, research on the instructional quality of general practice rotations is relatively scarce. AIM: We conducted a study to identify which aspects make a significant contribution to the instructional quality of general practice clerkships, as perceived by students. METHOD: After completing their general practice attachment, 155 fifth-year medical students filled out an evaluation questionnaire. Exploratory factor analysis and reliability analysis identified clusters of correlated independent variables. Subsequent regression analysis revealed the relations between the reduced set of independent variables and the dependent variable 'Instructional quality'. RESULTS: Both the quality of supervision and the size and diversity of the patient mix substantially affected students' experienced instructional quality. Opportunities and facilities to perform independently were correlated with instructional quality, but did not affect the instructiveness directly. CONCLUSIONS: Supervision, patient mix and independence are crucial factors for learning in general practice. This is consistent with findings in hospital settings. The perceived quality of instruction hinges on supervision, which is not only the variable most strongly related to instructional quality, but which also affects both the patient mix and students' independence.