What impact has the NIHR Academic Clinical Fellowship (ACF) scheme had on clinical academic careers in England over the last 10 years? A retrospective study.

OBJECTIVES: The Academic Clinical Fellowship (ACF) was introduced to support the early career clinical and research training of potential future clinical academics in England. The driver for the model was concern about falling numbers of clinical academic trainees. This study examines the impact of the ACF model, over its first 10 years, in developing clinical academic careers by tracking the progression of ACF trainees. DESIGN: Retrospective analysis of National Institute for Health Research (NIHR) ACF career progression. This was performed using mixed methods including routine data collections of career destination, analysis of application rates to doctoral level fellowships and supplemented by survey information that captured the perceived benefits and challenges from previous ACFs and their current career activities. PARTICIPANTS: 1239 NIHR ACFs who completed or left their posts between 2006 and March 2015. RESULTS: ACFs are perceived by the candidate population as attractive posts, with high numbers of applications leading to high fill rates. Balancing clinical and academic commitments is one of the reported challenges when completing an ACF. We have found that undertaking an ACF was shown to increase the likelihood of securing an externally funded doctoral training award and the vast majority of ACFs move into academic roles, with many completing PhDs. Previous ACFs continue to show positive career progression, predominantly in translational and clinical research. The knowledge acquired during the ACF continues to be useful in subsequent roles and trainees would recommend the scheme to others. CONCLUSIONS: The NIHR ACF scheme is successful as part of an integrated training pathway in developing careers in academic medicine and dentistry.

Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes.

Bone marrow stromal cells (BMSCs, also called bone-marrow-derived mesenchymal stromal cells) provide hematopoietic support and immunoregulation and contain a stem cell fraction capable of skeletogenic differentiation. We used immortalized human BMSC clonal lines for multi-level analysis of functional markers for BMSC subsets. All clones expressed typical BMSC cell-surface antigens; however, clones with trilineage differentiation capacity exhibited enhanced vascular interaction gene sets, whereas non-differentiating clones were uniquely CD317 positive with significantly enriched immunomodulatory transcriptional networks and high IL-7 production. IL-7 lineage tracing and CD317 immunolocalization confirmed the existence of a rare non-differentiating BMSC subtype, distinct from Cxcl12-DsRed(+) perivascular stromal cells in vivo. Colony-forming CD317(+) IL-7(hi) cells, identified at ∼ 1%-3% frequency in heterogeneous human BMSC fractions, were found to have the same biomolecular profile as non-differentiating BMSC clones using Raman spectroscopy. Distinct functional identities can be assigned to BMSC subpopulations, which are likely to have specific roles in immune control, lymphopoiesis, and bone homeostasis.

A human NK cell activation/inhibition threshold allows small changes in the target cell surface phenotype to dramatically alter susceptibility to NK cells.

NK cell activation is negatively regulated by the expression of target cell MHC class I molecules. We show that this relationship is nonlinear due to an NK cell activation/inhibition threshold. Ewing's sarcoma family tumor cell monolayers, which were highly susceptible to NK cells in vitro, developed a highly resistant phenotype when cultured as three-dimensional multicellular tumor spheroid structures. This suggested that tumor architecture is likely to influence the susceptibility to NK cells in vivo. Resistance of the multicellular tumor spheroid was associated with the increased expression of MHC class I molecules and greatly reduced NK cell activation, implying that a threshold of NK cell activation/inhibition had been crossed. Reducing MHC class I expression on Ewing's sarcoma family tumor monolayers did not alter their susceptibility to NK cells, whereas increased expression of MHC class I rendered them resistant and allowed the threshold point to be identified. This threshold, as defined by MHC class I expression, was predictive of the number of NK-resistant target cells within a population. A threshold permits modest changes in the target cell surface phenotype to profoundly alter the susceptibility to NK cells. Whereas this allows for the efficient detection of target cells, it also provides a route for pathogens and tumors to evade NK cell attack.