Educational outcomes in the era of the Affordable Care Act: impact of personalized education about non-small cell lung cancer.

INTRODUCTION: The Affordable Care Act is moving medical care-and medical education-toward a quality-driven environment. Quality medical education must be available when the health care provider is ready to learn, provide feedback, and maximize translation of knowledge from desk to clinic. To best accomplish these goals, medical education must be personalized to clinicians' needs. Research has defined multiple knowledge/performance gaps among oncologists who manage advanced non-small cell lung cancer (NSCLC). A study was conducted to determine the effectiveness with which a personalized learning approach for oncologists will diminish these gaps. METHODS: The authors undertook development, online distribution, and impact measurement of an NSCLC curriculum in which learners' responses to a preeducation self-assessment of knowledge, skills, and attitudes resulted in receipt of a personalized curriculum. Upon completion of the assessment, each learner received a personalized curriculum, which included up to 5 distinct activities selected to address identified knowledge and practice gaps. Feedback was provided at the completion of each activity. RESULTS: Ninety-two oncologists completed an individualized learning plan. Analysis shows that completion of the learning plan was associated with a high effect size (d = .70). Significant increases were seen in oncologists' ability to correctly identify the rationale for determining histological subtype (13% increase), prevalence of genetic abnormalities (21% increase, p = .04), appropriate use of maintenance therapy (31% increase, p = .01), and appropriate treatment regimens for squamous cell carcinoma (19% increase, p = .003) and of adenocarcinoma (44% increase, p < .001). DISCUSSION: This study demonstrates the feasibility and impact of a personalized targeted curriculum for improving the competence of oncologists treating patients with advanced NSCLC.

HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function.

The effects of HSP27 on human monocytes (MO) are predominantly antiinflammatory through preferential interleukin (IL)10 induction and by alteration of MO to immature dendritic cells (iDCs) or MO to macrophage (Mac) differentiation. Initial HSP27 inclusion in IL4+GM-CSF MO to iDC induction cultures allows Mac differentiation (CD14++, CD16+), decreases iDC (CD1a+) differentiation, and depresses DC induction of allogeneic T lymphocyte proliferation (MLR). HSP27 increased MO IL10 and M-CSF production but subsequent increased Mac differentiation isn't responsible for depressed MO to iDC differentiation and function. Mac function after IL10 induced MO to Mac differentiation is also altered by HSP27 inclusion so that Mac phagocytic activity and scavenger receptor expression (CD163) are depressed. HSP27, in addition to immature DCs, doesn't increase Mac differentiation but instead generates inhibitory DCs, which depress rather than stimulate T cell proliferation even during anti CD3+CD28 induction. Upon maturation, these HSP27-altered inhibitory DCs have increased production of the T cell and DC suppressive mediator, thrombospondin 1. HSP27's anti-inflammatory and immunodepressive effects include deranging MO differentiation to both Mac and DCs, altering their receptor expression, and inducing production of inhibitory mediators such as thrombospondin-1 as well as IL10. These data suggest HSP27 belongs to a new group of 'anti-danger signals'.

MHC Class II levels and intracellular localization in human dendritic cells are regulated by calmodulin kinase II.

Dendritic cells (DC) are professional APC, which activate the adaptive immune response. A Ca2+-calmodulin (CaM)-CaM kinase II (CaMKII) pathway regulates maturation and MHC Class II antigen presentation in human DC. The objective of this study was to characterize the mechanisms by which CaMKII modulates the levels and subcellular distribution of MHC Class II molecules. Inhibition of CaMKII via the highly specific, autoinhibitory peptide derived from the enzyme's regulatory domain resulted in rapid (60 min) and sustained (24 h) reduction of MHC Class II levels in antigen-stimulated, primary, human DC. The initial depletion of intracellular and cell surface MHC Class II was associated with its enhanced lysosomal trafficking and increased activity of specific proteases in the absence of effects on other transmembrane proteins (CD1b and CD34) or a detectable change in lysosomal degradation of exogenous protein. Inhibition of CaMKII also resulted in significant reductions in the level and stability of MHC Class II mRNA and the levels and nucleocytosolic localization of its major transcriptional regulator CIITA. These data support a model in which CaMKII regulates the levels and localization of MHC Class II protein in human DC via transcriptional, post-transcriptional, and post-translational mechanisms. These pathways are likely important to the physiologic regulation of MHC Class II as well as to its dysregulation in disease states associated with altered CaMKII function.

Calmodulin kinase II regulates the maturation and antigen presentation of human dendritic cells.

Dendritic cells (DC) are professional antigen-presenting cells, which activate the adaptive immune system. Upon receiving a danger signal, they undergo a maturation process, which increases their antigen presentation capacity, but the responsible regulatory mechanisms remain incompletely understood. A Ca2+-calmodulin (Cam)-Cam kinase II (CamK II) pathway regulates phagosome maturation in macrophages, and this pathway is inhibited by pathogenic microbes. Our hypothesis is that signal transduction events which control phagosome maturation also regulate antigen presentation. Stimulation of primary human DC or the human DC line KG-1, with particulate antigen, resulted in the activation of CamK II and its localization to the phagosome and plasma membrane. Two mechanistically distinct inhibitors of CamK II significantly reduced DC maturation, as determined by up-regulation of surface costimulatory and major histocompatibility complex (MHC) class II molecules and secretion of cytokines. Confocal microscopy demonstrated that the CamK II inhibitors blocked the antigen-induced increase in total cellular MHC class molecules as well as their trafficking to the plasma membrane. Inhibition of CamK II was associated with decreased presentation of particulate and soluble MHC class II-restricted antigen, with a greater effect on the former. These data support a model in which CamK II regulates critical stages of the maturation and antigen presentation capacity of human DC, particularly in response to stimulation via phagocytosis.