Platelet P-selectin initiates cross-presentation and dendritic cell differentiation in blood monocytes.

Dendritic cells (DCs) are adept at cross-presentation and initiation of antigen-specific immunity. Clinically, however, DCs produced by in vitro differentiation of monocytes in the presence of exogenous cytokines have been met with limited success. We hypothesized that DCs produced in a physiological manner may be more effective and found that platelets activate a cross-presentation program in peripheral blood monocytes with rapid (18 hours) maturation into physiological DCs (phDCs). Differentiation of monocytes into phDCs was concomitant with the formation of an "adhesion synapse," a biophysical junction enriched with platelet P-selectin and monocyte P-selectin glycoprotein ligand 1, followed by intracellular calcium fluxing and nuclear localization of nuclear factor κB. phDCs were more efficient than cytokine-derived DCs in generating tumor-specific T cell immunity. Our findings demonstrate that platelets mediate a cytokine-independent, physiologic maturation of DC and suggest a novel strategy for DC-based immunotherapies.

Clinical pharmacology of oncology agents in older adults: A comprehensive review of how chronologic and functional age can influence treatment-related effects.

Unique challenges exist when managing older adults with cancer. Associations between cancer and age-related physiologic changes have a direct impact on pharmacokinetics and pharmacodynamics of cancer therapies and can affect drug dosing, dose intensity, efficacy, safety and quality of life. The breadth and depth of these issues, however, have not been fully evaluated because the majority of clinical trials have focused on a younger and healthier population. As a consequence, little information is available to support clinicians in making evidence-based decisions regarding treatment with cancer therapies in older adults, especially those over age 75. Prior clinical pharmacology reviews summarized the literature on how age-related physiologic changes can influence and affect conventional and targeted anti-cancer treatments. Our article provides an updated review with expanded information that includes small molecule kinase inhibitors, monoclonal antibodies, immunotherapies, hormonal, conventional, and miscellaneous agents. Additionally, our article integrates how functional age, determined by the geriatric assessment (GA), can also influence treatment-related effects and health outcomes. Broadening cancer therapy trials to capture not only chronologic age but also functional age would allow clinicians to better identify subsets of older adults who benefit from treatment versus those most vulnerable to morbidity and/or mortality.

Nonredundant Roles of IL-21 and IL-4 in the Phased Initiation of Germinal Center B Cells and Subsequent Self-Renewal Transitions.

We examined the unique contributions of the cytokines IL-21 and IL-4 on germinal center (GC) B cell initiation and subsequent maturation in a murine model system. Similar to other reports, we found T follicular helper cell expression of IL-21 begins prior to T follicular helper cell migration into the B cell follicle and precedes that of IL-4. Consistent with this timing, IL-21 signaling has a greater influence on the perifollicular pre-GC B cell transition to the intrafollicular stage. Notably, Bcl6hi B cells can form in the combined absence of IL-21R- and STAT6-derived signals; however, these nascent GC B cells cease to proliferate and are more prone to apoptosis. When B cells lack either IL-21R or STAT6, aberrant GCs form atypical centroblasts and centrocytes that differ in their phenotypic maturation and costimulatory molecule expression. Thus, IL-4 and IL-21 play nonredundant roles in the phased progression of GC B cell development that can initiate in the combined absence of these cytokine signals.

Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help.

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers.

To understand how the Bcl6 transcriptional repressor functions in the immune system, we disrupted its RD2 repression domain in mice. Bcl6RD2(MUT) mice exhibit a complete loss of germinal center (GC) formation but retain normal extrafollicular responses. Bcl6RD2(MUT) antigen-engaged B cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B cell migration and may contribute to GC failure in Bcl6RD2(MUT) mice. The development of functional GC-TFH cells was partially impaired in Bcl6RD2(MUT) mice. In contrast to Bcl6(-/-) mice, Bcl6RD2(MUT) animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.

La victimisation homophobe et liée à la non-conformité de genre et l'adaptation scolaire et psychosociale chez les 14­22 ans : Résultats d'une enquête québécoise.

This article studied homophobic victimization and victimization based on gender nonconformity and its effects on the school and psychosocial adaptation of young Quebecers. A non-probabilistic sample of 262 youth (173 girls, 89 boys) aged 14 to 22 years old (M = 17.9 y.o.) was built. Bivariate comparisons and structural equation modeling were performed. Young LGBTQ showed lower sense of security at school, lower self-reported school achievement and higher psychological distress. Results indicated that homophobic victimization, friend social support, psychological distress and sense of security at school mediated school achievement of the young LGBTQ. Findings support the importance of implementing interventions to reduce homophobia in schools and highlight the central role played by peers in this endeavor.

Prevalence of obesity, type II diabetes mellitus, hyperlipidemia, and hypertension in the United States: findings from the GE Centricity Electronic Medical Record database.

This study analyzed GE Centricity Electronic Medical Record (EMR) data to examine the effects of body mass index (BMI) and obesity, key risk factor components of metabolic syndrome, on the prevalence of 3 chronic diseases: type II diabetes mellitus, hyperlipidemia, and hypertension. These chronic diseases occur with high prevalence and impose high disease burdens. The rationale for using Centricity EMR data is 2-fold. First, EMRs may be a good source of BMI/obesity data, which are often underreported in surveys and administrative databases. Second, EMRs provide an ideal means to track variables over time and, thus, allow longitudinal analyses of relationships between risk factors and disease prevalence and progression. Analysis of Centricity EMR data showed associations of age, sex, race/ethnicity, and BMI with diagnosed prevalence of the 3 conditions. Results include uniform direct correlations between age and BMI and prevalence of each disease; uniformly greater disease prevalence for males than females; varying differences by race/ethnicity (ie, African Americans have the highest prevalence of diagnosed type II diabetes and hypertension, while whites have the highest prevalence of diagnosed hypertension); and adverse effects of comorbidities. The direct associations between BMI and disease prevalence are consistent for males and females and across all racial/ethnic groups. The results reported herein contribute to the growing literature about the adverse effects of obesity on chronic disease prevalence and about the potential value of EMR data to elucidate trends in disease prevalence and facilitate longitudinal analyses.

Comparison of GE Centricity Electronic Medical Record database and National Ambulatory Medical Care Survey findings on the prevalence of major conditions in the United States.

The study objective was to facilitate investigations by assessing the external validity and generalizability of the Centricity Electronic Medical Record (EMR) database and analytical results to the US population using the National Ambulatory Medical Care Survey (NAMCS) data and results as an appropriate validation resource. Demographic and diagnostic data from the NAMCS were compared to similar data from the Centricity EMR database, and the impact of the different methods of data collection was analyzed. Compared to NAMCS survey data on visits, Centricity EMR data shows higher proportions of visits by younger patients and by females. Other comparisons suggest more acute visits in Centricity and more chronic visits in NAMCS. The key finding from the Centricity EMR is more visits for the 13 chronic conditions highlighted in the NAMCS survey, with virtually all comparisons showing higher proportions in Centricity. Although data and results from Centricity and NAMCS are not perfectly comparable, once techniques are employed to deal with limitations, Centricity data appear more sensitive in capturing diagnoses, especially chronic diagnoses. Likely explanations include differences in data collection using the EMR versus the survey, particularly more comprehensive medical documentation requirements for the Centricity EMR and its inclusion of laboratory results and medication data collected over time, compared to the survey, which focused on the primary reason for that visit. It is likely that Centricity data reflect medical problems more accurately and provide a more accurate estimate of the distribution of diagnoses in ambulatory visits in the United States. Further research should address potential methodological approaches to maximize the validity and utility of EMR databases.