IRX-2, a Novel Immunotherapeutic, Enhances Functions of Human Dendritic Cells

Background: In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Methodology/Principal Findings: Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Conclusion: Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy. © 2013 Schilling et al

Geographic range did not confer resilience to extinction in terrestrial vertebrates at the end-Triassic crisis

Rates of extinction vary greatly through geological time, with losses particularly concentrated in mass extinctions. Species duration at other times varies greatly, but the reasons for this are unclear. Geographical range correlates with lineage duration amongst marine invertebrates, but it is less clear how far this generality extends to other groups in other habitats. It is also unclear whether a wide geographical distribution makes groups more likely to survive mass extinctions. Here we test for extinction selectivity amongst terrestrial vertebrates across the end-Triassic event. We demonstrate that terrestrial vertebrate clades with larger geographical ranges were more resilient to extinction than those with smaller ranges throughout the Triassic and Jurassic. However, this relationship weakened with increasing proximity to the end-Triassic mass extinction, breaking down altogether across the event itself. We demonstrate that these findings are not a function of sampling biases; a perennial issue in studies of this kind

Neuronal circuitry for pain processing in the dorsal horn

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region

Ingestion of micronutrient fortified breakfast cereal has no influence on immune function in healthy children: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>This study investigated the influence of 2-months ingestion of an "immune" nutrient fortified breakfast cereal on immune function and upper respiratory tract infection (URTI) in healthy children during the winter season.</p> <p>Methods</p> <p>Subjects included 73 children (N = 42 males, N = 31 females) ranging in age from 7 to 13 years (mean ± SD age, 9.9 ± 1.7 years), and 65 completed all phases of the study. Subjects were randomized to one of three groups--low, moderate, or high fortification--with breakfast cereals administered in double blinded fashion. The "medium" fortified cereal contained B-complex vitamins, vitamins A and C, iron, zinc, and calcium, with the addition of vitamin E and higher amounts of vitamins A and C, and zinc in the "high" group. Immune measures included delayed-typed hypersensitivity, global IgG antibody response over four weeks to pneumococcal vaccination, salivary IgA concentration, natural killer cell activity, and granulocyte phagocytosis and oxidative burst activity. Subjects under parental supervision filled in a daily log using URTI symptoms codes.</p> <p>Results</p> <p>Subjects ingested 3337 ± 851 g cereal during the 2-month study, which represented 14% of total diet energy intake and 20-85% of selected vitamins and minerals. Despite significant increases in nutrient intake, URTI rates and pre- to- post-study changes in all immune function measures did not differ between groups.</p> <p>Conclusions</p> <p>Data from this study indicate that ingestion of breakfast cereal fortified with a micronutrient blend for two winter months by healthy, growing children does not significantly influence biomarkers for immune function or URTI rates.</p

Impulsivity and self-harm in adolescence: a systematic review

Research supports an association between impulsivity and self-harm, yet inconsistencies in methodology across studies have complicated understanding of this relationship. This systematic review examines the association between impulsivity and self-harm in community-based adolescents aged 11-25 years and aims to integrate findings according to differing concepts and methods. Electronic searches of EMBASE, MEDLINE, PsychINFO, CINAHL, PubMed and The Cochrane Library, and manual searches of reference lists of relevant reviews, identified 4,496 articles published up to July 2015, of which 28 met inclusion criteria. Twenty-four of the studies reported an association between broadly specified impulsivity and self-harm. However, findings varied according to the conception and measurement of impulsivity and the precision with which self-harm behaviours were specified. Specifically, lifetime non-suicidal self-injury was most consistently associated with mood-based impulsivity related traits. However, cognitive facets of impulsivity (relating to difficulties maintaining focus or acting without forethought) differentiated current self-harm from past self-harm. These facets also distinguished those with thoughts of self-harm (ideation) from those who acted on thoughts (enaction). The findings suggested that mood-based impulsivity is related to the initiation of self-harm, while cognitive facets of impulsivity are associated with the maintenance of self-harm. In addition, behavioural impulsivity is most relevant to self-harm under conditions of negative affect. Collectively, the findings indicate that distinct impulsivity facets confer unique risks across the life-course of self-harm. From a clinical perspective, the review suggests that interventions focusing on reducing rash reactivity to emotions or improving self-regulation and decision-making may offer most benefit in supporting those who self-harm

Developmental Considerations for Assessment and Treatment of Impulsivity in Older Adults

Impulsivity is an important factor in many clinical disorders, especially alcohol and substance use disorders. Most of the research on impulsivity in this domain has focused on adolescence and young adulthood, as this developmental period is characterized by onset of and escalation in alcohol and substance use, likely driven in part by brain development patterns. Although many individuals eventually “mature out” of these behaviors in middle adulthood, a critical subset of people do not. The role of impulsivity in middle-to-older adulthood, when certain individuals transition from normative to disordered substance use, has not been carefully examined. The goal of this paper is to review the literature on measuring and modifying impulsivity from adolescence through older adulthood, with a special focus on middle-to-older adulthood. We propose that impulsivity research should include data on middle-to-older adulthood as an important time of transition to disordered use. We consider how impulsivity might have unique meaning at different stages of the adult lifespan and suggest modifications for assessing and treating impulsivity in older adults

Functional Relationship between Skull Form and Feeding Mechanics in Sphenodon, and Implications for Diapsid Skull Development

The vertebrate skull evolved to protect the brain and sense organs, but with the appearance of jaws and associated forces there was a remarkable structural diversification. This suggests that the evolution of skull form may be linked to these forces, but an important area of debate is whether bone in the skull is minimised with respect to these forces, or whether skulls are mechanically “over-designed” and constrained by phylogeny and development. Mechanical analysis of diapsid reptile skulls could shed light on this longstanding debate. Compared to those of mammals, the skulls of many extant and extinct diapsids comprise an open framework of fenestrae (window-like openings) separated by bony struts (e.g., lizards, tuatara, dinosaurs and crocodiles), a cranial form thought to be strongly linked to feeding forces. We investigated this link by utilising the powerful engineering approach of multibody dynamics analysis to predict the physiological forces acting on the skull of the diapsid reptile Sphenodon. We then ran a series of structural finite element analyses to assess the correlation between bone strain and skull form. With comprehensive loading we found that the distribution of peak von Mises strains was particularly uniform throughout the skull, although specific regions were dominated by tensile strains while others were dominated by compressive strains. Our analyses suggest that the frame-like skulls of diapsid reptiles are probably optimally formed (mechanically ideal: sufficient strength with the minimal amount of bone) with respect to functional forces; they are efficient in terms of having minimal bone volume, minimal weight, and also minimal energy demands in maintenance