γδ T Cells Are Reduced and Rendered Unresponsive by Hyperglycemia and Chronic TNFα in Mouse Models of Obesity and Metabolic Disease

Epithelial cells provide an initial line of defense against damage and pathogens in barrier tissues such as the skin; however this balance is disrupted in obesity and metabolic disease. Skin γδ T cells recognize epithelial damage, and release cytokines and growth factors that facilitate wound repair. We report here that hyperglycemia results in impaired skin γδ T cell proliferation due to altered STAT5 signaling, ultimately resulting in half the number of γδ T cells populating the epidermis. Skin γδ T cells that overcome this hyperglycemic state are unresponsive to epithelial cell damage due to chronic inflammatory mediators, including TNFα. Cytokine and growth factor production at the site of tissue damage was partially restored by administering neutralizing TNFα antibodies in vivo. Thus, metabolic disease negatively impacts homeostasis and functionality of skin γδ T cells, rendering host defense mechanisms vulnerable to injury and infection

Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” γδ T cells

Id3 is a dominant antagonist of E protein transcription factor activity that is induced by signals emanating from the alphabeta and gammadelta T cell receptor (TCR). Mice lacking Id3 were previously shown to have subtle defects in positive and negative selection of TCRalphabeta+ T lymphocytes. More recently, Id3(-/-) mice on a C57BL/6 background were shown to have a dramatic expansion of gammadelta T cells.Here we report that mice lacking Id3 have reduced thymocyte numbers but increased production of gammadelta T cells that express a Vgamma1.1+Vdelta6.3+ receptor with restricted junctional diversity. These Vgamma1.1+Vdelta6.3+ T cells have multiple characteristics associated with "innate" lymphocytes such as natural killer T (NKT) cells including an activated phenotype, expression of the transcription factor PLZF, and rapid production of IFNg and interleukin-4. Moreover, like other "innate" lymphocyte populations, development of Id3(-/-) Vgamma1.1+Vdelta6.3+ T cells requires the signaling adapter protein SAP.Our data provide novel insight into the requirements for development of Vgamma1.1+Vdelta6.3+ T cells and indicate a role for Id3 in repressing the response of "innate" gammadelta T cells to SAP-mediated expansion or survival

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics

Incorporating clinical guidelines through clinician decision-making

<p>Abstract</p> <p>Background</p> <p>It is generally acknowledged that a disparity between knowledge and its implementation is adversely affecting quality of care. An example commonly cited is the failure of clinicians to follow clinical guidelines. A guiding assumption of this view is that adherence should be gauged by a standard of conformance. At least some guideline developers dispute this assumption and claim that their efforts are intended to inform and assist clinical practice, not to function as standards of performance. However, their ability to assist and inform will remain limited until an alternative to the conformance criterion is proposed that gauges how evidence-based guidelines are incorporated into clinical decisions.</p> <p>Methods</p> <p>The proposed investigation has two specific aims to identify the processes that affect decisions about incorporating clinical guidelines, and then to develop ad test a strategy that promotes the utilization of evidence-based practices. This paper focuses on the first aim. It presents the rationale, introduces the clinical paradigm of treatment-resistant schizophrenia, and discusses an exemplar of clinician non-conformance to a clinical guideline. A modification of the original study is proposed that targets psychiatric trainees and draws on a cognitively rich theory of decision-making to formulate hypotheses about how the guideline is incorporated into treatment decisions. Twenty volunteer subjects recruited from an accredited psychiatry training program will respond to sixty-four vignettes that represent a fully crossed 2 × 2 × 2 × 4 within-subjects design. The variables consist of criteria contained in the clinical guideline and other relevant factors. Subjects will also respond to a subset of eight vignettes that assesses their overall impression of the guideline. Generalization estimating equation models will be used to test the study's principal hypothesis and perform secondary analyses.</p> <p>Implications</p> <p>The original design of phase two of the proposed investigation will be changed in recognition of newly published literature on the relative effectiveness of treatments for schizophrenia. It is suggested that this literature supports the notion that guidelines serve a valuable function as decision tools, and substantiates the importance of decision-making as the means by which general principles are incorporated into clinical practice.</p

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.ope

PSR J1740-3052: a pulsar with a massive companion

We report on the discovery of a binary pulsar, PSR J1740-3052, during the Parkes multibeam survey. Timing observations of the 570-ms pulsar at Jodrell Bank and Parkes show that it is young, with a characteristic age of 350 kyr, and is in a 23 1-d, highly eccentric orbit with a companion whose mass exceeds 11 M.. An accurate position for the pulsar was obtained using the Australia Telescope Compact Array. Near-infrared 2.2-mum observations made with the telescopes at the Siding Spring observatory reveal a late-type star coincident with the pulsar position. However, we do not believe that this star is the companion of the pulsar, because a typical star of this spectral type and required mass would extend beyond the orbit of the pulsar. Furthermore, the measured advance of periastron of the pulsar suggests a more compact companion, for example, a main-sequence star with radius only a few times that of the Sun. Such a companion is also more consistent with the small dispersion measure variations seen near periastron. Although we cannot conclusively rule out a black hole companion, we believe that the companion is probably an early B star, making the system similar to the binary PSR J0045-7319