Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG

Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). Conclusions: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccine

Specialist role coaching and skill training periodisation: A football goalkeeping case study

© The Author(s) 2020. In sports like association football, professional teams are increasingly devoting resources to the role-based development of individual athletes and sub-groups. By employing ‘specialist coaches’ into athlete-support structures, clubs aim to facilitate individualised athlete training programs to enhance performance preparation as well as skill learning and talent development. Here, we discuss how contemporary pedagogical training approaches, like Nonlinear Pedagogy and the Constraints-Led approach, can enhance effectiveness of specialist role-based athlete development programs to facilitate performance functionality. We argue the need for a model of specialist role-based coaching practice in high performance sports organisations, based on a unified theoretical rationale, such as ecological dynamics. To exemplify the nature of specialist role-based coaching, a case study addresses how Nonlinear Pedagogy and Constraints-Led approach are being used for training professional football goalkeepers in an U23 years age group. Integrating key concepts from ecological dynamics, allied to principles of Nonlinear Pedagogy and the Constraints-Led approach, common skill training principles for specialist role coaches are highlighted. These illustrate the use of the recently introduced ‘Periodization of Skill Training’ framework for specialist role coaching, practically exemplifying a way to harness opportunities for performance enhancement and individualised talent development in the football goalkeeping context

Genomic epidemiology and population structure of Neisseria gonorrhoeae from remote highly endemic Western Australian populations

Background: Neisseria gonorrhoeae causes gonorrhoea, the second most commonly notified sexually transmitted infection in Australia. One of the highest notification rates of gonorrhoea is found in the remote regions of Western Australia (WA). Unlike isolates from the major Australian population centres, the remote community isolates have low rates of antimicrobial resistance (AMR). Population structure and whole-genome comparison of 59 isolates from the Western Australian N. gonorrhoeae collection were used to investigate relatedness of isolates cultured in the metropolitan and remote areas. Core genome phylogeny, multilocus sequencing typing (MLST), N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) in addition to hierarchical clustering of sequences were used to characterize the isolates. Results: Population structure analysis of the 59 isolates together with 72 isolates from an international collection, revealed six population groups suggesting that N. gonorrhoeae is a weakly clonal species. Two distinct population groups, Aus1 and Aus2, represented 63% of WA isolates and were mostly composed of the remote community isolates that carried no chromosomal AMR genotypes. In contrast, the Western Australian metropolitan isolates were frequently multi-drug resistant and belonged to population groups found in the international database, suggesting international transmission of the isolates. Conclusions: Our study suggests that the population structure of N. gonorrhoeae is distinct between the communities in remote and metropolitan WA. Given the high rate of AMR in metropolitan regions, ongoing surveillance is essential to ensure the enduring efficacy of the empiric gonorrhoea treatment in remote WA

Single and repeated moderate consumption of native or dealcoholized red wine show different effects on antioxidant parameters in blood and DNA strand breaks in peripheral leukocytes in healthy volunteers: a randomized controlled trial [ISRCTN68505294]

BACKGROUND: Red wine (RW) is rich in antioxidant polyphenols that might protect from oxidative stress related diseases, such as cardiovascular disease and cancer. Antioxidant effects after single ingestion of RW or dealcoholized RW (DRW) have been observed in several studies, but results after regular consumption are contradictory. Thus, we examined if single or repeated consumption of moderate amounts of RW or DRW exert antioxidant activity in vivo. METHODS: Total phenolic content and concentration of other antioxidants in plasma/serum, total antioxidant capacity (TEAC) in plasma as well as DNA strand breaks in peripheral leukocytes were measured in healthy non-smokers A) before, 90 and 360 min after ingestion of one glass of RW, DRW or water; B) before and after consumption of one glass of RW or DRW daily for 6 weeks. DNA strand breaks (SB) were determined by single cell gel electrophoresis (Comet Assay) in untreated cells and after induction of oxidative stress ex vivo with H(2)O(2 )(300 μM, 20 min). RESULTS: Both RW and DRW transiently increased total phenolic content in plasma after single consumption, but only RW lead to a sustained increase if consumed regularly. Plasma antioxidant capacity was not affected by single or regular consumption of RW or DRW. Effects of RW and DRW on DNA SB were conflicting. DNA strand breaks in untreated cells increased after a single dose of RW and DRW, whereas H(2)O(2 )induced SB were reduced after DRW. In contrast, regular RW consumption reduced SB in untreated cells but did not affect H(2)O(2 )induced SB. CONCLUSION: The results suggest that consumption of both RW and DRW leads to an accumulation of phenolic compounds in plasma without increasing plasma antioxidant capacity. Red wine and DRW seem to affect the occurrence of DNA strand breaks, but this cannot be referred to antioxidant effects

Plant Food Delphinidin-3-Glucoside Significantly Inhibits Platelet Activation and Thrombosis: Novel Protective Roles against Cardiovascular Diseases

Delphinidin-3-glucoside (Dp-3-g) is one of the predominant bioactive compounds of anthocyanins in many plant foods. Although several anthocyanin compounds have been reported to be protective against cardiovascular diseases (CVDs), the direct effect of anthocyanins on platelets, the key players in atherothrombosis, has not been studied. The roles of Dp-3-g in platelet function are completely unknown. The present study investigated the effects of Dp-3-g on platelet activation and several thrombosis models in vitro and in vivo. We found that Dp-3-g significantly inhibited human and murine platelet aggregation in both platelet-rich plasma and purified platelets. It also markedly reduced thrombus growth in human and murine blood in perfusion chambers at both low and high shear rates. Using intravital microscopy, we observed that Dp-3-g decreased platelet deposition, destabilized thrombi, and prolonged the time required for vessel occlusion. Dp-3-g also significantly inhibited thrombus growth in a carotid artery thrombosis model. To elucidate the mechanisms, we examined platelet activation markers via flow cytometry and found that Dp-3-g significantly inhibited the expression of P-selectin, CD63, CD40L, which reflect platelet α- and δ-granule release, and cytosol protein secretion, respectively. We further demonstrated that Dp-3-g downregulated the expression of active integrin αIIbβ3 on platelets, and attenuated fibrinogen binding to platelets following agonist treatment, without interfering with the direct interaction between fibrinogen and integrin αIIbβ3. We found that Dp-3-g reduced phosphorylation of adenosine monophosphate-activated protein kinase, which may contribute to the observed inhibitory effects on platelet activation. Thus, Dp-3-g significantly inhibits platelet activation and attenuates thrombus growth at both arterial and venous shear stresses, which likely contributes to its protective roles against thrombosis and CVDs

Gut microbiota functions: metabolism of nutrients and other food components

The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference