182 research outputs found
Pulmonary surfactant and neutrophil function in cystic fibrosis
No full textSIGLEAvailable from British Library Document Supply Centre-DSC:DXN032545 / BLDSC - British Library Document Supply CentreGBUnited Kingdo
Knock-down of LAR protein tyrosine phosphatase induces insulin resistance
No full textTo test the role of the leukocyte common antigen-related protein tyrosine phosphatase (LAR) as a regulator of insulin receptor (IR) signalling, an siRNA probe against LAR was developed. Knock-down of LAR induced post-receptor insulin resistance with the insulin-induced activation of PKB/Akt and MAP kinases markedly inhibited. The phosphorylation and dephosphorylation of the IR and insulin receptor substrate (IRS) proteins were unaffected by LAR knock-down. These results identify LAR as a crucial regulator of the sensitivity of two key insulin signalling pathways to insulin. Moreover, the siRNA probe provides a molecular tool of general applicability for further dissecting the precise targets and roles of LAR
How does fair trade, as practised by Trade Aid and MINKA, contribute to the aspirations of Quechua producers in Peru?
No full textAs part of a Master of Indigenous Studies from the University of Otago, Trade Aid staff member, Michelia Ward, conducted research throughout 2011 and 2012 on whether fair trade is able to contribute to the aspirations of indigenous producers. The research focused on fair trade as practiced by Trade Aid, New Zealand and one of its Peruvian partners, MINKA.Fair trade is a development mechanism that aims to support food and craft producers around the world to improve their lives through trade. Many indigenous communities are producers of craft or food products such as woven textiles and coffee, and have engaged in fair trade relationships selling mainly to Western consumers. Fair trade organisations have universal principles that provide guarantees to consumers about working conditions, fair payment and trading relations with producer groups. This research project focuses on whether a universal framework designed to bring development to disadvantaged and marginalized producers can work for unique indigenous cultures across multiple continents. This research focuses on Trade Aid in New Zealand and their partnership with a Peruvian fair trade organisation, MINKA, who works with Quechua producers in the Andes. Indigenous theorists place large value on local epistemes (knowledge systems) and local solutions to local problems. Is fair trade one of these local solutions, or just another solution imposed from the outside upon indigenous producers
DNA fusion vaccines enter the clinic
No full textInduction of effective immune attack on cancer cells in patients requires conversion of weak tumor antigens into strong immunogens. Our strategy employs genetic technology to create DNA vaccines containing tumor antigen sequences fused to microbial genes. The fused microbial protein engages local CD4+ T cells to provide help for anti-tumor immunity, and to reverse potential regulation. In this review, we focus on induction of CD8+ T cells able to kill target tumor cells. The DNA vaccines incorporate tumor-derived peptide sequences fused to an engineered domain of tetanus toxin. In multiple models, this design induces strong CD8+ T-cell responses, able to suppress tumor growth. For clinical relevance, we have used "humanized" mice expressing HLA-A2, successfully inducing cytolytic T-cell responses against a range of candidate human peptides. To overcome physical restriction in translating to patients, we have used electroporation. Clinical trials of patients with cancer are showing induction of responses, with preliminary indications of suppression of tumor growth and evidence for clinically manageable concomitant autoimmunity
Identification of 80K-H as a protein involved in GLUT4 vesicle trafficking
No full textPKC? (protein kinase C? ) is a serine/threonine protein kinase controlled by insulin, various growth factors and phosphoinositide 3-kinase. It has been implicated in controlling glucose transport in response to insulin by the translocation of GLUT4-(glucose transporter 4) containing vesicles to the plasma membrane instimulated cells. How PKC? modulates GLUT4 vesicle trafficking remains unknown. A yeast two-hybrid screen using full-length humanPKC? identified80K-Hprotein as an interactor withPKC? . GST (glutathione S-transferase) pull-down assays with GSTtagged 80K-H constructs confirmed the interaction and showed that the N-terminal portion of 80K-H was not required for the interaction. Immunoprecipitates of endogenous PKC? from Cho cells, 3T3-L1 adipocytes or L6 myotubes contained endogenous 80K-H, demonstrating a physiological interaction. Insulin stimulation enhanced the association 3–5-fold. Immunoprecipitates of endogenous 80K-H contained endogenous munc18c and immunoprecipitates of endogenous munc18c contained endogenous PKC? , with insulin markedly increasing the amount of co-immunoprecipitated protein in each case. These results show that insulin triggers interactions in vivo between PKC? , 80K-H and munc18c. Overexpression of 80K-H constructs mimicked the action of insulin in stimulating both glucose uptake and translocation of Myc-tagged GLUT4 in Cho cells, with the level of effect proportional to the ability of the constructs to associate with munc18c. These results identify 80K-H as a new player involved in GLUT4 vesicle transport and identify a link between a kinase involved in the insulin signalling cascade, PKC?, and a known component of the GLUT4 vesicle trafficking pathway, munc18c. The results suggest amodelwhereby insulin triggers the formation of a PKC?–80K-H–munc18c complex that enhances GLUT4 translocation to the plasma membrane
Fit for purpose? A case study: validation of immunological endpoint assays for the detection of cellular and humoral responses to anti-tumour DNA fusion vaccines.
No full textClinical trials are governed by an increasingly stringent regulatory framework, which applies to all levels of trial conduct. Study critical immunological endpoints, which define success or failure in early phase clinical immunological trials, require formal pre-trial validation. In this case study, we describe the assay validation process, during which the sensitivity, and precision of immunological endpoint assays were defined. The purpose was the evaluation of two multicentre phase I/II clinical trials from our unit in Southampton, UK, which assess the effects of DNA fusion vaccines on immune responses in HLA-A2+ patients with carcinoembryonic antigen (CEA)-expressing malignancies and prostate cancer. Validated immunomonitoring is being performed using ELISA and IFNgamma ELISPOTs to assess humoral and cellular responses to the vaccines over time. The validated primary endpoint assay, a peptide-specific CD8+ IFNgamma ELISPOT, was tested in a pre-trial study and found to be suitable for the detection of low frequency naturally occurring CEA- and prostate-derived tumour-antigen-specific T cells in patients with CEA-expressing malignancies and prostate cancer
DNA vaccination with electroporation induces increased antibody responses in patients with prostate cancer
No full textWe are evaluating the use of electroporation (EP) to deliver a novel DNA vaccine, p.DOM-PSMA(27). This vaccine encodes a domain (DOM) of fragment C of tetanus toxin to induce CD4(+) T cell help, fused to a tumor-derived epitope from prostate-specific membrane antigen (PSMA) for use in HLA-A2(+) patients with recurrent prostate cancer. We report on safety and tolerability and on antibody response to DOM as a first indication of the effect of EP in patients. In this open label phase I/II, two-arm, dose escalation trial DNA was delivered either by intramuscular injection or by intramuscular injection followed by EP (DNA+EP), with five patients per dose level. Three vaccinations were given at 0, 4, and 8 weeks,with booster doses at 24 and 48 weeks; here we allowed crossover between study arms if supported by the safety and immunological data. In the 20 patients in the first two dose cohorts we observed that beyond brief and acceptable pain at the injection site, EP did not appear to add toxicity to the vaccination. We evaluated humoral responses to DOM. Low anti-DOM IgG antibody responses were observed after intramuscular injection of DNA without EP (at week 12: mean 1.7- vs. 24.5-fold increase over baseline with DNA+EP). These could be boosted by delivery of DNA+EP at later time points. Delivery of DNA+EP at all five vaccinations yielded the highest levels of anti-DOM antibody. Responses persisted to 18 months of follow-up. These data establish EP as a potent method for stimulating humoral responses induced by DNA vaccination in humans
Altered phospholipid composition and aggregate structure of lung surfactant is associated with impaired lung function in young children with respiratory infections
No full textAlterations to pulmonary surfactant structure, composition, and function contribute to the severity of respiratory infections. Analysis of bronchoalveolar lavage fluid (BALF) from children undergoing diagnostic bronchoscopy for structural abnormalities (control group, n = 24), asthma (n = 18), lung infection (n = 30), and cystic fibrosis (CF, n = 15) showed that BALF phospholipid concentration decreased with age for the control group and was elevated in all disease groups. The fractional concentration of the major surface active component, dipalmitoyl phosphatidylcholine (PC16:0/16:0), correlated (r2 = 0.608, P < 0.01) with airway resistance (FEV1% predicted), and decreased PC16:0/16:0 was accompanied by increased concentrations of phospholipid components characteristic of cell membranes (PC16:0/18:1 and PI18:0/20:4). Median minimal surface tension, measured by pulsating bubble surfactometer, was elevated (P < 0.01) in both infection (17.5 mN/m) and CF (17.1 mN/m) compared with the control group (1.5 mN/m). Centrifugation (60,000 x g, 40 min) of BALF indicated that infection was accompanied by accumulation of large aggregate forms of surfactant, in contrast to previous reports of increased conversion to inactive small aggregate surfactant particles in ventilated patients with respiratory failure. This accumulation of surface-inactive, large aggregate forms of surfactant, possibly due to mixing with membrane material from inflammatory cells, may contribute to severity of lung disease in children with respiratory infections
2002 Australian Teacher Education Association Conference (2002 ATEA)
No full textHigher education communities are not immune from the demands of the knowledge. New technologies, rapidly evolving knowledge and policies promoting standards, outcomes and graduate attributes exhort pedagogical revision and renewal. Facilities are pressured by downsizing, global market competition and increased accountability to the public (Pierce, 1998). Consumer demands exhort educational institutions to renew their programs and processes to develop unique identities and approaches to educational provision.
This paper aims to describe the procedures, processes and protocols exercised by staff engaged in a strategic review of their Faculty of Education. It commences with an exploration of education reform and the reconceptualising of pedagogy in one learning organisation. The paper is written from the perspective of the author-participants. Outcomes to date are sharing in the context of discussing about organisation learning
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