T cell responses induced by adenoviral vectored vaccines can be adjuvanted by fusion of antigen to the oligomerization domain of C4b-binding protein.

Viral vectored vaccines have been shown to induce both T cell and antibody responses in animals and humans. However, the induction of even higher level T cell responses may be crucial in achieving vaccine efficacy against difficult disease targets, especially in humans. Here we investigate the oligomerization domain of the α-chain of C4b-binding protein (C4 bp) as a candidate T cell "molecular adjuvant" when fused to malaria antigens expressed by human adenovirus serotype 5 (AdHu5) vectored vaccines in BALB/c mice. We demonstrate that i) C-terminal fusion of an oligomerization domain can enhance the quantity of antigen-specific CD4(+) and CD8(+) T cell responses induced in mice after only a single immunization of recombinant AdHu5, and that the T cells maintain similar functional cytokine profiles; ii) an adjuvant effect is observed for AdHu5 vectors expressing either the 42 kDa C-terminal domain of Plasmodium yoelii merozoite surface protein 1 (PyMSP1(42)) or the 83 kDa ectodomain of P. falciparum strain 3D7 apical membrane antigen 1 (PfAMA1), but not a candidate 128kDa P. falciparum MSP1 biallelic fusion antigen; iii) following two homologous immunizations of AdHu5 vaccines, antigen-specific T cell responses are further enhanced, however, in both BALB/c mice and New Zealand White rabbits no enhancement of functional antibody responses is observed; and iv) that the T cell adjuvant activity of C4 bp is not dependent on a functional Fc-receptor γ-chain in the host, but is associated with the oligomerization of small (<80 kDa) antigens expressed by recombinant AdHu5. The oligomerization domain of C4 bp can thus adjuvant T cell responses induced by AdHu5 vectors against selected antigens and its clinical utility as well as mechanism of action warrant further investigation

Toward the Discovery of Vaccine Adjuvants: Coupling In Silico Screening and In Vitro Analysis of Antagonist Binding to Human and Mouse CCR4 Receptors

BACKGROUND: Adjuvants enhance or modify an immune response that is made to an antigen. An antagonist of the chemokine CCR4 receptor can display adjuvant-like properties by diminishing the ability of CD4+CD25+ regulatory T cells (Tregs) to down-regulate immune responses. METHODOLOGY: Here, we have used protein modelling to create a plausible chemokine receptor model with the aim of using virtual screening to identify potential small molecule chemokine antagonists. A combination of homology modelling and molecular docking was used to create a model of the CCR4 receptor in order to investigate potential lead compounds that display antagonistic properties. Three-dimensional structure-based virtual screening of the CCR4 receptor identified 116 small molecules that were calculated to have a high affinity for the receptor; these were tested experimentally for CCR4 antagonism. Fifteen of these small molecules were shown to inhibit specifically CCR4-mediated cell migration, including that of CCR4(+) Tregs. SIGNIFICANCE: Our CCR4 antagonists act as adjuvants augmenting human T cell proliferation in an in vitro immune response model and compound SP50 increases T cell and antibody responses in vivo when combined with vaccine antigens of Mycobacterium tuberculosis and Plasmodium yoelii in mice

Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases

Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion with flhDC increases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors

HOSPICIJ-POTREBA HUMANOG DRUŠTVA

Hrvatsko zakonodavstvo i regulativa palijativne skrbi imaju postavljene neke smjernice za razvoj u Republici Hrvatskoj. Međutim, da uhvatimo korak s razvijenim zemljama treba puno toga pravno i organizacijski urediti. Imamo znanje, imamo volju , imamo svijest nesebičnog djelovanja, ali nemamo financijske mogućnosti u ovom trenutku.O palijativnoj skrbi svaki pojedinac počinje razmišljati tek onda kada mu se razboli član njegove obitelji. Da smo u stanju podići ovu djelatnost u prioritete, našla bi se i sredstva za nju. Da bismo mogli iskoristiti znanje koje imamo treba odmah djelovati. To neće biti jednostavan proces, no u svijetu postoji puno modela i primjera, pa bi se uz iskustvo drugih, naš stručni kadar, te djelovanje na fleksibilnost hrvatske birokracije, okolnosti mogle promijeniti u pozitivnom smislu. Ne zbog nas, ali možda i za nas

The WiggleZ Dark Energy Survey: Survey Design and First Data Release

The WiggleZ Dark Energy Survey is a survey of 240,000 emission line galaxies in the distant universe, measured with the AAOmega spectrograph on the 3.9-m Anglo-Australian Telescope (AAT). The target galaxies are selected using ultraviolet photometry from the GALEX satellite, with a flux limit of NUV<22.8 mag. The redshift range containing 90% of the galaxies is 0.2<z<1.0. The primary aim of the survey is to precisely measure the scale of baryon acoustic oscillations (BAO) imprinted on the spatial distribution of these galaxies at look-back times of 4-8 Gyrs. Detailed forecasts indicate the survey will measure the BAO scale to better than 2% and the tangential and radial acoustic wave scales to approximately 3% and 5%, respectively. This paper provides a detailed description of the survey and its design, as well as the spectroscopic observations, data reduction, and redshift measurement techniques employed. It also presents an analysis of the properties of the target galaxies, including emission line diagnostics which show that they are mostly extreme starburst galaxies, and Hubble Space Telescope images, which show they contain a high fraction of interacting or distorted systems. In conjunction with this paper, we make a public data release of data for the first 100,000 galaxies measured for the project.Comment: Accepted by MNRAS; this has some figures in low resolution format. Full resolution PDF version (7MB) available at http://www.physics.uq.edu.au/people/mjd/pub/wigglez1.pdf The WiggleZ home page is at http://wigglez.swin.edu.au

Safety profile of autologous macrophage therapy for liver cirrhosis

This work was supported by a Medical Research Council UK grant (Biomedical Catalyst Major Awards Committee; reference MR/M007588/1) to S.J. Forbes. We thank Z.M. Younossi (Center for Outcomes Research in Liver Diseases, Washington, DC, USA) for academic use of the CLDQ instrument and L.J. Fallowfield (Sussex Health Outcomes Research & Education in Cancer (SHORE-C), University of Sussex, UK) for advice about health-related quality of life assessment.Peer reviewedPostprintPostprintPostprintPostprin

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS

Genetic errors of immunity distinguish pediatric non-malignant lymphoproliferative disorders

Background Pediatric non-malignant lymphoproliferative disorders (PLPD) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. Objective The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. Methods PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing (WES). Results WES identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, p = 0.03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs. 90%; p = 0.002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. Conclusion PLPD therefore defines children with high risk for mortality, and WES informs clinical risks and therapeutic opportunities for this diagnosis