Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis

<p>Abstract</p> <p>Background</p> <p>Melanoma vaccines have not been optimized. Adjuvants are added to activate dendritic cells (DCs) and to induce a favourable immunologic milieu, however, little is known about their cellular and molecular effects in human skin. We hypothesized that a vaccine in incomplete Freund's adjuvant (IFA) would increase dermal Th1 and Tc1-lymphocytes and mature DCs, but that repeated vaccination may increase regulatory cells.</p> <p>Methods</p> <p>During and after 6 weekly immunizations with a multipeptide vaccine, immunization sites were biopsied at weeks 0, 1, 3, 7, or 12. In 36 participants, we enumerated DCs and lymphocyte subsets by immunohistochemistry and characterized their location within skin compartments.</p> <p>Results</p> <p>Mature DCs aggregated with lymphocytes around superficial vessels, however, immature DCs were randomly distributed. Over time, there was no change in mature DCs. Increases in T and B-cells were noted. Th2 cells outnumbered Th1 lymphocytes after 1 vaccine 6.6:1. Eosinophils and FoxP3⁺cells accumulated, especially after 3 vaccinations, the former cell population most abundantly in deeper layers.</p> <p>Conclusions</p> <p>A multipeptide/IFA vaccine may induce a Th2-dominant microenvironment, which is reversed with repeat vaccination. However, repeat vaccination may increase FoxP3⁺T-cells and eosinophils. These data suggest multiple opportunities to optimize vaccine regimens and potential endpoints for monitoring the effects of new adjuvants.</p> <p>Trail Registration</p> <p>ClinicalTrials.gov Identifier: NCT00705640</p

Quark-meson-diquark model for two-color QCD

We introduce a two-flavor quark-meson-diquark model for two-color QCD and its extensions to include gauge-field dynamics as described by the Polakov loop. Grand potential and phase structure are being studied both in mean-field approximation and with the functional renormalization group. The model provides an explicit example for the importance of baryonic degrees of freedom: When they are omitted, the phase diagram closely resembles that of the corresponding (Polyakov)-quark-meson models for QCD, in particular including their critical endpoint. In order to reproduce the well established main features based on the symmetries and breaking patterns of two-color QCD, however, they must be included and there is no critical endpoint. The competing dynamics of collective mesonic and baryonic fluctuations is well described by the functional renormalization group equation in lowest order derivative expansion for the effective potential which we solve numerically on a two-dimensional grid in field space.Comment: 22 pages, pdflatex, 11 pdf figures; v2: minor revisions to the text, one additional figure, accepted for publication in PR

How sharp is the chiral crossover phenomenon for realistic meson masses?

The mass dependence of the chiral phase transition is studied in the linear $SU(3)\times SU(3)$ sigma-model to leading order in a $1/N_f$-expansion, $N_f$ denoting the number of flavours. For realistic meson masses we find a smooth crossover between $T\sim181.5$ to 192.6~[MeV]. The crossover looks more rapid in the light quark condensate than in thermodynamic quantities like the energy and entropy densities. The change in the light quark condensate in this temperature interval is $\sim$~50\% of the zero-temperature condensate value, while the entropy density increases by ($5.5\pm0.8)\cdot10^{-3}$~[GeV$^3$]. Since the numerical error is particularly large in this region, we cannot rule out a finite latent heat smaller than 0.2~[GeV/fm$^3$]. The chiral transition is washed out for an average pseudoscalar meson octet mass of 203~[MeV]. This gives an upper bound on the first-order transition region in the meson mass parameter space. The corresponding ratio of critical to realistic light current quark masses $m^{crit}_{u,d}/m_{u,d}$ is estimated as $0.26\pm0.08$. This result is by an order of magnitude larger than the corresponding mean-field value. Therefore theComment: LaTeX, HD--TVP--94--16, Please contact authors via email for figure

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma;however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands

Long-term results of radiotherapy for periarthritis of the shoulder: a retrospective evaluation

<p>Abstract</p> <p>Background</p> <p>To evaluate retrospectively the results of radiotherapy for periarthritis of the shoulder</p> <p>Methods</p> <p>In 1983–2004, 141 patients were treated, all had attended at least one follow-up examination. 19% had had pain for several weeks, 66% for months and 14% for years. Shoulder motility was impaired in 137/140 patients. Nearly all patients had taken oral analgesics, 81% had undergone physiotherapy, five patients had been operated on, and six had been irradiated. Radiotherapy was applied using regular anterior-posterior opposing portals and Co-60 gamma rays or 4 MV photons. 89% of the patients received a total dose of 6 Gy (dose/fraction of 1 Gy twice weekly, the others had total doses ranging from 4 to 8 Gy. The patients and the referring doctors were given written questionnaires in order to obtain long-term results. The mean duration of follow-up was 6.9 years [0–20 years].</p> <p>Results</p> <p>During the first follow-up examination at the end of radiotherapy 56% of the patients reported pain relief and improvement of motility. After in median 4.5 months the values were 69 and 89%, after 3.9 years 73% and 73%, respectively. There were virtually no side effects. In the questionnaires, 69% of the patients reported pain relief directly after radiotherapy, 31% up to 12 weeks after radiotherapy. 56% of the patients stated that pain relief had lasted for "years", in further 12% at least for "months".</p> <p>Conclusion</p> <p>Low-dose radiotherapy for periarthropathy of the shoulder was highly effective and yielded long-lasting improvement of pain and motility without side effects.</p

The SAMI Galaxy Survey: Cubism and covariance, putting round pegs into square holes

We present a methodology for the regularization and combination of sparse sampled and irregularly gridded observations from fibre-optic multiobject integral field spectroscopy. The approach minimizes interpolation and retains image resolution on combining subpixel dithered data. We discuss the methodology in the context of the Sydney-AAO multiobject integral field spectrograph (SAMI) Galaxy Survey underway at the Anglo-Australian Telescope. The SAMI instrument uses 13 fibre bundles to perform high-multiplex integral field spectroscopy across a 1° diameter field of view. The SAMI Galaxy Survey is targeting ~3000 galaxies drawn from the full range of galaxy environments. We demonstrate the subcritical sampling of the seeing and incomplete fill factor for the integral field bundles results in only a 10 per cent degradation in the final image resolution recovered. We also implement a new methodology for tracking covariance between elements of the resulting data cubes which retains 90 per cent of the covariance information while incurring only a modest increase in the survey data volume

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

The SAMI Galaxy Survey : data release one with emission-line physics value-added products

SAMI DR1 data products available from http://datacentral.aao.gov.au/asvo/surveys/sami/We present the first major release of data from the SAMI Galaxy Survey. This data release focuses on the emission-line physics of galaxies. Data Release One includes data for 772 galaxies, about 20% of the full survey. Galaxies included have the redshift range 0.004 <  z < 0.092, a large massrange (7.6 < log M∗/M⊙ < 11.6), and star-formation rates of ∼10−4 to ∼101 M⊙yr−1. For each galaxy, we include two spectral cubes and a set of spatially resolved 2D maps: single- and multi-component emission-line fits (with dust extinction corrections for strong lines), local dust extinction and star-formation rate. Calibration of the fibre throughputs, fluxes and differential-atmospheric-refraction has been improved over the Early Data Release. The data have average spatial resolution of 2.16 arcsec (FWHM) over the 15 arcsec diameter field of view and spectral (kinematic) resolution R= 4263 (σ= 30 km s−1) around Hα. The relative flux calibration is better than 5% and absolute flux calibration better than ±0.22 mag, with the latter estimate limited by galaxy photometry. The data are presented online through the Australian Astronomical Observatory’s Data Central.Publisher PDFPeer reviewe