Exosomal cancer immunotherapy is independent of MHC molecules on exosomes

Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, we investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. We show that ovalbumin-loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans

Spectrally and temporally resolved estimation of neural signal diversity

Quantifying the complexity of neural activity has provided fundamental insights into cognition, consciousness, and clinical conditions. However, the most widely used approach to estimate the complexity of neural dynamics, Lempel-Ziv complexity (LZ), has fundamental limitations that substantially restrict its domain of applicability. In this article we leverage the information-theoretic foundations of LZ to overcome these limitations by introducing a complexity estimator based on state-space models — which we dub Complexity via State-space Entropy Rate (CSER). While having a performance equivalent to LZ in discriminating states of consciousness, CSER boasts two crucial advantages: 1) CSER offers a principled decomposition into spectral components, which allows us to rigorously investigate the relationship between complexity and spectral power; and 2) CSER provides a temporal resolution two orders of magnitude better than LZ, which allows complexity analyses of e.g. event-locked neural signals. As a proof of principle, we use MEG, EEG and ECoG datasets of humans and monkeys to show that CSER identifies the gamma band as the main driver of complexity changes across states of consciousness; and reveals early entropy increases that precede the standard ERP in an auditory mismatch negativity paradigm by approximately 20ms. Overall, by overcoming the main limitations of LZ and substantially extending its range of applicability, CSER opens the door to novel investigations on the fine-grained spectral and temporal structure of the signal complexity associated with cognitive processes and conscious states

THE HIGH CADENCE TRANSIENT SURVEY (HITS). I. SURVEY DESIGN AND SUPERNOVA SHOCK BREAKOUT CONSTRAINTS

Indexación: Web of Science; Scopus.We present the first results of the High Cadence Transient Survey (HiTS), a survey for which the objective is to detect and follow-up optical transients with characteristic timescales from hours to days, especially the earliest hours of supernova (SN) explosions. HiTS uses the Dark Energy Camera and a custom pipeline for image subtraction, candidate filtering and candidate visualization, which runs in real-time to be able to react rapidly to the new transients. We discuss the survey design, the technical challenges associated with the real-time analysis of these large volumes of data and our first results. In our 2013, 2014, and 2015 campaigns, we detected more than 120 young SN candidates, but we did not find a clear signature from the short-lived SN shock breakouts (SBOs) originating after the core collapse of red supergiant stars, which was the initial science aim of this survey. Using the empirical distribution of limiting magnitudes from our observational campaigns, we measured the expected recovery fraction of randomly injected SN light curves, which included SBO optical peaks produced with models from Tominaga et al. (2011) and Nakar & Sari (2010). From this analysis, we cannot rule out the models from Tominaga et al. (2011) under any reasonable distributions of progenitor masses, but we can marginally rule out the brighter and longer-lived SBO models from Nakar & Sari (2010) under our best-guess distribution of progenitor masses. Finally, we highlight the implications of this work for future massive data sets produced by astronomical observatories, such as LSST.http://iopscience.iop.org/article/10.3847/0004-637X/832/2/155/meta;jsessionid=76BDFFFE378003616F6DBA56A9225673.c4.iopscience.cld.iop.or

Effect of non-random mating on genomic and BLUP selection schemes

<p>Abstract</p> <p>Background</p> <p>The risk of long-term unequal contribution of mating pairs to the gene pool is that deleterious recessive genes can be expressed. Such consequences could be alleviated by appropriately designing and optimizing breeding schemes i.e. by improving selection and mating procedures.</p> <p>Methods</p> <p>We studied the effect of mating designs, random, minimum coancestry and minimum covariance of ancestral contributions on rate of inbreeding and genetic gain for schemes with different information sources, i.e. sib test or own performance records, different genetic evaluation methods, i.e. BLUP or genomic selection, and different family structures, i.e. factorial or pair-wise.</p> <p>Results</p> <p>Results showed that substantial differences in rates of inbreeding due to mating design were present under schemes with a pair-wise family structure, for which minimum coancestry turned out to be more effective to generate lower rates of inbreeding. Specifically, substantial reductions in rates of inbreeding were observed in schemes using sib test records and BLUP evaluation. However, with a factorial family structure, differences in rates of inbreeding due mating designs were minor. Moreover, non-random mating had only a small effect in breeding schemes that used genomic evaluation, regardless of the information source.</p> <p>Conclusions</p> <p>It was concluded that minimum coancestry remains an efficient mating design when BLUP is used for genetic evaluation or when the size of the population is small, whereas the effect of non-random mating is smaller in schemes using genomic evaluation.</p

Does inter-vertebral range of motion increase after spinal manipulation? A prospective cohort study.

Background: Spinal manipulation for nonspecific neck pain is thought to work in part by improving inter-vertebral range of motion (IV-RoM), but it is difficult to measure this or determine whether it is related to clinical outcomes. Objectives: This study undertook to determine whether cervical spine flexion and extension IV-RoM increases after a course of spinal manipulation, to explore relationships between any IV-RoM increases and clinical outcomes and to compare palpation with objective measurement in the detection of hypo-mobile segments. Method: Thirty patients with nonspecific neck pain and 30 healthy controls matched for age and gender received quantitative fluoroscopy (QF) screenings to measure flexion and extension IV-RoM (C1-C6) at baseline and 4-week follow-up between September 2012-13. Patients received up to 12 neck manipulations and completed NRS, NDI and Euroqol 5D-5L at baseline, plus PGIC and satisfaction questionnaires at follow-up. IV-RoM accuracy, repeatability and hypo-mobility cut-offs were determined. Minimal detectable changes (MDC) over 4 weeks were calculated from controls. Patients and control IV-RoMs were compared at baseline as well as changes in patients over 4 weeks. Correlations between outcomes and the number of manipulations received and the agreement (Kappa) between palpated and QF-detected of hypo-mobile segments were calculated. Results: QF had high accuracy (worst RMS error 0.5o) and repeatability (highest SEM 1.1o, lowest ICC 0.90) for IV-RoM measurement. Hypo-mobility cut offs ranged from 0.8o to 3.5o. No outcome was significantly correlated with increased IV-RoM above MDC and there was no significant difference between the number of hypo-mobile segments in patients and controls at baseline or significant increases in IV-RoMs in patients. However, there was a modest and significant correlation between the number of manipulations received and the number of levels and directions whose IV-RoM increased beyond MDC (Rho=0.39, p=0.043). There was also no agreement between palpation and QF in identifying hypo-mobile segments (Kappa 0.04-0.06). Conclusions: This study found no differences in cervical sagittal IV-RoM between patients with non-specific neck pain and matched controls. There was a modest dose-response relationship between the number of manipulations given and number of levels increasing IV-RoM - providing evidence that neck manipulation has a mechanical effect at segmental levels. However, patient-reported outcomes were not related to this

A new low-field extremity magnetic resonance imaging and proposed compact MRI score: evaluation of anti-tumor necrosis factor biologics on rheumatoid arthritis

Magnetic resonance imaging (MRI) is a useful tool for evaluating disease activity and therapeutic efficacy in rheumatoid arthritis (RA). However, conventional whole-body MRI is inconvenient on several levels. We have therefore developed a new low-field extremity MRI (compact MRI, cMRI) and examined its clinical utility. Thirteen RA patients treated with anti-tumor necrosis factor (TNF) biologics were included in the study. The MRI was performed twice using a 0.21-T extremity MRI system. The MRI images were scored using our proposed cMRI scoring system, which we devised with reference to the Outcome Measures in Rheumatology Clinical Trials RA MRI score (OMERACT RAMRIS). In our cMRI scoring system, synovitis, bone edema, and bone erosion are separately graded on a scale from 0 to 3 by imaging over the whole hand, including the proximal interphalangeal joint. The total cMRI score (cMRIS) is then obtained by calculating the total bone erosion score × 1.5 + total bone edema score × 1.25 + total synovitis score. In this study, one patient showed a progression of bone destruction even under low clinical activity, as assessed by the disease activity score on 28 joints (DAS28); however, another patient’s cMRIS decreased concurrently with the decrease in DAS28, with the positive correlation observed between ΔDAS28 and ΔcMRIS (R = 0.055, P < 0.05). We conclude that cMRI and cMRIS are useful for assessing total disease activity and as a method linking MRI image evaluation to clinical evaluation

Preclinical transgenic and patient-derived xenograft models recapitulate the radiological features of human adamantinomatous craniopharyngioma

To assess the clinical relevance of transgenic and patient-derived xenograft models of adamantinomatous craniopharyngioma (ACP) using serial magnetic resonance imaging (MRI) and high resolution post-mortem microcomputed tomography (μ-CT), with correlation with histology and human ACP imaging. The growth patterns and radiological features of tumors arising in Hesx1(Cre/+) ;Ctnnb1(lox(ex3)/+) transgenic mice, and of patient-derived ACP xenografts implanted in the cerebral cortex, were monitored longitudinally in vivo with anatomical and functional MRI, and by ex vivo μ-CT at study end. Pathological correlates with hematoxylin and eosin stained sections were investigated. Early enlargement and heterogeneity of Hesx1(Cre/+) ;Ctnnb1(lox(ex3)/+) mouse pituitaries was evident at initial imaging at 8 weeks, which was followed by enlargement of a solid tumor, and development of cysts and hemorrhage. Tumors demonstrated MRI features that recapitulated those of human ACP, specifically, T1 -weighted signal enhancement in the solid tumor component following Gd-DTPA administration, and in some animals, hyperintense cysts on FLAIR and T1 -weighted images. Ex vivo μ-CT correlated with MRI findings and identified smaller cysts, which were confirmed by histology. Characteristic histological features, including wet keratin and calcification, were visible on μ-CT and verified by histological sections of patient-derived ACP xenografts. The Hesx1(Cre/+) ;Ctnnb1(lox(ex3)/+) transgenic mouse model and cerebral patient-derived ACP xenografts recapitulate a number of the key radiological features of the human disease and provide promising foundations for in vivo trials of novel therapeutics for the treatment of these tumors