An analysis of natural T cell responses to predicted tumor neoepitopes

Personalization of cancer immunotherapies such as therapeutic vaccines and adoptive T-cell therapy may benefit from efficient identification and targeting of patient-specific neoepitopes. However, current neoepitope prediction methods based on sequencing and predictions of epitope processing and presentation result in a low rate of validation, suggesting that the determinants of peptide immunogenicity are not well understood. We gathered published data on human neopeptides originating from single amino acid substitutions for which T cell reactivity had been experimentally tested, including both immunogenic and non-immunogenic neopeptides. Out of 1,948 neopeptide-HLA (human leukocyte antigen) combinations from 13 publications, 53 were reported to elicit a T cell response. From these data, we found an enrichment for responses among peptides of length 9. Even though the peptides had been pre-selected based on presumed likelihood of being immunogenic, we found using NetMHCpan-4.0 that immunogenic neopeptides were predicted to bind significantly more strongly to HLA compared to non-immunogenic peptides. Investigation of the HLA binding strength of the immunogenic peptides revealed that the vast majority (96%) shared very strong predicted binding to HLA and that the binding strength was comparable to that observed for pathogen-derived epitopes. Finally, we found that neopeptide dissimilarity to self is a predictor of immunogenicity in situations where neo- and normal peptides share comparable predicted binding strength. In conclusion, these results suggest new strategies for prioritization of mutated peptides, but new data will be needed to confirm their value.Fil: Bjerregaard, Anne-Mette. Technical University of Denmark; DinamarcaFil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Jurtz, Vanessa. Technical University of Denmark; DinamarcaFil: Barra, Carolina M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Hadrup, Sine Reker. Technical University of Denmark; DinamarcaFil: Szallasi, Zoltan. Technical University of Denmark; Dinamarca. Harvard Medical School; Estados UnidosFil: Eklund, Aron Charles. Technical University of Denmark; Dinamarc

Demographic and Clinical Variation in Veterans Health Administration Provision of Assistive Technology Devices to Veterans Poststroke

Objectives: To examine variation in provision of assistive technology (AT) devices and the extent to which such variation may be explained by patient characteristics or Veterans Health Administration (VHA) administrative region. Design: Retrospective population-based study. Setting: VHA. Participants: Veterans poststroke in fiscal years 2001 and 2002 (N=12,046). Interventions: Not applicable. Main Outcome Measure: Provision of 8 categories of AT devices. Results: There was considerable regional variation in provision of AT. For example, differences across administrative regions in the VHA ranged from 5.1 to 28.1 standard manual wheelchairs per 100 veterans poststroke. Using logistic regression, with only demographic variables as predictors of standard manual wheelchair provision, the c statistic was .62, and the pseudo R2 was 2.5%. Adding disease severity increased the c statistic to .67 and the pseudo R2 to 6.2%, and adding Veteran Integrated Network System further increased the c statistic to .72 and pseudo R2 to 9.8%. Conclusions: Our research showed significant variation in the provision of AT devices to veterans poststroke, and it showed that patient characteristics accounted for only 6.2% of the variation. VHA administrative region and disability severity accounted for equivalent amounts of the variation

Spatially explicit land-use and land-cover scenarios for the Great Plains of the United States

The Great Plains of the United States has undergone extensive land-use and land-cover change in the past 150 years, with much of the once vast native grasslands and wetlands converted to agricultural crops, and much of the unbroken prairie now heavily grazed. Future land-use change in the region could have dramatic impacts on ecological resources and processes. A scenario-based modeling framework is needed to support the analysis of potential land-use change in an uncertain future, and to mitigate potentially negative future impacts on ecosystem processes. We developed a scenario-based modeling framework to analyze potential future land-use change in the Great Plains. A unique scenario construction process, using an integrated modeling framework, historical data, workshops, and expert knowledge, was used to develop quantitative demand for future land-use change for four IPCC scenarios at the ecoregion level. The FORE-SCE model ingested the scenario information and produced spatially explicit land-use maps for the region at relatively fine spatial and thematic resolutions. Spatial modeling of the four scenarios provided spatial patterns of land-use change consistent with underlying assumptions and processes associated with each scenario. Economically oriented scenarios were characterized by significant loss of natural land covers and expansion of agricultural and urban land uses. Environmentally oriented scenarios experienced modest declines in natural land covers to slight increases. Model results were assessed for quantity and allocation disagreement between each scenario pair. In conjunction with the U.S. Geological Survey\u27s Biological Carbon Sequestration project, the scenario-based modeling framework used for the Great Plains is now being applied to the entire United States

{\eta} and {\eta}' mesons from Nf=2+1+1 twisted mass lattice QCD

We determine mass and mixing angles of eta and eta' states using Nf=2+1+1 Wilson twisted mass lattice QCD. We describe how those flavour singlet states need to be treated in this lattice formulation. Results are presented for three values of the lattice spacing, a=0.061 fm, a=0.078 fm and a=0.086 fm, with light quark masses corresponding to values of the charged pion mass in a range of 230 to 500 MeV and fixed bare strange and charm quark mass values. We obtain 557(15)(45) MeV for the eta mass (first error statistical, second systematic) and 44(5) degrees for the mixing angle in the quark flavour basis, corresponding to -10(5) degrees in the octet-singlet basis.Comment: 28 pages, 9 figures, version to appear in JHEP, extended discussion of autocorrelation times and comparison to results available in the literature, added a comment for FS-effects and clarified the description of our blocking procedur

Beneficial effect of 24-month bilateral subthalamic stimulation on quality of sleep in Parkinson's disease

BACKGROUND Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and sleep symptoms in Parkinson’s disease (PD). However, the long-term effects of STN-DBS on sleep and its relationship with QoL outcome are unclear. METHODS In this prospective, observational, multicenter study including 73 PD patients undergoing bilateral STN-DBS, we examined PDSleep Scale (PDSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, -activities of daily living, and -complications (SCOPA-A, -B, -C), and levodopa-equivalent daily dose (LEDD) preoperatively, at 5 and 24 months follow-up. Longitudinal changes were analyzed with Friedman-tests or repeated-measures ANOVA, when parametric tests were applicable, and Bonferroni-correction for multiple comparisons. Post-hoc, visits were compared with Wilcoxon signed-rank/t-tests. The magnitude of clinical responses was investigated using effect size. RESULTS Significant beneficial effects of STN-DBS were observed for PDSS, PDQ-8, SCOPA-A, -B, and -C. All outcomes improved significantly at 5 months with subsequent decrements in gains at 24 months follow-up which were significant for PDSS, PDQ-8, and SCOPA-B. Comparing baseline and 24 months follow-up, we observed significant improvements of PDSS (small effect), SCOPA-A (moderate effect), -C, and LEDD (large effects). PDSS and PDQ-8 improvements correlated significantly at 5 and 24 months follow-up. CONCLUSIONS In this multicenter study with a 24 months follow-up, we report significant sustained improvements after bilateral STN-DBS using a PD-specific sleep scale and a significant relationship between sleep and QoL improvements. This highlights the importance of sleep in holistic assessments of DBS outcomes

Reduction of Fibrogenesis by Selective Delivery of a Rho Kinase Inhibitor to Hepatic Stellate Cells in Mice

One of the pathways activated during liver fibrosis is the Rho kinase pathway, which regulates activation, migration, and contraction of hepatic stellate cells (HSC). Inhibition of this kinase by the Rho kinase inhibitor Y27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] has been shown to reduce fibrosis in animal models. However, kinase expression is ubiquitous, so any inhibitor may affect many cell types. We hypothesize that cell-specific delivery of a kinase inhibitor will be beneficial. Therefore, we conjugated Y27632 to the carrier mannose-6-phosphate (M6P) human serum albumin (HSA), which is taken up specifically in activated HSC through the M6P/insulin-like growth factor II receptor. This conjugate decreased protein expression of phosphorylated myosin light chain 2 (pMLC2) and vinculin, downstream of Rho kinase, in activated primary HSC and decreased the migration and contraction of HSC. In an ex vivo model, free Y27632 decreased contractility of rat aortas, whereas the Y27-conjugate did not, showing that the Y27-conjugate does not affect nontarget tissue. In chronic CCl(4)-induced liver fibrosis, both free drug and conjugate reduced HSC activation; however, only the Y27-conjugate significantly reduced collagen deposition. Treatment with the Y27-conjugate, but not with free drug, reduced pMLC2 expression in livers 24 h after injection, demonstrating prolonged inhibition of the Rho kinase pathway. The Rho kinase inhibitor Y27632 can be specifically targeted to HSC using M6PHSA, decreasing its effects in nontarget tissues. The targeted drug effectively reduced fibrotic parameters in vivo via the inhibition of the Rho kinase pathway

A Systematic Review of Music Therapy Practice and Outcomes with Acute Adult Psychiatric In-Patients

PMCID: PMC3732280This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited