Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Abstract 9: Compliance of a New Standard in Stroke Neuro Checks in a Comprehensive Stroke Center Compared to Primary Stroke Centers for IV Alteplase and Thrombectomy Patients

Background: Frequent neurological monitoring is required for patients who receive IV alteplase and/or thrombectomy. A new stroke neuro check called SNAP (Stroke Neuro Assessment by Providence) was introduced to this regional program. SNAP is defined by four components: (1) level of consciousness (LOC), 1a, 1b, 1c on NIH stroke scale (NIHSS) or GCS, (2) pupil reactivity, (3) movement of all extremities NIHSS 5a, 5b, 6a, 6b, and (4) trending originating symptoms of first NIHSS. Purpose: Examine SNAP check and provider follow-up compliance at a certified Comprehensive Stroke Center (CSC) with a neurocritical care unit and three certified Primary Stroke Centers (PSC) for all IV alteplase and/or thrombectomy. Methods: Data between January 2017 and March 2017 from four certified stroke centers were included. One low volume PSC, and patients treated by non-regular nursing staff were excluded from the analysis. SNAP check compliance was calculated as the number of documented SNAP checks divided by eligible opportunities and follow-up compliance as the number of contacted providers divided by all SNAP changes with an associated NIHSS change of 4 or more. Binomial regressions were used to test compliance for conducting SNAP by stroke certification type and components of SNAP. Results: Of 37 patients included, 59% were female, mean age was 72 (±15) years, and the median ED NIHSS was 9.0 [Interquartile range: 2.0, 17.5]. Provider follow-up compliance was 75% (6/8) and SNAP check compliance was 68% (3,131 completed/4,601 opportunities for 37 patients). There were significant differences in SNAP check compliance by assessment type with highest in LOC and lowest in trending originating symptoms (90% vs. 45%, p\u3c.001). The CSC hospital had a statistically significant higher SNAP check compliance of 82% compared to PSCs which had a combined compliance of 62% (p=0.003). Conclusions: The CSC had significantly higher overall compliance than the PSCs. However, there is a need for increased compliance with trending originating symptoms at all three hospitals. Our analysis suggest that a neurocritical care unit impacts compliance with a standard stroke neuro check at a Joint Commission certified CSC

Effects of Coadsorbed Water on the Heterogeneous Photochemistry of Nitrates Adsorbed on TiO2

Nitric acid, a well-known sink of NOx gases in the atmosphere, has been found to be photoactive while adsorbed on tropospheric particles. When adsorbed onto semiconductive metal oxides, nitrate’s photochemical degradation can be interpreted as a photocatalytic process. Yet, the photolysis of nitrate ions on the surface of aerosols can also be initiated by changes in the symmetry of the ion upon adsorption. In this study, we use quantum chemistry to model the vibrational spectra of adsorbed nitrate on TiO2, a semiconductor component of atmospheric aerosols, and determine the kinetics of the heterogeneous photochemical degradation of nitrate under simulated solar light. Frequencies and geometry calculations suggest that the symmetry of chemisorbed nitrate ion depends strongly on coadsorbed water, with water changing the reactive surface of TiO2. Upon irradiation, surface nitrate undergoes photolysis to yield nitrogen-containing gaseous products including NO2, NO, HONO, and N2O, in proportions that depend on relative humidity (RH). In addition, the heterogeneous photochemistry rate constant decreases an order of magnitude, from (5.7 ± 0.1) × 10–4 s–1 on a dry surface to (7.1 ± 0.8) × 10–5 s–1 when nitrate is coadsorbed with water above monolayer coverage. Little is known about the roles of coadsorbed water on the heterogeneous photochemistry of nitrates on TiO2, along with its impact on the chemical balance of the atmosphere. This work discusses the roles of water in the photolysis of surface nitrates on TiO2 and the concomitant renoxification of the atmosphere

Barriers to and Enablers of Implementation of High-Value Interventions by Renal Pharmacists: A Qualitative Study Informed by the Theoretical Domains Framework

ABSTRACTBackground: Previous studies have shown that patients with chronic kidney disease who are followed by a renal clinical pharmacist have improved clinical outcomes. In 2016, a consensus list of quality indicator drug therapy problems (QI-DTPs) was developed by renal clinical pharmacists to help prioritize which renal patients should receive interventions. Before QI-DTP interventions can be implemented in clinical practice, barriers to and enablers of their use need to be identified, to allow development of strategies to overcome the barriers and apply the enablers.Objective: To identify modifiable barriers to and enablers of implementation of renal QI-DTP interventions by renal clinical pharmacists.Methods: In this exploratory qualitative descriptive study, one-on-one, semistructured, audio-recorded telephone interviews were conducted with renal clinical pharmacists to identify the barriers to and enablers of implementation of renal QI-DTP interventions. The interviews consisted of questions developed according to the Theoretical Domains Framework.Results: Interviews were conducted with 13 renal pharmacists from across Canada. The main barriers to implementation of renal QI-DTP interventions that participants identified were knowledge gaps, prioritization, and nephrologist acceptance. The main enablers identified were training, colleague support, and better patient care.Conclusion: Three barriers to and three enablers of implementation of renal QI-DTP interventions were identified. These barriers and enablers can be used to help with pharmacist education and to optimize the care that pharmacists provide to renal patients.RÉSUMÉContexte : Des études précédentes démontrent une amélioration des résultats cliniques de patients souffrant d’une maladie rénale chronique, qui sont suivis par un pharmacien clinicien en néphrologie. En 2016, des pharmaciens cliniciens en néphrologie ont mis au point une liste consensuelle des indicateurs de qualité des problèmes de pharmacothérapie (QI-DTP) pour les aider à prioriser les patients souffrant d’une insuffisance rénale, qui doivent subir une intervention. Avant de mettre en place ces QI-DTP en pratique clinique, on doit déterminer les éléments qui entravent et facilitent leur utilisation pour pouvoir élaborer des stratégies visant à surmonter les obstacles et à appliquer les éléments facilitateurs.Objectif :Déterminer les éléments modifiables qui entravent et facilitent la mise en place des QI-DTP par les pharmaciens cliniciens en néphrologie lors d’interventions rénales.Méthodes : Dans cette étude exploratoire, descriptive et qualitative, des entretiens téléphoniques individuels, semi structurés et enregistrés ont été menés auprès de pharmaciens cliniciens en néphrologie pour determiner les éléments qui entravent et facilitent la mise en place de QI-DTP lors d’interventions rénales. Les entretiens consistaient en des questions préparées selon le Theoretical Domains Framework.Résultats : Les entretiens ont été menés auprès de 13 pharmaciens en néphrologie de partout au Canada. Les principaux éléments entravant la mise en place de QI-DTP lors d’interventions rénales déterminées par les participants étaient : le manque de connaissances, la priorisation et l’acception des néphrologues. Les principaux éléments facilitant la tâche étaient : la formation, le soutien des collègues et de meilleurs soins offerts aux patients.Conclusion : Trois éléments entravant et trois éléments facilitant la mise en place de QI-DTP lors d’interventions rénales ont été déterminés. Ils peuvent être utilisés pour contribuer à la formation du pharmacien et pour optimiser les soins offerts aux patients qui souffrent d’insuffisance rénale