Assessment of the immune landscapes of advanced ovarian cancer in an optimized in vivo model

BackgroundOvarian cancer (OC) is typically diagnosed late, associated with high rates of metastasis and the onset of ascites during late stage disease. Understanding the tumor microenvironment and how it impacts the efficacy of current treatments, including immunotherapies, needs effective in vivo models that are fully characterized. In particular, understanding the role of immune cells within the tumor and ascitic fluid could provide important insights into why OC fails to respond to immunotherapies. In this work, we comprehensively described the immune cell infiltrates in tumor nodules and the ascitic fluid within an optimized preclinical model of advanced ovarian cancer.MethodsGreen Fluorescent Protein (GFP)-ID8 OC cells were injected intraperitoneally into C57BL/6 mice and the development of advanced stage OC monitored. Nine weeks after tumor injection, mice were sacrificed and tumor nodules analyzed to identify specific immune infiltrates by immunohistochemistry. Ascites, developed in tumor bearing mice over a 10-week period, was characterized by mass cytometry (CyTOF) to qualitatively and quantitatively assess the distribution of the immune cell subsets, and their relationship to ascites from ovarian cancer patients.ResultsTumor nodules in the peritoneal cavity proved to be enriched in T cells, antigen presenting cells and macrophages, demonstrating an active immune environment and cell-mediated immunity. Assessment of the immune landscape in the ascites showed the predominance of CD8+, CD4+, B–, and memory T cells, among others, and the coexistance of different immune cell types within the same tumor microenvironment.ConclusionsWe performed, for the first time, a multiparametric analysis of the ascitic fluid and specifically identify immune cell populations in the peritoneal cavity of mice with advanced OC. Data obtained highlights the impact of CytOF as a diagnostic tool for this malignancy, with the opportunity to concomitantly identify novel targets, and define personalized therapeutic options

Do (and say) as I say: Linguistic adaptation in human-computer dialogs

© Theodora Koulouri, Stanislao Lauria, and Robert D. Macredie. This article has been made available through the Brunel Open Access Publishing Fund.There is strong research evidence showing that people naturally align to each other’s vocabulary, sentence structure, and acoustic features in dialog, yet little is known about how the alignment mechanism operates in the interaction between users and computer systems let alone how it may be exploited to improve the efficiency of the interaction. This article provides an account of lexical alignment in human–computer dialogs, based on empirical data collected in a simulated human–computer interaction scenario. The results indicate that alignment is present, resulting in the gradual reduction and stabilization of the vocabulary-in-use, and that it is also reciprocal. Further, the results suggest that when system and user errors occur, the development of alignment is temporarily disrupted and users tend to introduce novel words to the dialog. The results also indicate that alignment in human–computer interaction may have a strong strategic component and is used as a resource to compensate for less optimal (visually impoverished) interaction conditions. Moreover, lower alignment is associated with less successful interaction, as measured by user perceptions. The article distills the results of the study into design recommendations for human–computer dialog systems and uses them to outline a model of dialog management that supports and exploits alignment through mechanisms for in-use adaptation of the system’s grammar and lexicon

Risks and Benefits of Oral Anticoagulation Compared With Clopidogrel Plus Aspirin in Patients With Atrial Fibrillation According to Stroke Risk

Background and Purpose— In ACTIVE-W, oral anticoagulation (OAC) was more efficacious than combined clopidogrel plus aspirin (C+A) in preventing vascular events in patients with atrial fibrillation. However, because OAC carries important bleeding complications, risk stratification schemes have been devised to identify patients for whom the absolute benefits of OAC exceed its risks. Methods— Participants were risk-stratified with the widely-used CHADS 2 scheme. Treatment-specific rates of stroke and major bleeding were calculated for patients with a CHADS 2 =1 and compared to those with a CHADS 2 >1. Results— Observed stroke rates for those with a CHADS 2 =1 were 1.25% per year on C+A and 0.43% per year on OAC (RR=2.96, 95% CI: 1.26 to 6.98, P =0.01). Among patients with a CHADS 2 >1, the stroke rates were 3.15% per year on C+A and 2.01% per year on OAC (RR=1.58, 95% CI: 1.11 to 2.24, P =0.01) ( P for interaction between stroke risk category and efficacy of OAC=0.19). The risk of major bleeding during OAC was significantly lower among patients with CHADS 2 =1 (1.36% per year) compared with CHADS 2 >1 (2.75% per year) (RR=0.49, 95% CI 0.30 to 0.79, P =0.003). Conclusions— In this clinical trial, patients with a CHADS 2 =1 had a low risk of stroke, yet still derived a modest (<1% per year) but statistically significant absolute reduction in stroke with OAC and had low rates of major hemorrhage on OAC

In defense of the epistemic view of quantum states: a toy theory

We present a toy theory that is based on a simple principle: the number of questions about the physical state of a system that are answered must always be equal to the number that are unanswered in a state of maximal knowledge. A wide variety of quantum phenomena are found to have analogues within this toy theory. Such phenomena include: the noncommutativity of measurements, interference, the multiplicity of convex decompositions of a mixed state, the impossibility of discriminating nonorthogonal states, the impossibility of a universal state inverter, the distinction between bi-partite and tri-partite entanglement, the monogamy of pure entanglement, no cloning, no broadcasting, remote steering, teleportation, dense coding, mutually unbiased bases, and many others. The diversity and quality of these analogies is taken as evidence for the view that quantum states are states of incomplete knowledge rather than states of reality. A consideration of the phenomena that the toy theory fails to reproduce, notably, violations of Bell inequalities and the existence of a Kochen-Specker theorem, provides clues for how to proceed with this research program.Comment: 32 pages, REVTEX, based on a talk given at the Rob Clifton Memorial Conference, College Park, May 2003; v2: minor modifications throughout, updated reference

Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk.

INTRODUCTION: Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk. METHODS: We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene. RESULTS: No significant breast cancer associations were detected with any individual or combination of tag SNPs. CONCLUSION: It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Einstein, incompleteness, and the epistemic view of quantum states

Does the quantum state represent reality or our knowledge of reality? In making this distinction precise, we are led to a novel classification of hidden variable models of quantum theory. Indeed, representatives of each class can be found among existing constructions for two-dimensional Hilbert spaces. Our approach also provides a fruitful new perspective on arguments for the nonlocality and incompleteness of quantum theory. Specifically, we show that for models wherein the quantum state has the status of something real, the failure of locality can be established through an argument considerably more straightforward than Bell's theorem. The historical significance of this result becomes evident when one recognizes that the same reasoning is present in Einstein's preferred argument for incompleteness, which dates back to 1935. This fact suggests that Einstein was seeking not just any completion of quantum theory, but one wherein quantum states are solely representative of our knowledge. Our hypothesis is supported by an analysis of Einstein's attempts to clarify his views on quantum theory and the circumstance of his otherwise puzzling abandonment of an even simpler argument for incompleteness from 1927.Comment: 18 pages, 8 figures, 1 recipe for cupcakes; comments welcom

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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