Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients

CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions. Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors. Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery. Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future

Absence of lipid gel-phase domains in seven mammalian cell lines and in four primary cell types.

Fluorescence properties of 6-lauroyl-2-dimethylaminonaphthalene (Laurdan) are used to explore gel and liquid-crystalline phase domains coexistence in membranes of various cell types and in erythrocyte ghosts. Experiments and simulations were performed using liposomes composed of equimolar gel and liquid-crystalline phases in the absence and in the presence of 30 mol% cholesterol. In this model system two distinct coexisting phases can be easily recognized in the absence of cholesterol. When cholesterol is added to this phospholipid mixture, Laurdan parameters characteristic of the gel and of the liquid-crystalline phase are no longer resolvable. Coexisting domains of gel and liquid-crystalline phase were not detected in any of the examined cell membranes as judged by Laurdan excitation and emission Generalized Polarization (GP) spectra. Both in liposomes and in cell membranes, the behaviour of GP values as a function of excitation and emission wavelength corresponds to a homogeneous liquid-crystalline phase, despite the absolute GP values being relatively high, closer to the values observed in gel phase phospholipids. The presence of cholesterol appears to be the major cause for the homogeneity of phospholipids' dynamical properties in natural membranes, properties that appear close to the liquid-ordered phase state, defined to describe model systems with cholesterol concentration > or = 30 mol%

Cholesterol modifies water concentration and dynamics in phospholipid bilayers: a fluorescence study using Laurdan probe.

The effect of cholesterol on the gel, the liquid-crystalline, and mixed phospholipid phases has been studied using the fluorescence properties of 2-dimethylamino-6-lauroylnaphthalene (Laurdan). Laurdan sensitivity to the polarity and to the dynamics of its environment reveals that cholesterol affects phospholipid bilayers in the gel phase by expelling water and by increasing the amount of dipolar relaxation. In the liquid-crystalline phase, the effect of cholesterol is a reduction of both water concentration and amount of dipolar relaxation. Detailed studies of Laurdan excitation and emission spectral contours as a function of cholesterol concentration show that there are some cholesterol concentrations at which Laurdan spectral properties changes discontinuously. These peculiar cholesterol concentrations are in agreement with recent observations of other workers showing the formation of local order in the liquid-crystalline phase of phospholipids upon addition of phospholipid derivatives of pyrene. A local organization of phospholipids around cholesterol molecule seems to be produced by the presence of peculiar concentrations of cholesterol itself. This local organization is stable enough to be observed during the excited state lifetime of Laurdan of approximately 5-6 ns

Essays in business cycles : housing market, adaptive learning, and credit market imperfections

In this thesis, we focus on the housing sector, which is important to the economy but is under-researched in business cycles analysis. We discuss several housing sector related issues in dynamics stochastic general equilibrium (DSGE) models. To begin with, we conduct a sensitivity analysis using a simple DSGE model with the feature of sticky prices and a fixed housing supply, which is similar with the basic model in Iacoviello (2005) but with representative agents. Then we introduce credit market imperfections in two different ways. The first case is referred to as 'borrowing to invest', in which entrepreneurs take loans and accumulate production housing, which is a factor of production. We observe the financial accelerator (or decelerator) effect since their borrowing is related to output directly. The second case is referred to as 'borrowing to live', in which impatient households take loans to buy housing and gain utility from it. In contrast with the first case, we do not find the financial accelerator (or decelerator) effect, since the borrowing is not directly related to output anymore. First, we add a variable housing supply, thus we can discuss the supply side effect in the housing market, including both the direct effect and the feedback effect. The direct effect is the impact of a housing technology shock, and the feedback effect is the impact of a change in new housing production, which is caused by other shocks. We find, however, that the magnitudes of these two effects are negligible under the standard setting of the housing market that is commonly used in the literature of DSGE model with housing, such as Davis and Heathcote (2005), Iacoviello and Neri (2010). The key assumption in the standard setting is that every household trades housing in a given period. An empirical examination of the D.S. housing sector suggests us to (i) re-construct the housing market and (ii) introduce the feature of time to build to new housing production. After constructing the new setting for the housing market by introducing the probability of trading housing, we find that (i) the steady state ratios from the model are consistent with their empirical targets and (ii) the magnitudes of both the direct effect and the feedback effect are 60 times larger. Furthermore, the feature of time to build, together with the new setting of the housing market, allows us to observe overshooting behaviour on the real house price. Second, we discuss the impact of the assumption of adaptive learning, as we are convinced that the house price bubble is partially contributed by this alternative way of forming expectations. After writing the Nottingham Learning Toolbox,1 we find that, given the AR(l) learning model, in which variable is forecasted using its own lagged terms, the adaptive learning mechanism largely amplifies and propagates the effects of a goods sector technology shocks to the economy, and also, enlarges the impact of the time to build feature on the real house price. Furthermore, our sensitivity analysis shows that the values of initial beliefs are important to the mechanism but forecasting errors are not if the constant gain coefficient is small. Then we consider the assumption of heterogeneous expectations. From the impulse response analysis, we find that (i) the adaptive learning mechanism also has amplification and propagation effects to the economy when only a fraction of the population are learning agents; (ii) when two types of agents have equal weights, the impulse responses from heterogeneous expectations are much closer to those from rational expectations than those from adaptive learning; (iii) when rational agents are fully rational, the adaptive learning mechanism has larger amplification and propagation effects on the economy than when rational agents are partially rational. From the sensitivity analysis, We find that fully rational agents always have larger impacts on model variables than partially rational agents. Finally, we introduce credit market imperfections to the housing market, thus the mortgage market subjects to a costly verification problem. Our empirical analysis suggests that, while the default rate is countercyclical, the loan to value ratio is procyclical. Our impulse response analysis shows that, given a positive goods sector technology shock, the default rate is counter-cyclical, but the loan to value ratio is also countercyclical. The reason we suppose is that, in our model, credit constrained households have less housing in an economic upturn, thus the volume of loans they receive also decreases, leading to a fall in the loan to value ratio. Moreover, we illustrate that, when the mean of the idiosyncratic shock is time-invariant, we always have a positive relation between the default rate and the loan to value ratio. In order to overcome this co-movement, we show that a time-varying mean is necessary. 1 The Nottingham Learning Toolbox is a series of Matlab files that can solve a general form of DSGE models under adaptive learning and heterogeneous expectations. The toolbox solves the model using the Klein's QZ decomposition method, and facilitates the impulse response analysis. The Cambridge Learning Toolbox provides helpful reference for this toolbox at the initial stage.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Influence of cholesterol on phospholipid bilayers phase domains as detected by Laurdan fluorescence.

Coexisting gel and liquid-crystalline phospholipid phase domains can be observed in synthetic phospholipid vesicles during the transition from one phase to the other and, in vesicles of mixed phospholipids, at intermediate temperatures between the transitions of the different phospholipids. The presence of cholesterol perturbs the dynamic properties of both phases to such an extent as to prevent the detection of coexisting phases. 6-Lauroyl-2-dimethylaminopahthalene (Laurdan) fluorescence offers the unique advantage of well resolvable spectral parameters in the two phospholipid phases that can be used for the detection and quantitation of coexisting gel and liquid-crystalline domains. From Laurdan fluorescence excitation and emission spectra, the generalized polarization spectra and values were calculated. By the generalized polarization phospholipid phase domain coexistence can be detected, and each phase can be quantitated. In the same phospholipid vesicles where without cholesterol domain coexistence can be detected, above 15 mol% and, remarkably, at physiological cholesterol concentrations, > or = 30 mol%, no separate Laurdan fluorescence signals characteristic of distinct domains can be observed. Consequences of our results on the possible size and dynamics of phospholipid phase domains and their biological relevance are discussed