CRP Levels as a Prognostic Factor in Mycosis Fungoides

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most com- mon forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lympho- mas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/ SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantita- tive scales. Wilcoxon’s rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon’s test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon’s test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices

CRP Levels as a Prognostic Factor in Mycosis Fungoides

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most com- mon forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lympho- mas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/ SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantita- tive scales. Wilcoxon’s rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon’s test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon’s test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices

FOXP3 Predicts Response to Treatment in Mycosis Fungoid

Background: The role of the T-regulatory cells (Tregs) marker forkhead box Protein 3 (FOXP3) in mycoses fungoides (MF) pathogenesis is unclear and the results of previous studies are inconclusive. Objective: We aimed at ascertaining the possibility that FOXP3 expression may serve to predict MF stage and response to therapy. Patients and methods: Immunohistochemistry staining for FOXP3 was performed on 30 skin biopsies from patients with MF, and FOXP3 expression level was quantitatively graded. Disease stage, progression, and response to treatment were determined based on clinical and imaging evidence, and association with FOXP3 expression was assessed. Results: FOXP3 expression in the dermis correlated with poor response to treatment (P=0.047). A negative non-significant relationship between epidermal FOXP3 expression and clinical stage severity was observed (P=0.17). Conclusions: Dermal FOXP3 expression in MF lesions could be used to predict response to treatment in patients with MF

FOXP3 Predicts Response to Treatment in Mycosis Fungoid

Background: The role of the T-regulatory cells (Tregs) marker forkhead box Protein 3 (FOXP3) in mycoses fungoides (MF) pathogenesis is unclear and the results of previous studies are inconclusive. Objective: We aimed at ascertaining the possibility that FOXP3 expression may serve to predict MF stage and response to therapy. Patients and methods: Immunohistochemistry staining for FOXP3 was performed on 30 skin biopsies from patients with MF, and FOXP3 expression level was quantitatively graded. Disease stage, progression, and response to treatment were determined based on clinical and imaging evidence, and association with FOXP3 expression was assessed. Results: FOXP3 expression in the dermis correlated with poor response to treatment (P=0.047). A negative non-significant relationship between epidermal FOXP3 expression and clinical stage severity was observed (P=0.17). Conclusions: Dermal FOXP3 expression in MF lesions could be used to predict response to treatment in patients with MF

On the determinants of calcium wave propagation distance in astrocyte networks: nonlinear gap junctions and oscillatory modes

A new paradigm has recently emerged in brain science whereby glial cells should be considered on a par with neurons to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating calcium (Ca2+) waves. The propagation properties of these waves and their relations to intracellular signalling dynamics are however poorly understood. Here, we propose a novel model of the gap-junctional route for intercellular Ca2+ wave propagation in astrocytes that yields two major predictions. First, we show that long-distance regenerative signalling requires gap junctions with nonlinear transport properties. Second, we show that even with nonlinear gap junctions, long-distance regenerative signalling is favoured when internal Ca2+ dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings give rise to rich spatiotemporal dynamics and support complex propagation behaviours. These results suggest that the large variability of the wave propagation range that is consistently reported by experimental studies, is a result of the association of nonlinear gap junctions with heterogeneous astrocyte populations and/or low coupling

Nonlinear gap junctions enable long-distance propagation of pulsating calcium waves in astrocyte networks

A new paradigm has recently emerged in brain science whereby communications between glial cells and neuron-glia interactions should be considered together with neurons and their networks to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, have been shown to communicate with neurons and with each other. They are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating Ca2+ waves. An identified mode of propagation is based on cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP3) through gap junctions that locally trigger Ca2+ pulses via IP3-dependent Ca2+-induced Ca2+ release. It is, however, currently unknown whether this intracellular route is able to support the propagation of long-distance regenerative Ca2+ waves or is restricted to short-distance signaling. Furthermore, the influence of the intracellular signaling dynamics on intercellular propagation remains to be understood. In this work, we propose a model of the gap-junctional route for intercellular Ca2+ wave propagation in astrocytes showing that: (1) long-distance regenerative signaling requires nonlinear coupling in the gap junctions, and (2) even with nonlinear gap junctions, long-distance regenerative signaling is favored when the internal Ca2+ dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings are shown to give rise to rich spatiotemporal dynamics that support complex propagation behaviors. These results shed new light on the mechanisms implicated in the propagation of Ca2+ waves across astrocytes and precise the conditions under which glial cells may participate in information processing in the brain.Comment: Article: 30 pages, 7 figures. Supplementary Material: 11 pages, 6 figure

Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

Recent years have witnessed an increasing interest in neuron-glia communication. This interest stems from the realization that glia participates in cognitive functions and information processing and is involved in many brain disorders and neurodegenerative diseases. An important process in neuron-glia communications is astrocyte encoding of synaptic information transfer: the modulation of intracellular calcium dynamics in astrocytes in response to synaptic activity. Here, we derive and investigate a concise mathematical model for glutamate-induced astrocytic intracellular Ca2+ dynamics that captures the essential biochemical features of the regulatory pathway of inositol 1,4,5-trisphosphate (IP3). Starting from the well-known two-state Li-Rinzel model for calcium-induced-calcium release, we incorporate the regulation of the IP3 production and phosphorylation. Doing so we extended it to a three-state model (referred as the G-ChI model), that could account for Ca2+ oscillations triggered by endogenous IP3 metabolism as well as by IP3 production by external glutamate signals. Compared to previous similar models, our three-state models include a more realistic description of the IP3 production and degradation pathways, lumping together their essential nonlinearities within a concise formulation. Using bifurcation analysis and time simulations, we demonstrate the existence of new putative dynamical features. The cross-couplings between IP3 and Ca2+ pathways endows the system with self-consistent oscillator properties and favor mixed frequency-amplitude encoding modes over pure amplitude modulation ones. These and additional results of our model are in general agreement with available experimental data and may have important implications on the role of astrocytes in the synaptic transfer of information.Comment: 42 pages, 16 figures, 1 table. Figure filenames mirror figure order in the paper. Ending "S" in figure filenames stands for "Supplementary Figure". This article was selected by the Faculty of 1000 Biology: "Genevieve Dupont: Faculty of 1000 Biology, 4 Sep 2009" at http://www.f1000biology.com/article/id/1163674/evaluatio

Astrocyte networks and intercellular calcium propagation

International audienceAstrocytes organize in complex networks through connections by gap junction channels that are regulated by extra-and intracellular signals. Calcium signals generated in individual cells, can propagate across these networks in the form of intercellular calcium waves, mediated by diffusion of second messengers molecules such as inositol 1,4,5-trisphosphate. The mechanisms underpinning the large variety of spatiotemporal patterns of propagation of astrocytic calcium waves however remain a matter of investigation. In the last decade, awareness has grown on the morphological diversity of astrocytes as well as their connections in networks, which seem dependent on the brain area, developmental stage, and the ultra-structure of the associated neuropile. It is speculated that this diversity underpins an equal functional variety but the current experimental techniques are limited in supporting this hypothesis because they do not allow to resolve the exact connectivity of astrocyte networks in the brain. With this aim we present a general framework to model intercellular calcium wave propagation in astrocyte networks and use it to specifically investigate how different network topologies could influence shape, frequency and propagation of these waves

The remarkable effect of network topology on calcium wave propagation in astrocyte networks

International audienceOver the past two decades, our understanding of intercellular communication between glia has fundamentally switched from the idea of a syncytium to the recognition that glial cells might in fact organize as networks. In particular, astrocytes, the main type of glial cells in the cortex, can propagate calcium signals from one cell to the other through gap junctions. The reported speed and extent of propagation of these intercellular calcium signals however can largely vary. Of course, this variability in the propagation patterns may reflect different intracellular properties (biochemical, signaling). But experimental evidence also suggests that the way astrocytes connect to each other in the network (topology) varies depending on the brain region. Such different topologies may already bring forth, by themselves, different modes of intercellular calcium propagation. Here, we explore this possibility using a biophysically realistic model of large (i.e. >1000 cells) tridimensional astrocyte networks. In our networks, each astrocyte houses an individual model for intracellular calcium and IP3 dynamics and exchanges IP3 with connected astrocytes through gap junctions. Intensive numerical simulations of the model for different network connectivities revealed that the major classes of observed propagations can be emulated by a mere variation of the connection topology (i.e. keeping intracellular parameters unchanged). In particular our study indicates that calcium wave propagation is favored when the connections between astrocytes are mainly restricted to small inter-cell distances. This result is significant since, at constant number of cell-cell connections, space-constrained topologies exhibit large mean-shortest path. As a consequence, we obtain the non-trivial result that propagation is improved when the mean-shortest path of the network is large. Altogether, our findings provide theoretical support to the experimental observation that the spatial arrangement of astrocyte networks in the brain could bear some level of organization with deep implications on the regulation of network activity

On the determinants of calcium wave propagation distance in astrocyte networks: nonlinear gap junctions and oscillatory modes

A new paradigm has recently emerged in brain science whereby glial cells should be considered on a par with neurons to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating calcium (Ca2+) waves. The propagation properties of these waves and their relations to intracellular signalling dynamics are however poorly understood. Here, we propose a novel model of the gap-junctional route for intercellular Ca2+ wave propagation in astrocytes that yields two major predictions. First, we show that long-distance regenerative signalling requires gap junctions with nonlinear transport properties. Second, we show that even with nonlinear gap junctions, long-distance regenerative signalling is favoured when internal Ca2+ dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings give rise to rich spatiotemporal dynamics and support complex propagation behaviours. These results suggest that the large variability of the wave propagation range that is consistently reported by experimental studies, is a result of the association of nonlinear gap junctions with heterogeneous astrocyte populations and/or low coupling