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Showing papers by "Paris Descartes University published in 2007"


Journal ArticleDOI
TL;DR: It is shown that anthracyclin-induced CRT translocation induces the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface and is identified as a key feature determining anticancer immune responses.
Abstract: Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.

2,550 citations


Journal ArticleDOI
03 Aug 2007-Science
TL;DR: It is shown, by direct examination of blood monocyte functions in vivo, that a subset of monocytes patrols healthy tissues through long-range crawling on the resting endothelium, which initiated an early immune response and differentiated into macrophages.
Abstract: The cellular immune response to tissue damage and infection requires the recruitment of blood leukocytes. This process is mediated through a classical multistep mechanism, which involves transient rolling on the endothelium and recognition of inflammation followed by extravasation. We have shown, by direct examination of blood monocyte functions in vivo, that a subset of monocytes patrols healthy tissues through long-range crawling on the resting endothelium. This patrolling behavior depended on the integrin LFA-1 and the chemokine receptor CX(3)CR1 and was required for rapid tissue invasion at the site of an infection by this "resident" monocyte population, which initiated an early immune response and differentiated into macrophages.

1,790 citations


Journal ArticleDOI
TL;DR: For values outside 1.45‐3.25, the FIB‐4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results.

1,598 citations


Journal ArticleDOI
TL;DR: Cytopathological examination of CTC/CTM, sensitively enriched from blood, represents a potentially useful alternative and can now be employed in routine analyses as a specific diagnostic assay, and be tested in large, blind, multicenter clinical trials.

928 citations


Journal ArticleDOI
TL;DR: It is established that the von Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo.
Abstract: Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel–Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.

612 citations


Journal ArticleDOI
TL;DR: Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment of Pheochromocytoma that inadequate methods to distinguish malignant from benign tumors and a lack of effective treatments for malignancy are important problems requiring further resolution.
Abstract: Pheochromocytomas are rare, often hereditary, catecholamine producing tumors that can be difficult to diagnose and manage. This Review summarizes the recommendations for biochemical and genetic testing, localization and treatment, and is based on discussions at the First International Symposium on Pheochromocytoma, held in October 2005. The First International Symposium on Pheochromocytoma, held in October 2005, included discussions about developments concerning these rare catecholamine-producing tumors. Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment. Measurement of plasma or urinary fractionated metanephrines, the most accurate screening approach, was recommended as the first-line test for diagnosis; reference intervals should favor sensitivity over specificity. Localization studies should only follow reasonable clinical evidence of a tumor. Preoperative pharmacologic blockade of circulatory responses to catecholamines is mandatory. Because approximately a quarter of tumors develop secondary to germ-line mutations in any one of five genes, mutation testing should be considered; however, it is not currently cost effective to test every gene in every patient. Consideration of tumor location, presence of multiple tumors, presence of metastases, and type of catecholamine produced is useful in deciding which genes to test. Inadequate methods to distinguish malignant from benign tumors and a lack of effective treatments for malignancy are important problems requiring further resolution.

590 citations


Journal ArticleDOI
TL;DR: This work reports strong association between FCGR3B copy number and risk of systemic lupus erythematosus, microscopic polyangiitis and Wegener's granulomatosis in two independent cohorts from the UK and France.
Abstract: Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity.

472 citations


Journal ArticleDOI
TL;DR: Calreticulin exposure is required for the immunogenicity of γ -irradiation and UVC light-induced apoptosis and the ability to reprogram the immune cells for apoptosis.
Abstract: Calreticulin exposure is required for the immunogenicity of γ -irradiation and UVC light-induced apoptosis

435 citations


Journal ArticleDOI
13 Dec 2007-Nature
TL;DR: Functional studies and three new crystal structures of the rabbit skeletal muscle Ca2+-ATPase are presented, representing the phosphoenzyme intermediates associated withCa2+ binding, Ca2- translocation and dephosphorylation, that are based on complexes with a functional ATP analogue, beryllium fluoride and aluminium fluoride, respectively.
Abstract: The sarcoplasmic reticulum Ca2+-ATPase, a P-type ATPase, has a critical role in muscle function and metabolism. Here we present functional studies and three new crystal structures of the rabbit skeletal muscle Ca2+-ATPase, representing the phosphoenzyme intermediates associated with Ca2+ binding, Ca2+ translocation and dephosphorylation, that are based on complexes with a functional ATP analogue, beryllium fluoride and aluminium fluoride, respectively. The structures complete the cycle of nucleotide binding and cation transport of Ca2+-ATPase. Phosphorylation of the enzyme triggers the onset of a conformational change that leads to the opening of a luminal exit pathway defined by the transmembrane segments M1 through M6, which represent the canonical membrane domain of P-type pumps. Ca2+ release is promoted by translocation of the M4 helix, exposing Glu 309, Glu 771 and Asn 796 to the lumen. The mechanism explains how P-type ATPases are able to form the steep electrochemical gradients required for key functions in eukaryotic cells.

423 citations


Journal ArticleDOI
TL;DR: The precise role of microRNA-124a2 in pancreatic development remains to be deciphered, but it is identified as a regulator of a key transcriptional protein network in β-cells responsible for modulating intracellular signaling.

343 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examined the long-term impact of preventive treatment with perindopril on mortality in children with Duchenne muscular dystrophy (DMD), an X-linked disorder due to lack of dystrophin, is associated with muscle weakness and myocardial dysfunction.

Journal ArticleDOI
21 Sep 2007-Immunity
TL;DR: It is shown here that purified human pDCs crosspresented vaccinal lipopeptides and HIV-1 antigens from apoptotic cells to specific CD8+ T lymphocytes and the efficiency of crosspresentation was comparable to that of mDCs.

Journal ArticleDOI
TL;DR: The authors examined the use of film subtitles as an approximation of word frequencies in human interactions and explained variance in lexical decision times in addition to what is accounted for by the available French written frequency measures.
Abstract: We examine the use of film subtitles as an approximation of word frequencies in human interactions. Because subtitle files are widely available on the Internet, they may present a fast and easy way to obtain word frequency measures in language registers other than text writing. We compiled a corpus of 52 million French words, coming from a variety of films. Frequency measures based on this corpus compared well to other spoken and written frequency measures, and explained variance in lexical decision times in addition to what is accounted for by the available French written frequency measures.

Journal ArticleDOI
04 Jan 2007-Nature
TL;DR: During differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis, and in erythroid precursors undergoing terminal differentiation, HSp70 prevents active casp enzyme-3 from cleaving Gata-1 and inducing apoptosis.
Abstract: Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors. The transcription factor GATA-1, which performs an essential function in erythroid differentiation by positively regulating promoters of erythroid and anti-apoptotic genes, is cleaved by caspases in erythroid precursors undergoing cell death upon erythropoietin starvation or engagement of the death receptor Fas. In contrast, by an unknown mechanism, GATA-1 remains uncleaved when these cells undergo terminal differentiation upon stimulation with Epo. Here we show that during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage of GATA-1. In an in vitro assay, Hsp70 protects GATA-1 from caspase-3-mediated proteolysis through its peptide-binding domain. The use of RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin leads to GATA-1 cleavage, a decrease in haemoglobin content, downregulation of the expression of the anti-apoptotic protein Bcl-X(L), and cell death by apoptosis. These effects are abrogated by the transduction of a caspase-resistant GATA-1 mutant. Thus, in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis.

Journal ArticleDOI
TL;DR: Functional models of the cerebellum are proposed as a background for interpreting research focusing on cerebellar dysfunctions in schizophrenia, and the picture arising from this review is heterogeneous.
Abstract: The role of the cerebellum in schizophrenia has been highlighted by Andreasen's hypothesis of “cognitive dysmetria,” which suggests a general dyscoordination of sensorimotor and mental processes. Studies in schizophrenic patients have brought observations supporting a cerebellar impairment: high prevalence of neurological soft signs, dyscoordination, abnormal posture and propioception, impaired eyeblink conditioning, impaired adaptation of the vestibular-ocular reflex or procedural learning tests, and lastly functional neuroimaging studies correlating poor cognitive performances with abnormal cerebellar activations. Despite those compelling evidences, there has been, to our knowledge, no recent review on the clinical, cognitive, and functional literature supporting the role of the cerebellum in schizophrenia. We conducted a Medline research focusing on cerebellar dysfunctions in schizophrenia. Emphasis was given to recent literature (after 1998). The picture arising from this review is heterogeneous. While in some domains, the role of the cerebellum seems clearly defined (ie, neurological soft signs, posture, or equilibrium), in other domains, the cerebellar contribution to schizophrenia seems limited or indirect (ie, cognition) if present at all (ie, affectivity). Functional models of the cerebellum are proposed as a background for interpreting these results.

Journal ArticleDOI
TL;DR: It is shown that the cytotoxic function of lymphocytes requires the cooperation of two types of organelles: the lysosomal cytot toxic granule and the endosomal 'exocytic vesicle'.
Abstract: Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4

Journal ArticleDOI
TL;DR: Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin (IVIg) is now widely used for a number of autoimmune and inflammatory diseases.
Abstract: Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin (IVIg) is now widely used for a number of autoimmune and inflammatory diseases. Considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory effects in autoimmune and inflammatory disorders. The mechanisms of action of IVIg are complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network and of idiotype network, regulation of cell growth, and effects on the activation, differentiation, and effector functions of dendritic cells, and T and B cells.

Journal ArticleDOI
TL;DR: Some of the studies that have begun to elucidate the regulation and function of this key transcription factor in liver are reviewed.
Abstract: Dysregulations in hepatic lipid synthesis are often associated with obesity and type 2 diabetes, and therefore a perfect understanding of the regulation of this metabolic pathway appears essential to identify potential therapeutic targets. Recently, the transcription factor ChREBP (carbohydrate-responsive element-binding protein) has emerged as a major mediator of glucose action on lipogenic gene expression and as a key determinant of lipid synthesis in vivo. Indeed, liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in obese ob/ob mice. Since ChREBP cellular localization is a determinant of its functional activity, a better knowledge of the mechanisms involved in regulating its nucleo-cytoplasmic shuttling and/or its post-translational activation is crucial in both physiology and physiopathology. Here, we review some of the studies that have begun to elucidate the regulation and function of this key transcription factor in liver.


Journal ArticleDOI
31 May 2007-Nature
TL;DR: The findings show the existence of an accurate mechanism to reduce the deleterious consequences of oxidative damage and point to an important role for PCNA and RP-A in determining a functional hierarchy among different DNA pols in lesion bypass.
Abstract: Specialized DNA polymerases (DNA pols) are required for lesion bypass in human cells. Auxiliary factors have an important, but so far poorly understood, role. Here we analyse the effects of human proliferating cell nuclear antigen (PCNA) and replication protein A (RP-A) on six different human DNA pols--belonging to the B, Y and X classes--during in vitro bypass of different lesions. The mutagenic lesion 8-oxo-guanine (8-oxo-G) has high miscoding potential. A major and specific effect was found for 8-oxo-G bypass with DNA pols lambda and eta. PCNA and RP-A allowed correct incorporation of dCTP opposite a 8-oxo-G template 1,200-fold more efficiently than the incorrect dATP by DNA pol lambda, and 68-fold by DNA pol eta, respectively. Experiments with DNA-pol-lambda-null cell extracts suggested an important role for DNA pol lambda. On the other hand, DNA pol iota, together with DNA pols alpha, delta and beta, showed a much lower correct bypass efficiency. Our findings show the existence of an accurate mechanism to reduce the deleterious consequences of oxidative damage and, in addition, point to an important role for PCNA and RP-A in determining a functional hierarchy among different DNA pols in lesion bypass.

Journal ArticleDOI
01 Feb 2007-Urology
TL;DR: The results of this study have shown that histologic subtyping of PRCC allows for the identification of an independent prognostic factor.

Journal ArticleDOI
TL;DR: In this review, the advantages and limitations associated with the use of gene therapy to cure SCID are summarized and insertional mutagenesis and technological improvements aimed at increasing the safety of this strategy are discussed.
Abstract: Inherited and acquired diseases of the hematopoietic system can be cured by allogeneic hematopoietic stem cell transplantation. This treatment strategy is highly successful when an HLA-matched sibling donor is available, but if not, few therapeutic options exist. Gene-modified, autologous bone marrow transplantation can circumvent the severe immunological complications that occur when a related HLA-mismatched donor is used and thus represents an attractive alternative. In this review, we summarize the advantages and limitations associated with the use of gene therapy to cure SCID. Insertional mutagenesis and technological improvements aimed at increasing the safety of this strategy are also discussed.

Journal ArticleDOI
TL;DR: Exactly 100 years ago, Louis Lapicque published a paper on the excitability of nerves that is often cited in the context of integrate-and-fire neurons, and a translation of the original publication is discussed.
Abstract: Exactly 100 years ago, Louis Lapicque published a paper on the excitability of nerves that is often cited in the context of integrate-and-fire neurons. We discuss Lapicque's contributions along with a translation of the original publication.

Journal ArticleDOI
TL;DR: The tonic current mediated by ambient glutamate in rat hippocampal slices was unaffected when inhibiting vesicular release of transmitters from neurons but was increased upon inhibition of the enzyme converting glutamate in glutamine in glial cells, indicating that ambient glutamate is mainly of glial origin.
Abstract: In several neuronal types of the CNS, glutamate and GABA receptors mediate a persistent current which reflects the presence of a low concentration of transmitters in the extracellular space. Here, we further characterize the tonic current mediated by ambient glutamate in rat hippocampal slices. A tonic current of small amplitude (53.99 +/- 6.48 pA at +40 mV) with the voltage dependency and the pharmacology of NMDA receptors (NMDARs) was detected in virtually all pyramidal cells of the CA1 and subiculum areas. Manipulations aiming at increasing D-serine or glycine extracellular concentrations failed to modify this current indicating that the glycine binding sites of the NMDARs mediating the tonic current were saturated. In contrast, non-transportable inhibitors of glutamate transporters increased the amplitude of this tonic current, indicating that the extracellular concentration of glutamate primarily regulates its magnitude. Neither AMPA/kainate receptors nor metabotropic glutamate receptors contributed significantly to this tonic excitation of pyramidal neurons. In the presence of glutamate transporter inhibitors, however, a significant proportion of the tonic conductance was mediated by AMPA receptors. The tonic current was unaffected when inhibiting vesicular release of transmitters from neurons but was increased upon inhibition of the enzyme converting glutamate in glutamine in glial cells. These observations indicate that ambient glutamate is mainly of glial origin. Finally, experiments with the use-dependent antagonist MK801 indicated that NMDARs mediating the tonic conductance are probably extra-synaptic NMDARs.

Journal ArticleDOI
TL;DR: An algorithm for removing environmental noise from neurophysiological recordings such as magnetoencephalography (MEG) improves the value of data recorded in health and scientific applications by suppressing harmful noise, and reduces the need for deleterious spatial or spectral filtering.


Journal ArticleDOI
TL;DR: The results suggest that H19 could be used as a sensor of the epigenetic disturbance of the utilized techniques, with a striking effect of each manipulation associated to ART practices.
Abstract: Background: In the last few years, an increase in imprinting anomalies has been reported in children born from Assisted Reproductive Technology (ART). Various clinical and experimental studies also suggest alterations of embryo development after ART. Therefore, there is a need for studying early epigenetic anomalies which could result from ART manipulations, especially on single embryos. In this study, we evaluated the impact of superovulation, in vitro fertilization (IVF) and embryo culture conditions on proper genomic imprinting and blastocyst development in single mouse embryos. In this study, different experimental groups were established to obtain embryos from superovulated and non-superovulated females, either from in vivo or in vitro fertilized oocytes, themselves grown in vitro or not. The embryos were cultured either in M16 medium or in G1.2/G2.2 sequential medium. The methylation status of H19 Imprinting Control Region (ICR) and H19 promoter was assessed, as well as the gene expression level of H19, in individual blastocysts. In parallel, we have evaluated embryo cleavage kinetics and recorded morphological data. Results: We show that: 1. The culture medium influences early embryo development with faster cleavage kinetics for culture in G1.2/G2.2 medium compared to M16 medium.

Journal ArticleDOI
TL;DR: It is shown that, in the frail elderly, a value of diastolic blood pressure ≤60 mm Hg is associated with reduced survival, independent from large artery stiffness and left ventricular function, suggesting that more rational antihypertensive therapy, not only based on systolic pressure level, is needed.
Abstract: Isolated systolic hypertension is predominantly observed in the elderly because of increased arterial stiffness. Aggressive treatment leads to excessive lowering of diastolic blood pressure and favors the presence of a J-shaped curve association with mortality. We investigated whether, in the elderly, this pattern of association is a simple epiphenomenon of increased arterial stiffness and impaired cardiac function. In a cohort of 331 hospitalized subjects >70 years old (mean age±SD: 85±7 years), aortic pulse wave velocity and pressure wave reflections, by pulse wave analysis, and cardiac function, by ultrasound, were assessed. During a 2-year follow-up period, 110 subjects died. No association of prognosis with systolic pressure, pulse pressure, or pulse wave velocity was observed. A J-shaped association between diastolic pressure and overall and cardiovascular mortality was observed. Unadjusted Cox regression analysis showed that patients in the first tertile of diastolic pressure (≤60 mm Hg) had higher mortality. In Cox regression analysis, diastolic pressure ≤60 mm Hg was a predictor of mortality independently from cardiac–vascular properties, cardiovascular risk factors, and drug treatment. Multivariate regression analysis showed that increased age and low total peripheral resistance, but not left ventricular function, were the cardinal determinants of low diastolic pressure. An “optimal” diastolic pressure of 70 mm Hg in subjects with isolated systolic hypertension was found. We showed that, in the frail elderly, a value of diastolic blood pressure ≤60 mm Hg is associated with reduced survival, independent from large artery stiffness and left ventricular function, suggesting that more rational antihypertensive therapy, not only based on systolic pressure level, is needed.

Journal ArticleDOI
TL;DR: In this article, the authors evaluated the safety and global long-term outcome of vertical parasagittal hemphherotomy and found that 77% of the patients were seizure-free without further drug treatment.
Abstract: Objective Hemispherotomy techniques have been developed to reduce complication rates and achieve the best possible seizure control. We present the results of our pediatric patients who underwent vertical parasagittal hemispherotomy and evaluate the safety and global long-term outcome of this technique. Methods Eighty-three patients underwent vertical parasagittal hemispherotomy by the same neurosurgeon (OD) between 1990 and 2000. We reviewed all patients between 2001 and 2003 for a standard global evaluation. The general principle is to achieve, through a posterior frontal cortical window, the same line of disconnection as performed with the classic hemispherectomy, while leaving the majority of the hemisphere intact along with its afferent and efferent vascular supply. Methods Seventy-four percent of the patients were seizure-free; among them, 77% were seizure-free without further drug treatment. Twelve percent rarely had seizures (Engel Class II) and 14% continued to have seizures (Engel Class III or IV). The results varied according to the etiology, but this variation was not statistically significant. The early postoperative course was uneventful for 94% of the children, and shunt placement was necessary in 15%. We found a correlation between the preoperative delay and the Vineland Adaptive Behavior score: children with a longer duration of seizures had lower performances. Conclusion Vertical parasagittal hemispherotomy is an effective surgical technique for hemispheric disconnection. It allows complete disconnection of the hemisphere through a cortical window with good results in terms of seizure outcome and a comparably low complication rate.

Journal ArticleDOI
TL;DR: A generic approach for expressing and purifying structured RNA in Escherichia coli, using tools that parallel those available for recombinant proteins, based on a camouflage strategy, the tRNA scaffold, in which the recombinant RNA is disguised as a natural RNA and thus hijacks the host machinery, escaping cellular RNases.
Abstract: RNA has emerged as a major player in most cellular processes. Understanding these processes at the molecular level requires homogeneous RNA samples for structural, biochemical and pharmacological studies. So far, this has been a bottleneck, as the only methods for producing such pure RNA have been in vitro syntheses. Here we describe a generic approach for expressing and purifying structured RNA in Escherichia coli, using tools that parallel those available for recombinant proteins. Our system is based on a camouflage strategy, the 'tRNA scaffold', in which the recombinant RNA is disguised as a natural RNA and thus hijacks the host machinery, escaping cellular RNases. This opens the way to large-scale structural and molecular investigations of RNA function.