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1.
Eur J Cancer ; 202: 114004, 2024 May.
Article in English | MEDLINE | ID: mdl-38493668

ABSTRACT

BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.


Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Humans , Aged , Glioblastoma/therapy , Glioblastoma/drug therapy , Temozolomide/therapeutic use , Dacarbazine/therapeutic use , Antineoplastic Agents, Alkylating/therapeutic use , Retrospective Studies , Brain Neoplasms/therapy , Brain Neoplasms/drug therapy , Prognosis
2.
Ann Oncol ; 29(3): 681-686, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29206892

ABSTRACT

Background: Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods: We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results: Compared with the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas [19/40 (48%) versus 25/530 (5%), P < 10-12] and located at the skull base [46/72 (64%) versus 241/481 (50%), P = 0.03]. We found a higher frequency of PIK3CA mutations [14/40 (35%) versus 18/530 (3%), P < 10-8] and TRAF7 mutations [16/40 (40%) versus 140/530 (26%), P < 0.001] and a lower frequency of NF2-related tumors compared with the control population of meningiomas [3/40 (7.5%) versus 169/530 (32%), P < 0.001]. Conclusion: This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.


Subject(s)
Meningeal Neoplasms/genetics , Meningioma/genetics , Progesterone Congeners/adverse effects , Adult , Aged , Aged, 80 and over , Chlormadinone Acetate/adverse effects , Class I Phosphatidylinositol 3-Kinases/genetics , Cyproterone Acetate/adverse effects , DNA Mutational Analysis , Female , Humans , Megestrol Acetate/adverse effects , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Mutation , Retrospective Studies , Young Adult
4.
Med Mal Infect ; 46(6): 276-84, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27056661

ABSTRACT

OBJECTIVE: We aimed to assess the acceptability of antibiotic stewardship measures by family physicians. MATERIAL AND METHODS: We conducted an online cross-sectional survey in 2015 with a sample of family physicians practicing in a specific French region. RESULTS: Overall, 283 of 1171 family physicians (24%) completed the questionnaire. Decision-support tools for antibiotic prescribing and educational measures were well accepted by family physicians: 71% strongly agreed with a free distribution of urine dipstick tests and 54% with incentives to participate in antibiotic training sessions. Almost all family physicians did not agree with restrictive measures: 68% were for instance opposed to having to justify the prescription's compliance with guidelines on the prescription itself. Physicians also did not agree with restrictive measures when they only applied to physicians prescribing many antibiotics. CONCLUSION: Participants were probably the most motivated and aware of the topic physicians, but they were particularly hostile to the introduction of restrictive measures related to antibiotic prescribing. Our survey was conducted with a large sample of family physicians and could help orientate our country's antibiotic stewardship policy. However, family physicians are likely to oppose any measure aiming at restricting their freedom of prescription.


Subject(s)
Antimicrobial Stewardship , Attitude of Health Personnel , Physicians, Family/psychology , Primary Health Care/standards , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Cross-Sectional Studies , Decision Support Techniques , Drug Prescriptions/standards , Female , France , Humans , Inappropriate Prescribing/prevention & control , Male , Middle Aged , Patient Education as Topic/methods , Professional Autonomy , Professional Practice , Reagent Kits, Diagnostic , Surveys and Questionnaires , Urinary Tract Infections/diagnosis , Urinary Tract Infections/drug therapy , Urinary Tract Infections/microbiology , Urine/microbiology
5.
Br J Cancer ; 111(10): 2024-32, 2014 Nov 11.
Article in English | MEDLINE | ID: mdl-25314060

ABSTRACT

BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.


Subject(s)
Biomarkers, Tumor/genetics , Glioma/genetics , Glioma/pathology , Mutation/genetics , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/genetics , Telomerase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Female , Follow-Up Studies , Glioma/mortality , Humans , Isocitrate Dehydrogenase/genetics , Male , Middle Aged , Neoplasm Grading , Polymerase Chain Reaction , Prognosis , Survival Rate , Young Adult
6.
Eur J Immunol ; 27(11): 2793-9, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9394801

ABSTRACT

Here we describe a Rho-mediated apoptosis suppression pathway driven by Bcl-2 expression in the interleukin (IL)-4- or IL-2-dependent murine T cell line TS1 alpha beta. IL-2, but not IL-4, induces Bcl-2 expression through RhoA activation which is inhibited by the specific Rho family inhibitor, Clostridium difficile Toxin B, as well as by a dominant negative RhoA mutant. Using transient transfections of RhoA mutants tagged with the vesicular stomatitis virus glycoprotein, we show that a constitutively active RhoA mutant induces Bcl-2 expression and prevents apoptosis upon IL-4 withdrawal. Finally, we have identified the signaling pathway involved together with RhoA in Bcl-2 induction and show compelling evidence for the implication of phosphatidylinositol 3 kinase and protein kinase C.


Subject(s)
GTP-Binding Proteins/physiology , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Receptors, Interleukin-2/physiology , Signal Transduction/immunology , Animals , Apoptosis/genetics , Apoptosis/immunology , Cell Line , Down-Regulation/immunology , GTP-Binding Proteins/genetics , Humans , Interleukin-2/deficiency , Mice , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/pharmacology , Protein Kinase C/metabolism , Protein Kinase C/pharmacology , Proto-Oncogene Proteins c-bcl-2/drug effects , Transfection/immunology , rhoA GTP-Binding Protein
7.
EMBO J ; 15(13): 3315-21, 1996 Jul 01.
Article in English | MEDLINE | ID: mdl-8670832

ABSTRACT

The small GTPase rho is functionally involved in the formation of cytoskeletal structures like stress fibers or focal adhesion plaques. Shigella entry into HeLa cells induces a blossom-like membrane structure at the bacterial entry site. We show here that this membrane-folding process is rho-dependent. The three rho isoforms were recruited into bacterial entry sites with differential localization relative to the membrane structure. A rho-specific inhibitor abolished Shigella-induced membrane folding and impaired bacterial entry accordingly. S1-myosin labeling indicated that rho was involved in Shigella-induced actin polymerization but not actin nucleation in the bacterial invasion site. This provides a major link in the signalization cascade allowing entry of a bacterial pathogen into a eukaryotic cell.


Subject(s)
GTP Phosphohydrolases/metabolism , Isoenzymes/metabolism , Shigella/physiology , Amino Acid Sequence , Cell Membrane/metabolism , Cell Membrane/microbiology , Cytoskeleton/metabolism , Epithelial Cells , Epithelium/microbiology , Epithelium/ultrastructure , HeLa Cells , Humans , Microscopy, Electron, Scanning , Molecular Sequence Data , Shigella/ultrastructure
8.
J Biol Chem ; 271(17): 10217-24, 1996 Apr 26.
Article in English | MEDLINE | ID: mdl-8626586

ABSTRACT

Lethal toxin (LT) from Clostridium sordellii is one of the high molecular mass clostridial cytotoxins. On cultured cells, it causes a rounding of cell bodies and a disruption of actin stress fibers. We demonstrate that LT is a glucosyltransferase that uses UDP-Glc as a cofactor to covalently modify 21-kDa proteins both in vitro and in vivo. LT glucosylates Ras, Rap, and Rac. In Ras, threonine at position 35 was identified as the target amino acid glucosylated by LT. Other related members of the Ras GTPase superfamily, including RhoA, Cdc42, and Rab6, were not modified by LT. Incubation of serum-starved Swiss 3T3 cells with LT prevents the epidermal growth factor-induced phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, indicating that the toxin blocks Ras function in vivo. We also demonstrate that LT acts inside the cell and that the glucosylation reaction is required to observe its dramatic effect on cell morphology. LT is thus a powerful tool to inhibit Ras function in vivo.


Subject(s)
Bacterial Toxins/metabolism , Clostridium/pathogenicity , GTP-Binding Proteins/metabolism , Glucosyltransferases/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , 3T3 Cells , Actin Cytoskeleton/ultrastructure , Actins/chemistry , Amino Acid Sequence , Animals , Bacterial Toxins/toxicity , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Epidermal Growth Factor/pharmacology , GTP Phosphohydrolases/metabolism , Glucose/metabolism , Guanosine Triphosphate/metabolism , HeLa Cells/drug effects , HeLa Cells/ultrastructure , Humans , Kinetics , Mice , Molecular Sequence Data , Threonine/metabolism , Uridine Diphosphate Glucose/metabolism , rac GTP-Binding Proteins , rap GTP-Binding Proteins
9.
Proc Natl Acad Sci U S A ; 92(23): 10629-33, 1995 Nov 07.
Article in English | MEDLINE | ID: mdl-7479854

ABSTRACT

The rho family of GTP-binding proteins regulates actin filament organization. In unpolarized mammalian cells, rho proteins regulate the assembly of actin-containing stress fibers at the cell-matrix interface. Polarized epithelial cells, in contrast, are tall and cylindrical with well developed intercellular tight junctions that permit them to behave as biologic barriers. We report that rho regulates filamentous actin organization preferentially in the apical pole of polarized intestinal epithelial cells and, in so doing, influences the organization and permeability of the associated apical tight junctions. Thus, barrier function, which is an essential characteristic of columnar epithelia, is regulated by rho.


Subject(s)
Actins/physiology , Botulinum Toxins , Cell Polarity/physiology , GTP-Binding Proteins/metabolism , Intestines/cytology , Tight Junctions/physiology , rho GTP-Binding Proteins , ADP Ribose Transferases/metabolism , Actins/ultrastructure , Blotting, Western , Cadherins/metabolism , Cell Adhesion , Cell Communication , Cells, Cultured , Epithelial Cells , Fluorescent Antibody Technique , GTP-Binding Proteins/genetics , Humans , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Precipitin Tests , Recombinant Proteins/metabolism , Signal Transduction , Tight Junctions/ultrastructure , Zonula Occludens-1 Protein , rhoC GTP-Binding Protein
10.
Infect Immun ; 63(10): 4063-71, 1995 Oct.
Article in English | MEDLINE | ID: mdl-7558320

ABSTRACT

The bacterial pathogen Clostridium difficle synthesizes two high-molecular-weight toxins (A and B), which exhibit toxic effects in vivo and in vitro. Here, we present evidence that the major intracellular targets of these two toxins are the Rho GTPases. Overexpression of RhoA, RhoB, or RhoC GTPases in transfected HeLa cells conferred an increased resistance to toxins A and B, indicating that these toxins cause their cytopathic effects primarily by affecting Rho proteins. In addition, toxin A and B treatment appeared to result in modification of Rho, since Rho isolated from toxin-treated cells had a decreased ability to be ADP-ribosylated by Clostridium botulinum C3 exoenzyme. In contrast, the lethal toxin (LT) of Clostridium sordellii, although structurally and immunologically related to C. difficile toxin B, appeared to induce cytopathic effects independently of the Rho GTPases. Overexpression of RhoA in transfected HeLa cells did not protect them from the effect of LT, and Rho isolated from lysates of LT-treated cells was not resistant to modification by C3. Immunofluorescence studies showed that LT treatment caused a cytopathic effect that was very different from those described for C. difficile toxins A and B, resulting in an increase in cortical F-actin, with a concomitant decrease in the number of stress fibers, and in the formation of numerous microvilli containing the actin-bundling protein fimbrin/plastin.


Subject(s)
Bacterial Proteins , Bacterial Toxins/toxicity , Clostridioides difficile/pathogenicity , Enterotoxins/toxicity , GTP-Binding Proteins/physiology , Membrane Proteins/physiology , rho GTP-Binding Proteins , Cytoskeleton , HeLa Cells , Humans , Transfection , rhoA GTP-Binding Protein , rhoB GTP-Binding Protein , rhoC GTP-Binding Protein
12.
J Biol Chem ; 269(14): 10706-12, 1994 Apr 08.
Article in English | MEDLINE | ID: mdl-8144660

ABSTRACT

Clostridium difficile toxin B exhibits cytotoxic activity that is characterized by the disruption of the microfilamental cytoskeleton. Here we studied whether the GTP-binding Rho protein, which reportedly participates in the regulation of the actin cytoskeleton, is involved in the toxin action. Toxin B treatment of Chinese hamster ovary cells reveals a time- and concentration-dependent decrease in the ADP-ribosylation of Rho by Clostridium botulinum C3 exoenzyme in the cell lysate. Disruption of the microfilament system induced by C. botulinum C2 toxin or cytochalasin D does not cause impaired ADP-ribosylation of Rho. Toxin B exhibits its effects on Rho not only in intact cells but also when added to cell lysates. Besides endogenous Rho, RhoA-glutathione S-transferase (Rho-GST) fusion protein added to cell lysate showed decreased ADP-ribosylation after toxin B treatment. Immunoblot analysis reveals identical amounts of Rho-GST and no change in molecular mass after toxin B treatment compared with controls. ADP-ribosylation of Rho-GST purified from toxin B-treated cell lysate is inhibited, indicating a modification of Rho itself. Finally, transfection of rhoA DNA under the control of a strong promoter into cells protects them from the activity of toxin B. Altogether, the data indicate that C. difficile toxin B acts directly or indirectly on Rho proteins to inhibit ADP-ribosylation and suggest that the cytotoxic effect of toxin B involves Rho.


Subject(s)
Bacterial Proteins , Bacterial Toxins/pharmacology , Botulinum Toxins , Clostridioides difficile , GTP-Binding Proteins/drug effects , 3T3 Cells , ADP Ribose Transferases/metabolism , Adenosine Diphosphate Ribose/metabolism , Amino Acid Sequence , Animals , CHO Cells , Cell Survival/drug effects , Cells, Cultured , Cricetinae , Mice , Molecular Sequence Data , Signal Transduction , rhoA GTP-Binding Protein
13.
EMBO J ; 12(3): 921-31, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8458345

ABSTRACT

We have developed a new tool for studying the role of rho in actin stress fibre formation. Clostridium botulinum exoenzyme C3 which affects actin microfilament assembly by ADP-ribosylation of p21 rho was genetically fused in various ways to diphtheria toxin (DT). The resulting chimeric toxins were tested on Vero cells. Chimeras of C3 and both the A and B fragments of diphtheria toxin had reduced cell binding activities but were apparently able to penetrate into Vero cells by the same mechanism as DT. Upon exposure to low pH, DC3B, a fusion protein of C3 and DT B fragment, had a high affinity for the DT receptor, but was apparently not able to translocate to the cytosol upon acidification. In spite of this, addition of picomolar concentrations of DC3B to the growth medium caused disruption of the cell microfilament system associated with vinculin and blocked cell growth efficiently, indicating that the C3 part of DC3B reached the cytosol, albeit by a different mechanism than that of whole diphtheria toxin. The chimeric DC3B toxin was also applied to Vero cells infected by Listeria monocytogenes, a pathogenic bacterium that uses an unknown mechanism of actin polymerization to move rapidly in the cytosol. DC3B inhibited the bacterially induced microfilament assembly indicating that L. monocytogenes utilizes a cellular rho dependent mechanism in this process.


Subject(s)
ADP Ribose Transferases , Actins/metabolism , Botulinum Toxins , Diphtheria Toxin , GTP-Binding Proteins/physiology , Recombinant Fusion Proteins , ADP Ribose Transferases/genetics , Animals , Chlorocebus aethiops , Cloning, Molecular , Diphtheria Toxin/genetics , Escherichia coli , Listeria monocytogenes/isolation & purification , Mice , Recombinant Fusion Proteins/genetics , Vero Cells , Vinculin/metabolism , rho GTP-Binding Proteins
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