Personne : Carrondo Cottin, Sylvine
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Université Laval. Département de biologie moléculaire, de biochimie médicale et de pathologie
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- PublicationRestreintGap junctions in human glioblastomas: implications for suicide gene therapy.(Newsrx, 2021-07-22) Carrondo Cottin, Sylvine; Gould, Peter Vincent; Cantin, Léo; Caruso, ManuelGlioblastoma is a very aggressive astrocytic tumor and most patients have 1-year survival time after diagnosis. A promising therapeutic strategy is the local delivery of the herpes simplex virus thymidine kinase gene in the tumor bed followed by ganciclovir treatment. The presence of functional gap junctions is highly relevant for the success of suicide gene therapy. Connexins are expressed in practically all tissues and form gap junctions that allow intercellular communication. Connexin 43 (Cx43) is the major connexin member being expressed in astrocytes but its status in glioblastoma is not well defined. We have investigated by immunofluorescence the presence of Cx43 in 74 human glioblastoma samples; its expression was detected in 77% of the samples analyzed. We report here that glioblastoma is a heterogenous disease as regards Cx43 expression with presentations, in which Cx43 expression is unaltered, reduced or totally lost. A predominant Cx43 cytoplasmic localization was observed in four out of eight primary glioblastoma cultures that we have established. This aberrant localization reduced gap junctionnal intercellular communication by 50 to 75% as compared with primary cell cultures displaying gap junctional plaques. However, the bystander effect evaluated after lentiviral delivery of the herpes simplex virus thymidine kinase gene and ganciclovir treatment was detected in all Cx43-positive primary cell cultures, and it was independant of the Cx43 localization. These findings may have important clinical implications for the design of anticancer cytotoxic therapies that rely on the gap junction-mediated bystander effect for their success
- PublicationAccès libreOccipital nerve stimulation for non-migrainous chronic headaches : a systematic review protocol(BioMed Central, 2019-07-22) Carrondo Cottin, Sylvine; Gallani, Nevair; Prud'homme, Michel; Cantin, LéoBackground: Defined as a headache lasting at least 15 days per month, chronic headache is reported by 3% of the general population, and a substantial proportion of them are refractory to current therapies. Occipital nerve stimulation (ONS) is a treatment option, but is still considered as a last resort treatment especially because of its invasive nature and the cost associated. Some reviews reported a limited efficacy of ONS for the treatment of migraines, with a high risk of complications. However, results reporting its efficacy and safety on other headache disorders are unclear. The aim of this review is to assess the efficacy and safety of ONS in regards to non-migrainous chronic headaches. Methods: We will conduct a systematic review and meta-analysis of studies evaluating the use of ONS in comparison to sham stimulation or the best available treatment in patients with chronic headache. MEDLINE, CINHAL, EMBASE, PsycINFO, ECRI Institute Library, WIKISTIM, the Cochrane Library databases, and clinical trial registries will be searched for eligible studies. The review will include adult patients diagnosed with chronic headache excluding migraine. Two independent reviewers will process to the screening of studies according to titles, abstracts, and then full texts. The primary outcome is the overall reduction of head pain severity. The secondary outcomes are rates of reduction in the severity of head pain, headache frequency, and duration, use of medication, impairment, quality of life, healthcare utilization, return to work, and adverse events. Extracted data will include patients’ and procedure characteristics, details on comparative treatment or sham, and clinical outcomes. The risk of bias of the studies will be also independently assessed using the Cochrane risk of bias tools. Discussion: This systematic review will allow us to better evaluate the potential role of ONS for the treatment of patients with chronic headache that are refractory to less invasive therapies. It will help to determine the degree of safety of ONS. Moreover, it will help to design and conduct future randomized controlled trials focused on patients who may better respond to such treatment
- PublicationAccès libreGemcitabine intercellular diffusion mediated by gap junctions : new implications for cancer therapy(BioMed Central, 2010-06-10) Carrondo Cottin, Sylvine; Ghani, Karim; Campos Lima, Pedro Otavio de; Caruso, ManuelBackground: Solid tumors are often poorly vascularized, with cells that can be 100 μm away from blood vessels. These distant cells get less oxygen and nutrients and are exposed to lower doses of chemotherapeutic agents. As gap junctions allow the passage of small molecules between cells, we tested the possibility that the chemotherapeutic agent gemcitabine can diffuse through gap junctions in solid tumors. Results: We first showed with a dye transfer assay that the glioblastoma and the osteosarcoma cells used in this study have functional gap junctions. These cells were genetically engineered to express the herpes simplex virus thymidine kinase (TK), and induced a "bystander effect" as demonstrated by the killing of TK-negative cells in presence of the nucleoside analogue ganciclovir (GCV). The ability of gemcitabine to induce a similar bystander effect was then tested by mixing cells treated with 3 μM gemcitabine for 24 hours with untreated cells at different ratios. In all cell lines tested, bystander cells were killed with ratios containing as low as 5% treated cells, and this toxic effect was reduced in presence of α-glycyrrhetinic acid (AGA), a specific gap junction inhibitor. We also showed that a 2- or a 24-hour gemcitabine treatment was more efficient to inhibit the growth of spheroids with functional gap junctions as compared to the same treatment made in presence of AGA. Finally, after a 24-hour gemcitabine treatment, the cell viability in spheroids was reduced by 92% as opposed to 51% in presence of AGA. Conclusion: These results indicate that gemcitabine-mediated toxicity can diffuse through gap junctions, and they suggest that gemcitabine treatment could be more efficient for treating solid tumors that display gap junctions. The presence of these cellular channels could be used to predict the responsiveness to this nucleoside analogue therapy.
- PublicationAccès libreExpression et localisation de la connexine 43 dans le glioblastome : implication pour la thérapie génique(2008) Carrondo Cottin, Sylvine; Caruso, ManuelL’effet de proximité est essentiel à la réussite de la stratégie thymidine kinase (HSV-tk)/ganciclovir (GCV) dans le traitement du cancer. Cette propriété correspond au transfert de GCV phosphorylé des cellules tumorales HSV-tk+ vers les cellules tumorales HSV-tk–, et est essentiellement médiée par les jonctions gap (JGs) constituées de molécules de connexine (Cx). Une perte d’expression et/ou une localisation périnucléaire des connexines est souvent décrite dans les tumeurs, ce qui pourrait conduire, en théorie, à une diminution de l’efficacité du traitement HSV-tk/GCV. L’approche HSV-tk/GCV a été testée au cours d’essais cliniques pour le traitement du glioblastome bien que l’expression de la Cx43 (principal constituant des JGs dans les astrocytes) ne soit parfaitement définie. Au cours de mes travaux, l’expression de la Cx43, sa localisation et sa fonctionnalité ont été étudiées dans des lignées établies, des biopsies et des cultures primaires de glioblastome. Dans les trois lignées immortalisées de glioblastome étudiées, la Cx43 se retrouve essentiellement localisée dans les endosomes et les lysosomes comparativement aux cellules HeLa/Cx43 qui présentent une localisation membranaire de la Cx43. Des JGs ont été observées dans la lignée U87, mais très peu dans les lignées SKI-1 et U251. De façon surprenante, les lignées SKI-1 et U87 présentent une capacité jonctionnelle supérieure à celle des cellules HeLa/Cx43. De plus, un important effet de proximité a pu être mesuré dans les cellules SKI-1 et U87 suite au traitement par le GCV. L’utilisation d’un inhibiteur spécifique de la perméabilité des JGs a confirmé que l’effet de proximité induit dans ces lignées est principalement dû aux JGs. De plus, la transfection d’un mutant dominant négatif de la Cx43 ou de siARN spécifiques des ARNm de la Cx43 a permis d’identifier la Cx43 comme le principal constituant des JGs dans ces lignées de glioblastome. L’expression de la Cx43 a été mesurée sur soixante-quatorze biopsies de glioblastome. Si son expression est souvent plus faible que dans le tissu sain, seulement 23% des échantillons sont dépourvus de Cx43. Huit lignées primaires ont été dérivées de résections de patients, et sept d’entre elles expriment la Cx43, cependant à différents niveaux d’intensité. Quatre lignées démontrent une localisation cytoplasmique de la Cx43. Malgré la localisation cytoplasmique prédominante de la Cx43, ces cellules sont capables de communiquer entre elles efficacement comme l’essai de double marquage en cytométrie de flux l’a démontré. Un vecteur lentiviral contenant le gène HSV-tk a été construit afin de mener les tests d’effet de proximité. Il a ainsi été mis en évidence que quelle que soit la localisation de la Cx43, l’effet de proximité est significatif dans toutes les lignées exprimant la Cx43 et inexistant lorsque la Cx43 n’est pas présente. Ces résultats démontrent que la Cx43 est exprimée dans la majorité des glioblastomes. La Cx43 peut être exprimée dans les lignées établies et les lignées primaires de glioblastome au niveau de la membrane plasmique ou dans le cytoplasme. Cette localisation aberrante ne bloque pas le transfert intercellulaire de molécules, ce qui suggère que les rares JGs présentes à la surface sont hautement fonctionnelles. Ces résultats indiquent que l’approche HSV-tk/GCV est un candidat valable pour le traitement du glioblastome, contrairement à d’autres tumeurs pour lesquelles la perte d’expression de Cx est bien documentée. Il serait ainsi intéressant que l’expression de la Cx43 soit étudiée dans les biopsies utilisées lors du diagnostic et constitue ainsi un prérequis pour le recrutement des patients lors d’essais cliniques.
- PublicationAccès libreSpinal cord stimulation in the treatment of neuropathic pain : current perspectives of indications, cost-effectiveness, complications and results(Fakultet zdravstvenih studija, 2017-09-25) Camporeze, Bruno; Carrondo Cottin, Sylvine; Simm, Renata Faria; Estevão, Iracema Araújo; Mathias Junior, Luis Roberto; Aguiar, Paulo Henrique PiresIntroduction: The spinal cord stimulation (SCS) has been described as a valuable neuromodulating procedure in the management of chronic and medically untreated neuropathic pain. Although, many studies have discussed the use of this technique, a question still remains regarding its efficacy in different medical conditions with different etiology in the long term. The aim of this paper is to discuss the risks, complications, cost-effectiveness and results of SCS in patients affected by chronic neuropathic pain based on the comprehensive literature review. Methods: Bibliographic search of references from 1950 to 2016 using the databases MEDLINE, LILACS, SciELO, PubMed, and applied language as selection criteria, choosing preferably recent articles written in Portuguese, Spanish or English. Results: Based on literature review, SCS is a safe, reversible, adjustable and nondestructive surgical procedure demonstrating a significant effect in the reduction of pain intensity and improvement in quality of life in these patients. Furthermore, in spite of the initial high cost to its application, SCS has been associated with lower rates of complications and high rates of cost-effectiveness when compared to standard therapies. Conclusion: Although used in medical conditions with different etiology, the procedure is still an effective and a cost-effective approach to neuropathic pain, mainly in patients affected by failed back pain syndrome (FBSS) and complex regional pain syndrome (CRPS).
- PublicationRestreintBilateral stereotactic anterior capsulotomy for obsessive-compulsive disorder : long-term follow-up.(London British Medical Association, 2021-06-03) Carrondo Cottin, Sylvine; Picard, Claude; Roy, Martin; Cantin, Léo; D'Astous, MireilleBackground and purpose: Psychosurgery, such as anterior capsulotomy, is a therapeutic option for treatment-resistant obsessive-compulsive disorder (OCD). In this paper, we present a prospective, long-term follow-up study aimed at evaluating both the efficacy and the safety of anterior capsulotomy for the treatment of severe, refractory OCD. Methods: Twenty-four patients were surgically treated in our centre between 1997 and 2009, 19 of whom were included in this study. Patients were assessed at 3, 6, 12, and 24 months and last follow-up (mean of 7 years) was carried out by phone. OCD symptom severity was evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). A patient with an improvement rate of over 35% in the Y-BOCS score was considered a responder, while a patient with a 25% improvement was considered a partial responder. Results: With a mean improvement of 31% in the Y-BOCS score at long-term follow-up, 36.8% of the patients responded fully to the procedure and 10.5% were considered partial responders, for an overall response rate of 47.3% of patients. At the end of the study, 3/19 patients had recovered (Y-BOCS score <8) and 3/19 were in remission (Y-BOCS score <16). No cases of mortality were reported and the overall adverse event rate was 57.9%. Only 2 patients had permanent surgical complications. Conclusions: Anterior capsulotomy is an effective and safe technique for the treatment of severe refractory OCD in patients who have no other alternative to improve their symptoms.
- PublicationRestreintEffects of tonic spinal cord stimulation on external mechanical and thermal stimuli perception using quantitative sensory testing: a multicenter stimulation ON-OFF study on chronic pain patients(Wolters Kluwer, 2020-03-01) Carrondo Cottin, Sylvine; Bordeleau, Martine; Prud'homme, Michel; Cantin, LéoObjectives: Tonic spinal cord stimulation (SCS) is currently used to treat neuropathic pain. With this type of stimulation, an implantable pulse generator generates electrical paresthesias in the affected area through 1 or more epidural leads. The goal of this study was to evaluate the impact of tonic SCS on the sensory perception of chronic pain patients using quantitative sensory testing (QST). Materials and Methods: Forty-eight patients (mean age: 57 y) with chronic leg pain due to failed back surgery syndrome or complex regional pain syndrome treated with SCS were recruited from 3 research centers. Test procedures included 2 sessions (stimulation On or Off), with measures of detection thresholds for heat, touch, vibration, and of pain thresholds for cold, heat, pressure, the assessment of dynamic mechanical allodynia, and temporal pain summation. Three different areas were examined: the most painful area of the most painful limb covered with SCS-induced paresthesias (target area), the contralateral limb, and the ipsilateral upper limb. Wilcoxon signed-rank tests were used to compare the mean difference between On and Off for each QST parameter at each area tested. P-values <0.05 were considered significant. Results: Regarding the mean difference between On and Off, patients felt less touch sensation at the ipsilateral area (−0.4 ± 0.9 g, P=0.0125) and were less sensitive at the contralateral area for temporal pain summation (−4.9 ± 18.1 on Visual Analog Scale 0 to 100, P=0.0056) with SCS. Discussion: It is not clear that the slight changes observed were clinically significant and induced any changes in patients’ daily life. Globally, our results suggest that SCS does not have a significant effect on sensory perception.
- PublicationRestreintA pilot placebo controlled randomized trial of dexamethasone for chronic subdural hematoma(Fédération des sciences neurologiques du Canada, 2016-02-08) Carrondo Cottin, Sylvine; Mathieu, François; Marcotte, Nicolas; Prud'homme, MichelBackground: Current opinions regarding the use of dexamethasone in the treatment of chronic subdural hematomas (CSDH) are only based on observational studies. Moreover, the use of corticosteroids in asymptomatic or minimally symptomatic patient with this condition remains controversial. Here, we present data from a prospective randomized pilot study of CSDH patients treated with dexamethasone or placebo. Methods: Twenty patients with imaging-confirmed CSDH were recruited from a single center and randomized to receive dexamethasone (12 mg/day for 3 weeks followed by tapering) or placebo as a conservative treatment. Patients were followed for 6 months and the rate of success of conservative treatment with dexamethasone versus placebo was measured. Parameters such as hematoma thickness and clinical changes were also compared before and after treatment with chi-square tests. Adverse events and complications were documented. Results: During the 6-month follow-up, one of ten patients treated with corticosteroids had to undergo surgical drainage and three of ten patients were treated surgically after placebo treatment. At the end of the study, all remaining patients had complete radiological resolution. No significant differences were observed in terms of hematoma thickness profile and impression of change; however, patients experienced more severe side effects when treated with steroids as compared with placebo. Dexamethasone contributed to many serious adverse events. Conclusions: Given the small sample size, these preliminary results have not shown a clear beneficial effect of dexamethasone against placebo in our patients. However, the number of secondary effects reported was much greater for corticosteroids, and dexamethasone treatment was responsible for significant complications.
- PublicationRestreintEffects of tonic spinal cord stimulation on sensory perception in chronic pain patients : a systematic review.(Wiley Online Library, 2018-12-02) Carrondo Cottin, Sylvine; Bordeleau, Martine; Meier, Kaare; Prud'homme, MichelObjectives: Even if spinal cord stimulation (SCS) is widely used and effective in treating intractable chronic neuropathic pain conditions, little is known about its possible impacts on sensory perception. Quantitative sensory testing (QST) is a useful tool to assess this issue. The aim of this study was to review the impact of tonic SCS on somatosensory perception quantified by QST in chronic pain patients. Materials and methods: Relevant articles and abstracts were searched in all languages from CINAHL, Cochrane, Embase, MEDLINE, and Web of Knowledge data bases. Data were extracted and included studies were assessed for risk of bias. Results: Out of 5610 records, 15 peer-reviewed articles were eligible and included. The results are heterogeneous due to inadequate comparability among studies for populations (a total of 224 patients diagnosed with more than 13 chronic pain conditions), QST parameters (22 measured with 25 different devices) and experimental procedures (study design, comparator, evaluation time, and area tested). The wide variety of studies, designs, populations, and measures included in this review did not lead to strong evidence on how conventional ("tonic") SCS affects sensory processing in patients with chronic pain. Conclusions: The data available tend to suggest that conventional SCS does not interfere with perception of external stimuli. New studies that follow a standardized procedure and consider the possible influence of sensory profile, after-effect bias, and confounding factors are required to confirm this observation. Moreover, the impact on sensory perception of other SCS modalities and alternative electrical neuromodulation therapies could also be explored.
- PublicationRestreintGeneration of a high-titer packaging cell line for the production of retroviral vectors in suspension and serum-free media.(Nature Publishing Group, 2007-10-11) Carrondo Cottin, Sylvine; Ghani, Karim; Kamen, Amine A.; Caruso, ManuelSeveral patients with severe combined immunodeficiency-X1 disease and adenosine deaminase deficiency have been cured by retroviral-mediated gene therapy. Despite the earlier success, the production of retroviral vectors for clinical gene therapy is cumbersome, costly and lacks safety features because of the adherent nature of packaging cells and the necessity to supplement the culture media with bovine serum. The aim of this study was to generate a retrovirus packaging cell line that could be used for the production of large clinical batch vectors. Bicistronic vectors containing an internal ribosomal entry site followed by a selection gene were used to express Moloney murine leukemia gag-pol and amphotropic envelope viral proteins in HEK293 cells. The candidate clone (293GP-A2) that was selected as the packaging cell line could release recombinant green fluorescent protein retroviruses at 4 x 10⁷ infectious viral particles per ml. Similar titers were achieved after these cells were adapted to grow in suspension and serum-free media. Furthermore, using the same culture conditions viral titers proved to be stable for a 3-month culture period. The 293GP-A2 packaging cell line has the potential to be cultured in bioreactors, opening the possibility for large-scale use of retroviral vectors in late stage clinical trials.