Publications by authors named "Patrice Ravel"

19 Publications

  • Page 1 of 1

An R package for generic modular response analysis and its application to estrogen and retinoic acid receptor crosstalk.

Sci Rep 2021 Mar 31;11(1):7272. Epub 2021 Mar 31.

Inserm U1194, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.

Modular response analysis (MRA) is a widely used inference technique developed to uncover directions and strengths of connections in molecular networks under a steady-state condition by means of perturbation experiments. We devised several extensions of this methodology to search genomic data for new associations with a biological network inferred by MRA, to improve the predictive accuracy of MRA-inferred networks, and to estimate confidence intervals of MRA parameters from datasets with low numbers of replicates. The classical MRA computations and their extensions were implemented in a freely available R package called aiMeRA ( https://github.com/bioinfo-ircm/aiMeRA/ ). We illustrated the application of our package by assessing the crosstalk between estrogen and retinoic acid receptors, two nuclear receptors implicated in several hormone-driven cancers, such as breast cancer. Based on new data generated for this study, our analysis revealed potential cross-inhibition mediated by the shared corepressors NRIP1 and LCoR. We designed aiMeRA for non-specialists and to allow biologists to perform their own analyses.
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http://dx.doi.org/10.1038/s41598-021-86544-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012374PMC
March 2021

Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy.

Int J Cancer 2018 12 1;143(11):3008-3018. Epub 2018 Oct 1.

Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.

mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127 CD62L ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (T ) expansion in vivo limits the efficacy of the bi-therapy by altering the antitumor CD8 T-cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent T induction considerably improved the efficacy of the bi-therapy by enhancing CD8 T cells-mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit T .
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http://dx.doi.org/10.1002/ijc.31842DOI Listing
December 2018

Valine/isoleucine variants drive selective pressure in the VP1 sequence of EV-A71 enteroviruses.

BMC Infect Dis 2017 05 8;17(1):333. Epub 2017 May 8.

Cirad, UMR 17, Intertryp, TA-A17/G, Campus International de Baillarguet, 34398, Montpellier Cedex 5, France.

Background: In 2011-2012, Northern Vietnam experienced its first large scale hand foot and mouth disease (HFMD) epidemic. In 2011, a major HFMD epidemic was also reported in South Vietnam with fatal cases. This 2011-2012 outbreak was the first one to occur in North Vietnam providing grounds to study the etiology, origin and dynamic of the disease. We report here the analysis of the VP1 gene of strains isolated throughout North Vietnam during the 2011-2012 outbreak and before.

Methods: The VP1 gene of 106 EV-A71 isolates from North Vietnam and 2 from Central Vietnam were sequenced. Sequence alignments were analyzed at the nucleic acid and protein level. Gene polymorphism was also analyzed. A Factorial Correspondence Analysis was performed to correlate amino acid mutations with clinical parameters.

Results: The sequences were distributed into four phylogenetic clusters. Three clusters corresponded to the subgenogroup C4 and the last one corresponded to the subgenogroup C5. Each cluster displayed different polymorphism characteristics. Proteins were highly conserved but three sites bearing only Isoleucine (I) or Valine (V) were characterized. The isoleucine/valine variability matched the clusters. Spatiotemporal analysis of the I/V variants showed that all variants which emerged in 2011 and then in 2012 were not the same but were all present in the region prior to the 2011-2012 outbreak. Some correlation was found between certain I/V variants and ethnicity and severity.

Conclusions: The 2011-2012 outbreak was not caused by an exogenous strain coming from South Vietnam or elsewhere but by strains already present and circulating at low level in North Vietnam. However, what triggered the outbreak remains unclear. A selective pressure is applied on I/V variants which matches the genetic clusters. I/V variants were shown on other viruses to correlate with pathogenicity. This should be investigated in EV-A71. I/V variants are an easy and efficient way to survey and identify circulating EV-A71 strains.
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http://dx.doi.org/10.1186/s12879-017-2427-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422960PMC
May 2017

Tim-3 Expression on Tumor-Infiltrating PD-1CD8 T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma.

Cancer Res 2017 03 21;77(5):1075-1082. Epub 2016 Nov 21.

INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8 T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8 T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1Tim-3 subset of CD8 T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3PD1CD8 T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0274DOI Listing
March 2017

Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia.

Malar J 2016 06 14;15:319. Epub 2016 Jun 14.

Institut de Biologie Computationnelle (IBC), Montpellier, France.

Background: Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008-2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential.

Methods: To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010-2011 from 16 health centres in malaria endemics areas in Cambodia.

Results: Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance.

Conclusions: The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia.
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http://dx.doi.org/10.1186/s12936-016-1370-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908689PMC
June 2016

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity.

Cancer Res 2016 07 17;76(14):4100-12. Epub 2016 May 17.

INSERM UMR1098, TIMC LabEx LipSTIC, Besançon, France. University of Bourgogne Franche-Comté, UMR1098, Besançon, France. Department of Medical Oncology, University Hospital of Besançon, Besançon, France.

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3 (+)Helios(+)Ki67(+) regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes(+)CD8(+) T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100-12. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2452DOI Listing
July 2016

Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator.

Int J Pharm 2015 Nov 9;495(1):410-419. Epub 2015 Sep 9.

Institut Charles Gerhardt UMR5253 Equipe MACS, UFR Sciences Pharmaceutiques et Biologiques - Université de Montpellier, France.

Textured mannitol powder is widely used as a pharmaceutical excipient for tablet compaction. In order to choose the right tableting parameters, it is necessary to understand its mechanical behavior during deformation under industrial tableting conditions. The aim of this study was to evaluate the mechanical behavior during deformation of a textured mannitol using a rotary tablet press simulator. Mean yield pressure (Py) obtained by Heckel modeling, Walker coefficients (W) and Stress Rate Sensitivity (SRS) were compared to reference excipients, known for either their plastic (microcrystalline cellulose) or fragmentary (lactose and dibasic calcium phosphate) deformation behavior. Py, W and SRS values showed that the studied textured mannitol has a fragmentary deformation mechanism. Furthermore, this mechanical behavior was not sensitive to lubrication, which is characteristic of fragmentary excipients.
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http://dx.doi.org/10.1016/j.ijpharm.2015.09.007DOI Listing
November 2015

TNFRII polymorphism is associated with response to TNF blockers in rheumatoid arthritis patients seronegative for ACPA.

Joint Bone Spine 2014 Jul 22;81(4):370-2. Epub 2014 Jan 22.

Laboratoire de génétique des maladies rares et auto-inflammatoires (centre de référence), CHU Montpellier, Montpellier, France.

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http://dx.doi.org/10.1016/j.jbspin.2013.12.005DOI Listing
July 2014

PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer.

Cancer Res 2013 Jan 7;73(1):128-38. Epub 2012 Nov 7.

INSERM U970 PARCC, Sorbonne Paris-Cité, France.

Head and neck cancers positive for human papillomavirus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory Foxp3(+) T cells and programmed death-1 (PD-1)(+) T cells in the microenvironment of tumors that were positive or negative for HPV, in two groups that were matched for various clinical and biologic parameters. HPV-positive head and neck cancers were more heavily infiltrated by regulatory T cells and PD-1(+) T cells and the levels of PD-1(+) cells were positively correlated with a favorable clinical outcome. In explaining this paradoxical result, we showed that these PD-1(+) T cells expressed activation markers and were functional after blockade of the PD-1-PD-L1 axis in vitro. Approximately 50% of PD-1(+) tumor-infiltrating T cells lacked Tim-3 expression and may indeed represent activated T cells. In mice, administration of a cancer vaccine increased PD-1 on T cells with concomitant tumor regression. In this setting, PD-1 blockade synergized with vaccine in eliciting antitumor efficacy. Our findings prompt a need to revisit the significance of PD-1-infiltrating T cells in cancer, where we suggest that PD-1 detection may reflect a previous immune response against tumors that might be reactivated by PD-1/PD-L1 blockade.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-2606DOI Listing
January 2013

Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase-derived epitopes: potential synergistic effect with chemotherapy response.

Clin Cancer Res 2012 May 8;18(10):2943-53. Epub 2012 Mar 8.

INSERM, Unité Mixte de Recherche 1098, F-25020 Besançon cedex, France.

Purpose: To investigate the presence and impact of spontaneous telomerase-specific CD4 T-cell responses in cancer patients.

Experimental Design: A multistep approach was used to design novel pan-HLA-DR-restricted peptides from telomerase. T-cell clones isolated from cancer patients were used to characterize the polarization of telomerase-specific CD4 response. The presence of spontaneous CD4 T-cell response against telomerase was monitored in 84 metastatic non-small cell lung cancer (NSCLC) patients before first-line chemotherapy (CT) using IFN-γ ELISPOT assay. Then we analyzed the impact of the pretherapeutic telomerase-specific CD4 T immunity on clinical outcome in patients according to their respective response to CT.

Results: We described four novel telomerase-derived CD4 epitopes referred as universal cancer peptides (UCP) that effectively bind to most commonly found human MHC class II alleles. UCP-specific CD4 T-cell repertoire is present in human and UCP-specific CD4 T-cell clones generated from cancer patients exhibited high avidity and are Th1 polarized. Significant frequency (38%) of naturally occurring UCP-specific T-cell responses were detected before CT in advanced NSCLC but not in healthy volunteers. This response was shown to significantly increase overall survival (OS) of patients responding to CT (Median OS: 53 vs. 40 weeks, P = 0.034).

Conclusions: These results show for the first time a potential synergistic effect of telomerase-specific CD4 T-cell response with CT response in NSCLC and underline the potential role of tumor-specific CD4 T-cell response on the efficiency of conventional anticancer therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-3185DOI Listing
May 2012

A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens.

Blood 2011 Nov 9;118(18):4853-62. Epub 2011 Sep 9.

Inserm U970 PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Paris, France.

Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8(+) T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8(+) T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8(+) T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44(high)) and activated (ICOS(+)) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8(+) T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.
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http://dx.doi.org/10.1182/blood-2011-01-329656DOI Listing
November 2011

A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients.

J Immunother 2010 Nov-Dec;33(9):991-8

Service d'Immunologie Biologique Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France.

Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.
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http://dx.doi.org/10.1097/CJI.0b013e3181f4c208DOI Listing
May 2011

Targeting human telomerase reverse transcriptase with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo.

Blood 2010 Apr 3;115(15):3025-32. Epub 2010 Feb 3.

Unité de Rétrovirologie Moléculaire, Institut Pasteur, Paris.

The success of active immunotherapy is based on the vaccine's ability to overcome immune tolerance through recalibrating the immune system so that it is able to recognize tumor antigens as foreign rather than self. In this study, we used a lentiviral vector system to target human telomerase reverse transcriptase (lv-hTERT), a widely expressed tumor antigen. Immunization of HLA-A*0201 transgenic HHD mice with recombinant lv-hTERT vector induces potent and diversified cytotoxic T lymphocyte responses that recognize in vitro murine tumor cells, which overexpress telomerase. Compared with peptide-based vaccinations, the lv-hTERT vector triggers better and more sustained CD8(+) T-cell response against self/TERT epitope in vivo. The study found that the additional use of a heterologous boosted vaccination drastically improves self/TERT-specific CD8 responses in lv-hTERT primed mice. Both primary and long-lasting self/TERT-specific CD8(+) T-cell responses induced with Iv-hTERT vector required the presence of CD4 T cells in vivo. This lv-hTERT-based active immunotherapy efficiently inhibits the growth of telomerase expressing tumors (B16/HLA-A2.1 murine melanoma) in HHD mice. These data show that targeting hTERT with lentivector is highly effective in stimulating a broad range of CD8 T-cell immunity that can be exploited for cancer immunotherapy.
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http://dx.doi.org/10.1182/blood-2009-11-253641DOI Listing
April 2010

Long-term follow-up of DYT1 dystonia patients treated by deep brain stimulation: an open-label study.

Mov Disord 2010 Feb;25(3):289-99

CHRU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, France.

Long-term efficacy of internal globus pallidus (GPi) deep-brain stimulation (DBS) in DYT1 dystonia and disease progression under DBS was studied. Twenty-six patients of this open-label study were divided into two groups: (A) with single bilateral GPi lead, (B) with a second bilateral GPi lead implanted owning to subsequent worsening of symptomatology. Dystonia was assessed with the Burke Scale. Appearance of new symptoms and distribution according to body region were recorded. In the whole cohort, significant decreases in motor and disability subscores (P < 0.0001) were observed at 1 year and maintained up to 10 years. Group B showed worsening of the symptoms. At 1 year, there were no significant differences between Groups A (without subsequent worsening) and B; at 5 years, a significant difference was found for motor and disability scores. Within Group B, four patients exhibited additional improvement after the second DBS surgery. In the 26 patients, significant difference (P = 0.001) was found between the number of body regions affected by dystonia preoperatively and over the whole follow-up. DBS efficacy in DYT1 dystonia can be maintained up to 10 years (two patients). New symptoms appear with long-term follow-up and may improve with additional leads in a subgroup of patients.
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http://dx.doi.org/10.1002/mds.22802DOI Listing
February 2010

A candidate molecular signature associated with tamoxifen failure in primary breast cancer.

Breast Cancer Res 2008 17;10(5):R88. Epub 2008 Oct 17.

Université de Lyon, Faculté de Pharmacie de Lyon, France.

Introduction: Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.

Methods: Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.

Results: Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERalpha, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-alpha, gamma-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERalpha, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERalpha, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERalpha alone (likelihood ratio test).

Conclusions: We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.
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http://dx.doi.org/10.1186/bcr2158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614524PMC
February 2009

[Multidisciplinary monitoring and psychosocial support reduce complications of opiate dependence in pregnant women: 114 pregnancies].

Presse Med 2007 Nov 21;36(11 Pt 1):1571-80. Epub 2007 Sep 21.

Service de gynécologie obstétrique C et de médecine materno-foetale, Hôpital Arnaud de Villeneuve, CHU, Montpellier.

Purpose: Drug abuse during pregnancy is an important public health problem. Montpellier University Hospital established a center for addiction and pregnancy in 1997 to provide multidisciplinary prenatal care aimed at reducing maternal and fetal risks during pregnancy and afterwards. This study assesses the trends in drug-taking behavior and pregnancy outcome among women receiving this prenatal care.

Methods: This exploratory prospective study examined participants in this program during its first 5 years (1997-2002). Women were included if they had been: pregnant, addicted to opiates, enrolled in the program for at least 15 days, and if their delivery took place at Montpellier Hospital. We recorded how often they came to prenatal care, drug-taking behavior, social and economic level, and obstetrical and neonatal outcomes.

Results: The study included 114 women. Those receiving drug substitution at the onset of pregnancy mainly saw general practitioners (64/89 at the beginning of pregnancy), who most often prescribed buprenorphine (70/105 at the end of pregnancy). More than two thirds of patients (n=78) abused several substances. Heroine abuse decreased (p<0.01) over pregnancy, and social and economic level rose (p<0.001). Mean gestational age at delivery was 38.5 weeks. Neonatal withdrawal syndrome remained an important problem and required treatment in 89 infants (78%). No mothers abandoned their infant.

Conclusion: Multidisciplinary prenatal care with medical, social, and psychological support can decrease opiate abusers' risks during pregnancy even when the drug treatment program is essentially unsupervised.
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http://dx.doi.org/10.1016/j.lpm.2007.05.017DOI Listing
November 2007

Preparation and use of 131I magic gel as a dosimeter for targeted radionuclide therapy.

Cancer Biother Radiopharm 2006 Oct;21(5):427-36

Nuclear Medicine Department, University Hospital, Toulouse, France.

Clinical interest in targeted radiotherapy is increasing, but accurate dosimetry studies are difficult to achieve. The aim of this study was to investigate the preparation and use of a "normoxic" polymer gel (with a tissue-equivalent density), known as MAGIC gel, and magnetic resonance imaging (MRI) for nonsealed source dosimetry. MAGIC gel samples were mixed with deionized water (MAGIC95) or a solution of 131I (131I-MAGIC95). By measuring the radioinduced variations of R2 values (relaxivity) of irradiated gels, we analyzed the response of MAGIC95 and MAGIC samples to external photon beam or 131I irradiation (131I-MAGIC95). MRI showed that a homogeneous dose distribution from 131I can be achieved if the MAGIC gel, at a temperature of approximately 35 degrees C, is mixed in 131I solution and the resulting mixture shaken gently for 30 minutes. It is important that the vials are completely filled, as residual air reduces polymerization and causes spontaneous polymerization stripes. Responses of MAGIC95 or MAGIC gels to external photon beam irradiation are similar. The variations of R2 values for 131I-MAGIC95 gel depend on the absorbed dose and not on the duration of the irradiation being reproducible from one batch of gel to another. MAGIC gel responses to 131I or external beam irradiation (EBI) are different. Our preliminary results suggest that radiolabeled "normoxic" polymer can be easily and safely produced. Radiolabeled MAGIC gel may, therefore, be suitable for the creation of phantoms dedicated to nonsealed source dosimetry.
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http://dx.doi.org/10.1089/cbr.2006.21.427DOI Listing
October 2006

Thallium SPECT-based stereotactic targeting for brain tumor biopsies. A technical note.

Stereotact Funct Neurosurg 2004 19;82(2-3):70-6. Epub 2004 Mar 19.

Department of Neurosurgery (Research Group on Movement Disorders), University Hospital, Montpellier, France.

MR or CT images acquired under stereotactic conditions are often used to plan and guide brain tumor biopsies. The objective of this study was to design and test a methodology to increase target selection reliability by acquiring stereotactic 201Tl-SPECT data and by integrating them into the surgical planning. The three-headed Philips gamma camera system (Prism 3000) was adapted to stereotactic acquisitions (patient pallet, headholder). A software was developed for the stereotactic target determination based on SPECT images (pixel with the highest metabolic activity inside the tumor). The whole system accuracy was tested with the Elekta phantom adapted to SPECT imaging. The methodology was applied to one brain tumor biopsy. Comparison of the specific phantom coordinates evaluated in SPECT with the theoretical ones did not reveal any significant difference. In this way, our methodology including our homemade software (identification of the stereotactic frame, determination of the pixel with highest metabolic activity within the tumor in the stereotactic coordinate system) was validated. No significant geometric deformations were detected. Clinical feasibility was confirmed in 1 patient with a brain glioma. This study illustrates the feasibility and the accuracy of SPECT acquisitions with the stereotactic Leksell G-frame. The clinical relevance of this methodology is under evaluation. This definition of the target, based on the point with the highest metabolic activity within the tumor, might lead to improved diagnosis in biopsies and patient management. Furthermore, it might prepare the future for therapy aimed at delivering a therapeutic agent within a tumor.
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http://dx.doi.org/10.1159/000077403DOI Listing
October 2004

Evolution of brain impedance in dystonic patients treated by GPI electrical stimulation.

Neuromodulation 2004 Apr;7(2):67-75

Departments of Pediatric Neurosurgery (Research Group on Movement Disorders) and Nuclear Medicine, University Hospital, Montpellier; Laboratory of Mathematical and Theoretical Physics, University of Science, Montpellier II; Laboratory of Industrial Physics and Information Processing, University of Montpellier I, France.

Deep Brain Stimulation is an effective treatment of generalized dystonia. Optimal stimulation parameters vary between patients. This article investigates the influence of electrical brain impedance and delivered current on the brain response to stimulation. Twenty-four patients were bilaterally stimulated in the globus pallidus internus through two implanted four-contact electrodes. The variation of brain impedance and current measurements was correlated with stimulation parameters, time course, and clinical outcome. When a contact was activated, a statistically significant and reversible decrease of brain impedance was found. Impedance and current values and their variations with time significantly differed between patients. The absolute impedance did not significantly correlate with the final outcome. We conclude that the reversible decrease of impedance reflects an adaptive long-term mechanism, which could be due to a plasticity phenomenon, but has no prognostic value. Impedance and current measurements give new complementary information for parameter adjustment and trouble shooting and should therefore be included in all patients' follow-up.
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http://dx.doi.org/10.1111/j.1094-7159.2004.04009.xDOI Listing
April 2004