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1.
Bull Cancer ; 110(12): 1234-1243, 2023 Dec.
Article in French | MEDLINE | ID: mdl-38445648

ABSTRACT

INTRODUCTION: The prognosis of metastatic non-small cell lung cancer (NSCLC) has been improved by the use of immune checkpoint inhibitors (ICI). Unfortunately, in some cases, cancer cells will develop resistance mechanisms. In case of progression in a limited number of lesions (oligoprogression), focal treatment with radiotherapy is proposed while continuing the ICI therapy. METHODS: A cohort of 37 patients with metastatic NSCLC treated with nivolumab (anti-PD-1) in second or subsequent line and who received focal radiotherapy for oligoprogression with continuation of nivolumab was compared with a control cohort of 87 patients no oligoprogressor treated par immunotherapy. RESULTS: After a median follow-up of 37 months [18; 62], the median progression free survival (PFS) in the radiotherapy-treated cohort was 15.04 versus 5.04 months in the control cohort, with a statistically significant difference (P=0.048). The median PFS following focal radiotherapy in the oligoprogressor group was 7.5 months. In univariate analysis, the presence of lung metastasis was associated with increased PFS, in contrast to the presence of brain metastases, which were associated with decreased PFS in the radiotherapy group. The median overall survival was not reached in both groups, with no significant difference between the two cohorts. CONCLUSION: The combination of focal radiotherapy in case of oligoprogression and continued treatment with nivolumab in the treatment of metastatic NSCLC in the second or subsequent line of treatment seems to be with an increase in PFS.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Radiation Oncology , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Nivolumab/therapeutic use , Lung Neoplasms/therapy , Immunotherapy
2.
Hum Mol Genet ; 17(14): 2132-43, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18434328

ABSTRACT

Myotubular myopathy (XLMTM, OMIM 310400) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small myofibers with frequent occurrence of central nuclei. Myotubularin is a ubiquitously expressed phosphoinositide phosphatase with a muscle-specific role in man and mouse that is poorly understood. No specific treatment exists to date for patients with myotubular myopathy. We have constructed an adeno-associated virus (AAV) vector expressing myotubularin in order to test its therapeutic potential in a XLMTM mouse model. We show that a single intramuscular injection of this vector in symptomatic Mtm1-deficient mice ameliorates the pathological phenotype in the targeted muscle. Myotubularin replacement in mice largely corrects nuclei and mitochondria positioning in myofibers and leads to a strong increase in muscle volume and recovery of the contractile force. In addition, we used this AAV vector to overexpress myotubularin in wild-type skeletal muscle and get insight into its localization and function. We show that a substantial proportion of myotubularin associates with the sarcolemma and I band, including triads. Myotubularin overexpression in muscle induces the accumulation of packed membrane saccules and presence of vacuoles that contain markers of sarcolemma and T-tubules, suggesting that myotubularin is involved in plasma membrane homeostasis of myofibers. This study provides a proof-of-principle that local delivery of an AAV vector expressing myotubularin can improve the motor capacities of XLMTM muscle and represents a novel approach to study myotubularin function in skeletal muscle.


Subject(s)
Cell Membrane/metabolism , Genetic Therapy , Muscle, Skeletal/metabolism , Myopathies, Structural, Congenital/genetics , Myopathies, Structural, Congenital/therapy , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Animals , Cell Line , Cell Membrane/chemistry , Cell Membrane/genetics , Cell Membrane/pathology , Dependovirus/genetics , Dependovirus/metabolism , Female , Genetic Vectors/genetics , Homeostasis , Injections, Intramuscular , Male , Mice , Muscle, Skeletal/chemistry , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Myopathies, Structural, Congenital/metabolism , Myopathies, Structural, Congenital/physiopathology , Phenotype , Protein Tyrosine Phosphatases, Non-Receptor/administration & dosage , Protein Tyrosine Phosphatases, Non-Receptor/analysis , Protein Tyrosine Phosphatases, Non-Receptor/metabolism
3.
Mol Ther ; 15(1): 53-61, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17164775

ABSTRACT

alpha-Sarcoglycanopathy (limb-girdle muscular dystrophy type 2D, LGMD2D) is a recessive muscular disorder caused by deficiency in alpha-sarcoglycan, a transmembrane protein part of the dystrophin-associated complex. To date, no treatment exists for this disease. We constructed recombinant pseudotype-1 adeno-associated virus (rAAV) vectors expressing the human alpha-sarcoglycan cDNA from a ubiquitous or a muscle-specific promoter. Evidence of specific immune response leading to disappearance of the vector was observed with the ubiquitous promoter. In contrast, efficient and sustained transgene expression with correct sarcolemmal localization and without evident toxicity was obtained with the muscle-specific promoter after intra-arterial injection into the limbs of an LGMD2D murine model. Transgene expression resulted in restoration of the sarcoglycan complex, histological improvement, membrane stabilization, and correction of pseudohypertrophy. More importantly, alpha-sarcoglycan transfer produced full rescue of the contractile force deficits and stretch sensibility and led to an increase of the global activity of the animals when both posterior limbs are injected. Our results establish the feasibility for AAV-mediated alpha-sarcoglycan gene transfer as a therapeutic approach.


Subject(s)
Dependovirus/genetics , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Muscles/metabolism , Sarcoglycans/deficiency , Sarcoglycans/metabolism , Animals , Cell Membrane Permeability , Dependovirus/classification , Dystrophin/metabolism , Gene Expression , Gene Expression Regulation , Hypertrophy/genetics , Hypertrophy/metabolism , Hypertrophy/pathology , Injections, Intra-Arterial , Kinetics , Mice , Organ Specificity , Phenotype , Promoter Regions, Genetic/genetics , Protein Binding , Sarcoglycans/genetics
4.
Mol Ther ; 15(1): 53-61, 2007 Jan.
Article in English | MEDLINE | ID: mdl-28182933

ABSTRACT

α-Sarcoglycanopathy (limb-girdle muscular dystrophy type 2D, LGMD2D) is a recessive muscular disorder caused by deficiency in α-sarcoglycan, a transmembrane protein part of the dystrophin-associated complex. To date, no treatment exists for this disease. We constructed recombinant pseudotype-1 adeno-associated virus (rAAV) vectors expressing the human α-sarcoglycan cDNA from a ubiquitous or a muscle-specific promoter. Evidence of specific immune response leading to disappearance of the vector was observed with the ubiquitous promoter. In contrast, efficient and sustained transgene expression with correct sarcolemmal localization and without evident toxicity was obtained with the muscle-specific promoter after intra-arterial injection into the limbs of an LGMD2D murine model. Transgene expression resulted in restoration of the sarcoglycan complex, histological improvement, membrane stabilization, and correction of pseudohypertrophy. More importantly, α-sarcoglycan transfer produced full rescue of the contractile force deficits and stretch sensibility and led to an increase of the global activity of the animals when both posterior limbs are injected. Our results establish the feasibility for AAV-mediated α-sarcoglycan gene transfer as a therapeutic approach.

5.
Birth ; 31(4): 302-7, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15566343

ABSTRACT

BACKGROUND: Training programs are commonly viewed as an effective way to improve breastfeeding-related practices of health professionals. The objective of this study was to determine whether a 3-day training program for maternity ward professionals was followed by an increase in duration of any breastfeeding. METHODS: A before-and-after study was conducted involving two retrospective random samples of 308 mothers who had delivered a healthy singleton infant of 37 weeks' or more gestation and 2,500 g or more birthweight in a level 3 maternity ward in a university hospital in France. Data were gathered from medical records and postal questionnaire. RESULTS: Study participants included 169 mothers (54.9%) in the pre-intervention sample and 178 (57.8%) in the post-intervention sample. The prevalence of any breastfeeding at birth was 77.5 percent (70.5%-83.6%) in the pre-intervention sample and 82.6 percent (76.2%-87.8%) in the post-intervention sample(p=0.24); the median duration of any breastfeeding was 13 weeks and 16 weeks, respectively(chi2 log-rank test=5.8, p=0.02). The decreased risk of weaning in the post-intervention sample persisted after adjustment for baseline characteristics (adjusted hazard ratio=0.70 [0.54-0.91]). It was paralleled by significant improvement in maternity ward practices that are known to affect the duration of breastfeeding. CONCLUSION: An intensive 3-day training program for maternity ward professionals can be followed by a significant but moderate increase in the duration of any breastfeeding. Multifaceted interventions involving prenatal components and community support should be planned in Western countries with low to intermediate prevalence of breastfeeding.


Subject(s)
Breast Feeding/statistics & numerical data , Education, Medical, Continuing , Medical Staff, Hospital/education , Adult , Female , France/epidemiology , Hospitals, University , Humans , Infant, Newborn , Male , Maternal Health Services , Obstetrics and Gynecology Department, Hospital , Pregnancy , Random Allocation , Retrospective Studies , Surveys and Questionnaires , Treatment Outcome
6.
Muscle Nerve ; 27(5): 616-23, 2003 May.
Article in English | MEDLINE | ID: mdl-12707983

ABSTRACT

Defects in human calpain 3 are responsible for limb-girdle muscular dystrophy type 2A, an autosomal-recessive disorder characterized mainly by late-onset proximal muscular atrophy. A corresponding murine model has previously been generated by gene targeting. In this report, muscular activity of calpain 3-deficient (capn3(-/-)) mice was evaluated at different ages. Growth curves showed a progressive global muscular atrophy. Histological examination throughout the lifespan of mice confirmed the dystrophic lesions. Whole animal tests showed only a mild significant impairment of the forelimbs. Studies of the mechanical properties of selected isolated fast- and slow-twitch muscles demonstrated that slow-twitch muscles were significantly weaker in capn3(-/-) mice than in wild-type mice. Three different tests showed that there was no membrane disruption, suggesting a nonmechanical etiology of capn3(-/-) mice dystrophy. These findings are consistent with a mechanism involving signaling systems.


Subject(s)
Calpain/genetics , Calpain/metabolism , Muscle Proteins , Muscle, Skeletal/physiology , Muscular Dystrophies/metabolism , Animals , Disease Models, Animal , Electric Impedance , Female , Mice , Mice, Mutant Strains , Muscle Contraction/physiology , Muscle Fibers, Fast-Twitch/metabolism , Muscle Fibers, Slow-Twitch/metabolism , Muscle, Skeletal/cytology , Muscular Dystrophies/genetics , Muscular Dystrophies/physiopathology , Phenotype
7.
Eur J Obstet Gynecol Reprod Biol ; 106(2): 134-8, 2003 Feb 10.
Article in English | MEDLINE | ID: mdl-12551778

ABSTRACT

OBJECTIVE: To assess the impact of a continuing medical education program based on the WHO's 10 steps to successful breast-feeding. STUDY DESIGN: An observational before-and-after study at a teaching hospital. Data for two random samples of 50 women before and 50 after the intervention were collected from medical records and completed by a mail questionnaire. RESULTS: Seventy-six percent of mothers initiated breast-feeding in the two samples. The median duration of breast-feeding was 12 weeks and did not differ between the before and after groups. The percentage of newborns separated from their mother more than 4h a night decreased substantially after the intervention (13% versus 52% before the intervention, P<0.01). In-hospital formula provision also decreased after the intervention (63% of newborns versus 82% before intervention, P=0.07). CONCLUSION: This pilot study has enabled authors to document the feasibility of evaluating the impact of continuing education of maternity ward staff.


Subject(s)
Breast Feeding , Health Personnel/education , Education, Medical, Continuing , Female , Humans , Infant , Infant, Newborn , Lactation , Male , Obstetrics and Gynecology Department, Hospital , Patient Education as Topic , Pilot Projects , Pregnancy , Program Evaluation , Retrospective Studies
8.
J Muscle Res Cell Motil ; 23(3): 255-64, 2002.
Article in English | MEDLINE | ID: mdl-12500905

ABSTRACT

This report describes the characterisation of the expression profile of several myogenic determination genes during human embryogenesis. The data were obtained from axial structures and limb buds of human embryos aged between 3 and 8 weeks of development. Using in situ hybridisation to detect Pax3 and MyoD gene family mRNAs, and immunochemistry to follow Six and Eya protein accumulation, we have been able to establish the chronology of accumulation of these gene products. As in mouse, the first transcripts detected in myotomes of 3 week-old embryos are Pax3 and Myf5, followed by the expression of myogenin. MyoD appears to be activated well after Myf5, myogenin and MRF4 in the early myotome, whereas, in limb bud muscles, the presence of all four of these mRNAs is concomitant from 6 weeks. Six1, Six4 and Six5 homeoproteins are detected later than Myf5 activation. These Six homeoproteins are first observed in the cytoplasm of myogenin expressing cells. At later stages of development, Six1 and Six5, but not Six4, are translocated into the nuclei of myogenic cells, concomitantly with MyHCemb expression. Eya1 and Eya2 proteins, potential Six cofactors, were also detected in myogenin positive cells, but their accumulation was delayed and was mainly cytoplasmic. These results preclude that early activation of Myf5, myogenin and MRF4 is under the control of Six and Eya proteins, while Six and Eya proteins would be involved in later steps of myogenic differentiation.


Subject(s)
Cell Differentiation/genetics , Gene Expression Regulation, Developmental/genetics , Homeodomain Proteins/metabolism , Muscle, Skeletal/embryology , MyoD Protein/genetics , Somites/metabolism , Trans-Activators/metabolism , Transcription Factors , Body Patterning/genetics , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cytoplasm/genetics , Cytoplasm/metabolism , DNA-Binding Proteins/genetics , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins , Muscle Proteins/genetics , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Myogenic Regulatory Factor 5 , Myogenic Regulatory Factors/genetics , Myogenin/genetics , Nuclear Proteins , PAX3 Transcription Factor , Paired Box Transcription Factors , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Transport/genetics , Protein Tyrosine Phosphatases , RNA, Messenger/metabolism , Somites/cytology
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