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J Robert

Publications and source records attributed to J Robert.

At least 37 records · Page 2Linked to original sources
PubMed2004

Pharmacogenetics and pharmacogenomics as new tools to optimise cancer chemotherapy.

Pharmacogenetics takes into account the individual variability of the genome and its relationships with drug activity. Numerous gene polymorphisms occurring at the level of drug metabolising enzymes, drug transporters or drug targets have been identified; they may be responsible for an alteration of the phenotype, and of individual changes in drug efficacy and/or toxicity. Pharmacogenomics takes into account the genetic alterations present in tumours and their role in drug activity. It may be possible to establish correlations between the activity of a drug and the level of expression of tumour genes, and thus select the most appropriate drugs to prescribe for the treatment of individual tumours. Pharmacogenetics and pharmacogenomics are acting synergistically for the personalisation of treatments, on the basis of the constitutive singularity of patients and of the molecular characteristics of tumours.

Antineoplastic Agents↗
PubMed2003

DNA topoisomerase IIalpha expression and the response toprimary chemotherapy in breast cancer.

The alpha isoform of Topoisomerase IIalpha (Topo IIalpha) is a proliferation marker as well as a target for several chemotherapeutic agents such as anthracyclines. In vitro studies have demonstrated the relationship between the Topo IIalpha expression level and chemosensitivity of target cancer cells. To verify this effect in vivo, we selected 125 patients presenting with T(2)>3 cm and T(3) N(0-1) M(0) breast tumours who were treated by six cycles of primary chemotherapy, including epirubicin before any surgery. Therapy response was assessed by clinical and X-ray mammogram measurements of tumour shrinkage. The pretherapeutic core biopsies were immunostained with a monoclonal antibody (Ki-S7) against Topo IIalpha. Ki-S7 positivity ranged from 0 to 50% (median, 15%). A high percentage of Ki-S7-positive cells (>15%) was associated with tumour regression under chemotherapy (OR=2.88, CI: 1.3-6.4, P=0.004). Ki-S7 further emerged as an independent predictor of tumour regression (OR=3.34, CI: 1.41-7.93, P=0.006), together with tumour size of less than 40 mm (OR=3.82, CI: 1.58-9.25, P=0.002) and negative oestrogen receptor (ER) status (OR=3.35, CI: 1.43-7.86, P=0.005), in a multivariate analysis including tumour size, SBR grade, ER and PR status, Ki-67, p53 and Her-2/neu. Our clinical results confirm in vitro data on the relationship between Topo IIalpha expression and tumour chemosensitivity and thus may have important practical implications.

Adult↗
PubMed2003

Probing complex RNA structures by mechanical force.

RNA secondary structures of increasing complexity are probed combining single molecule stretching experiments and stochastic unfolding/refolding simulations. We find that force-induced unfolding pathways cannot usually be interpreted by solely invoking successive openings of native helices. Indeed, typical force-extension responses of complex RNA molecules are largely shaped by stretching-induced, long-lived intermediates including non-native helices. This is first shown for a set of generic structural motifs found in larger RNA structures, and then for Escherichia coli's 1540-base long 16S ribosomal RNA, which exhibits a surprisingly well-structured and reproducible unfolding pathway under mechanical stretching. Using out-of-equilibrium stochastic simulations, we demonstrate that these experimental results reflect the slow relaxation of RNA structural rearrangements. Hence, micromanipulations of single RNA molecules probe both their native structures and long-lived intermediates, so-called "kinetic traps", thereby capturing -at the single molecular level- the hallmark of RNA folding/unfolding dynamics.

Computer Simulation↗
PubMed2003

Multidrug-resistant tuberculosis: eight years of surveillance in France.

The aim of this study was to evaluate the annual prevalence of multidrug-resistant tuberculosis (MDRTB) and to describe the characteristics of the patients with MDRTB in France. Annual questionnaire surveys from 1992-1999 were mailed to all French microbiological laboratories performing mycobacterial cultures. A total of 264 distinct patients were reported to the National Reference Centre for Resistance of Mycobacteria to Antituberculosis Drugs during the 8-yr surveillance period resulting in a mean annual prevalence of MDRTB of 0.6%. A mean of 16% of the MDRTB patients were reported over several subsequent years. The majority of patients were male (69.7%), foreign-born (55.7%), with a previous history of treatment (65.9%), and pulmonary involvement (92.8%) with smear-positive results (59.1%). Human immunodeficiency virus (HIV) coinfection was present in 20.8% of the patients. Strains were resistant only to isoniazid and rifampin in 37.9% of the cases, and additional resistance to both streptomycin and ethambutol was present in 25.8%. HIV coinfection and female status were statistically associated with primary resistance, whereas smear-positive results were associated with secondary resistance. Foreign-birth and smear-positive results were associated with a chronic status. The prevalence of multidrug-resistant tuberculosis is low in France (<1%). However, a substantial proportion of patients remain positive for several years, suggesting nonoptimal management. Therefore, as recommended by the World Health Organization, a few reference teams, working in collaboration with national associations of physicians and microbiologists, should be established to improve the outcome of multidrug-resistant tuberculosis.

Adolescent↗
PubMed2003

Evolution of the immunomodulatory role of the heat shock protein gp96.

In mammals, certain heat shock proteins (hsps) participate in specialized responses to stressors associated with pathogens or tumors, and as such, act as agents of immune surveillance interacting with both innate and adaptive immunity. We are investigating the conservation of this role throughout the class of vertebrates. We have shown that in Xenopus as in mammals, gp96, the major resident of the endoplasmic reticulum, generates MHC-restricted thymus-dependent immunity in vivo and CR in vitro against minor histocompatibility (H) antigens. By as yet unclear mechanisms that may involve classical MHC-unrestricted cytotoxic CD8+ T cells, gp96 also elicits peptide-specific responses against MHC-class I-negative tumors in adult frogs that may involve cytotoxic NK, MHC-unrestricted CD8+ T and NK/T cells. In naturally MHC class I-deficient but immunocompetent Xenopus larvae, gp96 also generates an innate type of anti-tumor response that is independent of chaperoned peptides. Finally, in a subset of Xenopus sIgM+ B cells, a substantial fraction of gp96 is directed to the cell surface by an active process that is upregulated by bacterial stimulation. This may allow gp96 to access the extracellular compartment without necrosis. Given the dual abilities of gp96 to chaperone antigenic peptides and to modulate innate immune responses, we propose that stimulated B cells that are up-regulating surface gp96 can directly interact with antigen presenting cells (APC) and/or T helper (Th) cells to trigger or amplify immune responses.

Adjuvants, Immunologic↗
PubMed2002

Thoracoscopic sympathectomy using ultrasonic coagulating shears: a technical improvement in the treatment of palmar hyperhidrosis.

Thoracoscopic sympathectomy has emerged in recent years as the treatment of choice for primary palmar hyperhidrosis when medical treatment fails. Postoperative complications have been reported in large series, however, including neurologic problems such as temporary or definitive Horner syndrome and peripheral nerve injuries. The authors report the use of ultrasonic coagulating scissors instead of electrocautery for the dissection and removal of a segment of sympathetic chain in an 11-year-old girl. A bilateral procedure was performed sequentially through three 5-mm axillary trocars on each side. The use of ultrasonic shears eliminates the risk of distal nerve injury induced by the spread of electric current and could possibly reduce the incidence of the above-mentioned complications.

Child↗
PubMed2002

[Evolution of susceptibility of aerobic gram-negative aerobic bacilli to quinolones and fluoroquinolones in a university hospital (1992-2000)].

Susceptibility to quinolones of aerobic gram-negative bacilli was assessed in a 2000-bed university hospital from 1992 to 2000. There was a significant downward trend in the rate of susceptibility to nalidixic acid (Nal) for Enterobacteriaceae as a whole from 1992 to 2000 (86% vs 82%), and E. coli (92% vs 84%), and an upward trend for K. pneumoniae (74% vs 82%), the latter being related to the control of the spread of epidemic ESBL producing strains. The overall susceptibility of Enterobacteriaceae to ciprofloxacin (Cip) paralleled the susceptibility to Nal: decreased susceptibility for Enterobacteriaceae as a whole (96% vs 89%) and E. coli (99% vs 91%). A clear decrease in the level of susceptibility to Cip occurred during the study period among the Nal-resistant strains as demonstrated by the decrease in the median zone diameter (D) observed among the Nal-resistant strains of E. coli (26 mm in 1992 vs 19 mm in 1998-2000). The zone diameter distribution pattern changed from an unimodal distribution in 1992 to a trimodal distribution in 2000 secondary to the occurrence of a population of resistant strains (D = 13 mm) and of a highly resistant population (D = 6 mm). Finally, the susceptibility to Cip of P. aeruginosa strains remained stable around 62% throughout the study period.

4-Quinolones↗
PubMed2002

[Contribution of salmeterol in ambulatory practice to the improvement of asthma and quality of life in childhood].

International guidelines on asthma recommend to add inhaled long-acting b2-agonists in patients insufficiently controlled with an inhaled corticosteroid alone. A multicentre prospective study was carried out in 250 children (age 8.4 +/- 2.7 years) whose asthma remained symptomatic with impaired lung function despite a treatment with 400-1000 micrograms/day of beclomethasone or equivalent. Salmeterol 100 micrograms/day was added to the previous dose of inhaled corticosteroid for 2 months. PEFR was improved as soon as the first month of treatment (67.2 +/- 44.4 L/min, p < 0.001) and at month 2 (75.0 +/- 44.1 L/min, p < 0.001). The percentage of symptomatic patients, the number of days and nights with symptoms, the number of days with prn bronchodilator use were significantly reduced (p < 0.001). The decrease in the distress and severity scores of the Childhood Asthma Questionnaire indicated an improvement in quality of life due to better asthma control. This study showed that lung function and symptoms were significantly improved as soon as the first month of treatment, improvement maintained thereafter, with a better quality of life and a good tolerability.

Adolescent↗
PubMed2001

MHC-restricted and -unrestricted CD8 T cells: an evolutionary perspective.

BACKGROUND: In mammals, cytotoxic CD8 T cells are crucial effectors of a typical adaptive cellular immune response. They recognize and kill cells that express at their surface antigenic peptides complexed to major histocompatibility complex (MHC) class I molecules. Although T cells (undefined as to CD determinants) and associated in vitro cytotoxic activity have been described in a few amphibian and teleost species, their in vivo functions have yet to be characterized. METHODS AND RESULTS: CD8 function has been investigated in the frog Xenopus by antibody depletion, skin allografting, and tumor transplantation. Injection of adult frogs with anti-Xenopus CD8 monoclonal antibody effects transient CD8 T-cell depletion in vivo that correlates with delayed rejection of MHC-disparate skin allografts and an impaired immune response against transplanted syngeneic MHC class I-negative tumors. CONCLUSIONS: For the first time, CD8 T cells have been shown to be involved in acute skin allograft rejection in an ectothermic vertebrate. Our data also suggest that, at least in Xenopus, T cells that express a CD8 epitope may be effectors in MHC-unrestricted anti-tumor responses.

Animals↗
PubMed2001

Effects of the combination of camptothecin and doxorubicin or etoposide on rat glioma cells and camptothecin-resistant variants.

From the rat C6 glioma cell line in culture, we selected camptothecin-resistant variants by growth in the presence of increasing amounts of this drug (C6(CPT10), C6(CPT50)and C6(CPT100), growing respectively with 10, 50 and 100 ng ml(-1)camptothecin). The degree of resistance to camptothecin ranged between 15-fold (C6(CPT10)) and 30-fold (C6(CPT50)and C6(CPT100)). The C6(CPT10)cell line presented a collateral sensitivity to etoposide (3.6-fold), while the C6(CPT50)and C6(CPT100)cell lines were cross-resistant to etoposide (1.8-fold) The resistant lines were characterised by a two-fold reduced content and catalytic activity of topoisomerase I, and C6(CPT50)and C6(CPT100)presented a significant increase in topoisomerase IIalpha content and catalytic activity and a marked overexpression of P-glycoprotein. We explored the cytotoxicity of combinations of a topoisomerase I inhibitor (camptothecin) and a topoisomerase II inhibitor (doxorubicin or etoposide) at several molar ratios, allowing the evaluation of their synergistic or antagonistic effects on cell survival using the median effect principle. The simultaneous combination of camptothecin and doxorubicin or etoposide was additive or antagonistic in C6 cells, slightly synergistic in the C6(CPT10)line and never more than additive in the C6(CPT50)and C6(CPT100)cell lines. The sequential combination of doxorubicin and camptothecin gave additivity in the order camptothecin --> doxorubicin and antagonism in the order doxorubicin --> camptothecin. Clinical protocols combining a topoisomerase I and a topoisomerase II inhibitor should be considered with caution because antagonistic effects have been observed with combinations of camptothecin and doxorubicin.

Animals↗
PubMed2001

Buckling of actin-coated membranes under application of a local force.

The mechanical properties of composite membranes obtained by self-assembly of actin filaments with giant fluid vesicles are studied by micromanipulation with optical tweezers. These complexes exhibit typical mechanical features of a solid shell, including a finite in-plane shear elastic modulus ( approximately 10(-6) N/m). A buckling instability is observed when a localized force of the order of 0.5 pN is applied perpendicular to the membrane plane. Although predicted for polymerized vesicles, this is the first evidence of such an instability.

Actins↗
PubMed2001

Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population.

We studied the association of breast cancer with the polymorphic polyglutamine repeat of the androgen receptor (AR) in 255 incident cases of breast cancer and 461 matched controls from the Quebec City metropolitan area. Women for whom the sum of both of the AR (CAG)n-repeats alleles is 39 or less (short-allele AR genotypes) have one-half the risk of breast cancer compared with women for whom the sum of AR (CAG)n-repeats is 40 or more [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3-0.83; P = 0.007]. This association is stronger in postmenopausal women (180 cases, 297 controls; OR, 0.36; 95% CI, 0.19-0.7; P = 0.003). We also observed an interaction between the type of menopause (natural versus surgical) and the AR genotype on breast cancer risk. Alternately, when subjects were grouped according to their (CAG)n-repeat genotype [homozygous for short alleles (CAG)n < or = 20; other genotypes ("long allele")], results were similar (OR. 0.5; 95% CI, 0.27-0.82; P = 0.007). Thus, women with short-alleles AR genotypes appear to be protected against breast cancer. Short-alleles AR genotypes were observed in 16% of the general population as represented by the control group. Short polyglutamine repeats in the AR protein have been reported to be associated with an increase in the capacity of the receptor to activate transcription of reporter genes in vitro. Furthermore, androgens have been previously shown to inhibit in vitro the growth of breast cancer cell lines. This suggests that differences in the number of polyglutamines in the AR protein may influence individual risk of breast cancer, especially in postmenopausal women, and that this apparent protection could be the consequence of an increased response/sensitivity to androgens.

Breast Neoplasms↗
PubMed2001

Separation and determination of liposomal and non-liposomal daunorubicin from the plasma of patients treated with Daunoxome.

Several liposomal formulations of anthracyclines have been developed recently and are currently used in the clinical setting. We describe a technique of separation and quantification of the liposomal and non-liposomal forms of daunorubicin in the plasma of patients treated with DaunoXome, a liposomal formulation of daunorubicin. The method we propose is based upon the property of liposomes to cross reversed-phase C18 silicagel cartridges without being retained, while non-liposomal drug is retained on the stationary phase and is eluted with methanol. Extraction of liposomal and non-liposomal daunorubicin from plasma, therefore, is performed in two steps. This technique is rapid, can be automated in order to handle large series of samples, and the plasma can be frozen after sampling by addition of glycerol. The recovery of liposomal daunorubicin as well as the precision, linearity and accuracy of the technique appear satisfactory for pharmacokinetic purposes.

Antibiotics, Antineoplastic↗
PubMed2001

Atom symmetry break and metastable level coupling in rare gas atom-surface van der Waals interaction.

van der Waals interactions between an atom and a planar surface exhibit a quadrupolar component in D(2)(z)-D(2)/3 (D, atomic dipole; ź, normal to surface). This coupling is responsible for an atom symmetry break, mixing levels of the same parity such as metastable 3P0, 3P2 levels of rare gas atoms. The strongly exoenergic 3P0-3P2 transition in Ar and Kr is observed by a time-of-flight technique, using as a surface the edge of a copper slit. The results confirm the predicted strong peaking of the angular distribution of inelastically scattered atoms and give a good estimate of the transition probability.

Journal Article↗
PubMed2001

Viscoelastic properties of actin-coated membranes.

In living cells, cytoskeletal filaments interact with the plasma membrane to form structures that play a key role in cell shape and mechanical properties. To study the interaction between these basic components, we designed an in vitro self-assembled network of actin filaments attached to the outer surface of giant unilamellar vesicles. Optical tweezers and single-particle tracking experiments are used to study the rich dynamics of these actin-coated membranes (ACM). We show that microrheology studies can be carried out on such an individual microscopic object. The principle of the experiment consists in measuring the thermally excited position fluctuations of a probe bead attached biochemically to the membrane. We propose a model that relates the power spectrum of these thermal fluctuations to the viscoelastic properties of the membrane. The presence of the actin network modifies strongly the membrane dynamics with respect to a fluid, lipid bilayer one. It induces first a finite (omega=0) two-dimensional (2D) shear modulus G(0)(2D) approximately 0.5 to 5 microN/m in the membrane plane. Moreover, the frequency dependence at high frequency of the shear modulus [G(')(2D)(f ) approximately f(0.85+/-0.07)] and of the bending modulus (kappa(ACM)(f) approximately f(0.55+/-0.21)) demonstrate the viscoelastic behavior of the composite membrane. These results are consistent with a common exponent of 0.75 for both moduli as expected from our model and from prior measurements on actin solutions.

Actins↗