Tc vs Carrier Concentration in Cubic Fulleride Superconductors.
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Journal Article↗
Biomedical subjects
J Robert
Publications and source records attributed to J Robert.
Bigger tobacco companies offer a deal on adolescent smokers.
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Adolescent↗
CTX, a novel molecule specifically expressed on the surface of cortical thymocytes in Xenopus.
CTX, a novel developmentally regulated type-I transmembrane protein is expressed specifically by a large fraction of cortical thymocytes in the amphibian Xenopus. This apparently monomeric 55-kDa glycoprotein is composed of two immunoglobulin domains, one variable (V) and one constant (C2 type), followed by a transmembrane and a 64-amino acid cytoplasmic domain. The first immunoglobulin domain is a V-J segment that is generated without gene rearrangement. In the genome, the V and C2 domains are both encoded by two half-domain exons. Two CTX loci are found per haploid genome, and they exhibit sequence differences with a high replacing/silent ratio in the CDR1-like region of the V domain, suggesting that these differences were selected. The cytoplasmic domain contains a motif that is highly conserved evolutionarily in several types of proteins, including adenylyl cyclases. Based on its unique tissue distribution, the variability of its V region and the motif of its cytoplasmic domain, CTX is a candidate for a new type of specific molecule involved in thymocyte selection.
Amino Acid Sequence↗
On the mechanism of action of doxorubicin encapsulation in nanospheres for the reversal of multidrug resistance.
We had previously shown that doxorubicin encapsulation in polyisohexylcyanocrylate nanospheres could circumvent the P-glycoprotein-mediated multidrug resistance (MDR) exhibited by C6 rat glioblastoma in culture. We then investigated what could be the mechanism of such a circumvention. The cytotoxicity of free and encapsulated doxorubicin was evaluated in two MDR variants of the C6 cell line in a device allowing the separation of cells from drugs by a polycarbonate membrane of 0.2 micron pore size. We observed that the progressive disruption of the nanospheres allowed their doxorubicin content to reach the cell monolayer and exert its cytotoxicity in a fashion similar to that exhibited by free doxorubicin. However, no circumvention of MDR is obtained by doxorubicin encapsulation when drug-containing nanospheres are separated from the cells by the polycarbonate membrane. In addition, no effect on azidopine binding to P-glycoprotein-enriched membranes is exerted by unloaded nanospheres, even after their spontaneous degradation in cell-culture medium. Taken together, these results suggest that a physical contact between doxorubicin-containing nanospheres and the cells is required for the circumvention of MDR. The role of degradation products from the nanospheres as modulators of P-glycoprotein activity can be ruled out.
Animals↗
Production, characterization and control of a Neisseria meningitidis hexavalent class 1 outer membrane protein containing vesicle vaccine.
An experimental serogroup B meningococcal vaccine was prepared from two genetically engineered strains; each expressing three different class 1 outer membrane proteins (OMPs) (PorA). The two strains expressed the subtypes P1.7,16;P1.5,2;P1.19,15 and P1.5c,10;P1.12,13;P1.7h,4, respectively. Outer membrane vesicles (OMV) were prepared from these strains by deoxycholate extraction, mixed with aluminiumphosphate as adjuvant and formulated to final vaccines. The class 1 OMPs represent ca 90% of the protein in the vaccine. The vaccine was found safe for human use and induced a bactericidal immune response in mice against five of the six wild type strains, which served as donors for the various por A genes.
Animals↗
Imidazole derivatives of pyrrolidonic and piperidonic as potential inhibitors of human placental aromatase in vitro.
Inhibitory activities towards human Placental aromatase of novel pyrrolidinone and piperidinone drugs were investigated and compared with those of aminoglutethimide (AG) in vitro. All compounds showing a stronger inhibitory effect than this of AG had the following common structural feature: an imidazole side-chain in C-3 position, with a substituted or non-substituted aromatic ring in the C-2 position and an aliphatic chain (n-butyl or n-octyl) or a phenyl moiety on the nitrogen of the pyrrolidone or piperidone ring. When the C-3 side-chain did not bear any imidazole ring, no activity was observed. Respective Ki values for the competitive inhibition exerted by the more potent inhibitors 10, 11, 13 and 21 with androstenedione as substrate were 19.2, 20.3, 16.8 and 15.4 microM, respectively (Ki AG= 77.0 microM).
Aminoglutethimide↗
Physical deconditioning may be a mechanism for the skeletal muscle energy phosphate metabolism abnormalities in chronic heart failure.
The aim of our study was to investigate the contribution of physical deconditioning in skeletal muscle metabolic abnormalities in patients with chronic heart failure (CHF). Phosphate metabolism was studied in the leg muscle at rest and during exercise by using phosphate 31 nuclear magnetic resonance spectroscopy in a group of 14 patients with New York Heart Association class II and III CHF and left ventricular ejection fraction <40% and in two groups of age-matched healthy volunteers: one group of 7 sedentary and another of 7 trained subjects. Phosphocreatine depletion rate, intracellular pH, and adenosine diphosphate levels in the muscle during exercise were not statistically different in the CHF patients and in the sedentary healthy subjects, but both groups were statistically different from the trained healthy subjects, who had slower phosphocreatine depletion rates, as well as less intracellular acidosis and lower adenosine diphosphate levels during exercise (p = 0.02; analysis of variance). Our results suggest that metabolic changes occurring in the skeletal muscle of patients with CHF may contribute to the limitation of exercise capacity and are most likely to be a consequence of physical deconditioning because they are very similar to what is observed in sedentary and otherwise healthy subjects as compared with trained subjects.
Adult↗
Effects of modulators of multidrug resistance on the expression of the MDR1 gene on human KB cells in culture.
The effect of four modulators of multidrug resistance (MDR) on the expression of the MDR1 gene was studied in two resistant variants of the KB cell lines, KB V1 and KB A1. This was done using a semi-quantitative assay based on mRNA reverse transcription coupled with polymerase chain reaction of the cDNA obtained. An automatic DNA sequencer was used for the measurement of the fluorescent amplification products and the MDR1 signal was compared to that of the beta-actin gene of the cells. After 24 h incubation with 15 microM of the modulators, MDR1 gene expression was slightly but significantly decreased by two of them, quinine and cyclosporine A, whereas verapamil and S-9788 had very little effect on this parameter. The effect were more pronounced in the KB A1 line than in the KB V1 line. The effect of quinine was studied over a longer time period (4-48 h) and was shown to be maximum at 24 h. These results favor the existence of a direct effect of some MDR reverters, especially quinine, on the expression of the MDR1 gene and could partially explain their modulating effect of MDR.
Antibiotics, Antineoplastic↗
Delayed choices in atom Stern-Gerlach interferometry.
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Journal Article↗
Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention.
1. In order to develop a predictive model for the preclinical evaluation of anthracycline cardiotoxicity and the means of preventing it, we have studied the functional parameters of perfused hearts isolated from rats receiving repeated doses of several anthracyclines. 2. The anthracyclines studied were doxorubicin, epirubicin, pirarubicin and daunorubicin, and we also studied a liposomal formulation of daunorubicin (DaunoXome) and the co-administration of dexrazoxane (ICRF-187) and doxorubicin. 3. Anthracyclines were administered i.p. at equimolar doses corresponding to 3 mg kg-1 per injection of doxorubicin, every other day for a total of six doses. Dexrazoxane was used at the dose of 30 mg kg-1 per injection and was administered either 30 min before or 30 min after doxorubicin. We evaluated any general toxicity towards the animals as well as alterations of left ventricular contractility and relaxation ex vivo. 4. Epirubicin and daunorubicin were significantly less cardiotoxic than doxorubicin, and neither pirarubicin nor DaunoXome caused significant alterations in cardiac function. There was a direct relationship between the decrease in cardiac contractility or relaxation and anthracycline accumulation in the heart, evaluated after the same treatment schedule. 5. Dexrazoxane induced a significant protection against doxorubicin-induced cardiac toxicity when administered 30 min before doxorubicin, whereas this protection was ineffective when administered 30 min after doxorubicin. Direct perfusion of DaunoXome in isolated hearts of untreated animals resulted in a 12-fold reduction of the accumulation of daunorubicin in heart tissue as compared to the perfusion of free daunorubicin, and did not cause alterations in cardiac function at a dosage for which free daunorubicin induced major alterations. 6. The isolated perfused rat heart appears to be a valuable model for screening of new anthracyclines and of strategies for circumventing anthracycline cardiotoxicity.
Animals↗
[Expression of the MDR1 gene in five human cell lines of medullary thyroid cancer and reversion of the resistance to doxorubicine by ciclosporin A and verapamil].
Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. Multidrug resistance (MDR) is one of the involved mechanisms. In this work we have studied the MDR1 gene expression in five MTC human cell lines that we have isolated and we have compared this expression to that of normal thyroid tissue. We have also tried to reverse the resistance to doxorubicin with verapamil (VRP) and ciclosporin A (CSA). MDR1 ARNm expression was studied and quantified by polymerase chain reaction (PCR) in normal and pathological thyroid tissues. The doxorubicin-induced cytotoxicity was evaluated with the 3,-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total glutathione (GSH) or intracellular lactate dehydrogenase (LDH) measurements. We found an increase of MDR1 ARNm in MTC as compared with normal tissues. Doxorubicin was cytotoxic after a 48-h coincubation with the cells. Three microM CSA and 10 microM VRP reversed the doxorubicin resistance only after a 48-h coincubation, generally followed with a 24 h-post-incubation. In these conditions, the GSH levels were decreased only by VRP in all the five cell lines. In conclusion, a chemoresistance related to the MDR1 gene overexpression was found in the five human MTC lines tested. VRP and CSA reversed the resistance to doxorubicin in all the MTC cell lines tested.
Antineoplastic Agents↗
[Multidrug resistance and its reversal. General review of fundamental aspects].
Among the mechanisms by which cancer cells evade chemotherapy, multidrug resistance (MDR) is certainly the best known. MDR is characterised by cross-resistance between numerous natural products used in cancer treatment, especially antibiotics and plant alkaloids. MDR results from a defect in cell accumulation of the drugs, which are actively effluxed from cells by a plasma membrane pump, which is a high molecular weight glycoprotein termed P-glycoprotein. This protein is encoded by a gene called mdr1, and can be inhibited by a variety of pharmacological compounds. The activation of the mdr1 gene can occur via numerous types of stimulation, especially anticancer drugs themselves, which can induce mdr1 gene transcription. P-glycoprotein is an ATPase transporter which is believed to extrude xenobiotics from the plasma membrane rather than from cytoplasm. Although potential sites of interaction of P-glycoprotein with its various ligands have been identified, especially at the level of putative transmembrane domains, the exact mechanism for drug pumping has never been elucidated. Reversal of MDR in vitro is easy to obtain and to characterise. An important development aims at identifying substances able to reverse MDR in the clinical setting, that are devoid of any pharmacological properties other than interaction with P-glycoprotein. Other targets can be postulated for these MDR modulators, whose combination could well lead to a synergistic reversal of drug resistance.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The role of congruence between patient and therapist in chronic low back pain patients.
OBJECTIVE: To determine the role of congruence in the perception of the evolution of back pain during treatment and in the expectations about the future of back pain problems. Congruence was defined as the agreement between patient and therapist on various aspects of back pain problems and of treatment. DESIGN: Semistructured interviews at the beginning and the end of treatment. SUBJECTS: Seventy-one back pain patients and their therapists (6 chiropractors and 6 rheumatologists). MAIN OUTCOME MEASURES: Synthesized index of congruence based on 24 questions asked of both the patient and his/her therapist. RESULTS: The distribution of the congruence scores indicated a high level of congruence in 39.4% of the cases, an average level in 35.2% and a low level in 25.4%. The results demonstrated that congruence was significantly associated with the perception of an improvement in back pain. This positive perception was nevertheless associated with the expectation of persistence or recurrence of the back pain problem in the future. Noncongruence was correlated with the patient's estimation of a less favorable evolution of the back pain problem during the treatment and with a major difficulty for both the therapist and the patient to express clear expectations about the future of the patient's back pain problem. CONCLUSIONS: Congruence mainly reflects an agreement that the treatment is aimed at the management of a long-term condition rather than at the resolution of the back pain problem. Congruent patients seem to accept living with their back problems, a position shared by their therapists, whereas noncongruent patients do not seem to share this conception of back pain.
Adult↗
[MRI in the early diagnosis of spinal metastases of bronchial cancer].
MRI of the whole spine and radionuclide bone scan were performed prospectively on 50 consecutive patients with newly diagnosed non small-cell lung carcinoma. The final diagnosis of vertebral metastasis was made by means of follow-up studies. The prevalence of vertebral metastasis was 24% (12/50 patients). The sensitivity of MR imaging (92%) was superior to that of radionuclide bone scan (67%) in the detection of vertebral involvement, the specificity was the same (94%). MRI of the spine was not useful as a screening procedure before treatment, but offered advantages over radionuclide bone scan in patients with symptoms and when bone scintigraphy detected abnormal foci, including identification of additional vertebral metastatic foci and better analysis of the extent of metastatic involvement within vertebrae.
Adult↗
[A study of the expression of MDR1 gene in solid tumors. Initial results of a multicenter evaluation].
The results obtained from 12 laboratories, dealing with six identical malignant solid tumors, assessing MDR1 phenotype using molecular techniques and immunohistochemistry have been compared. Moreover, comparisons between results of MDR1 gene expression, quantified by RT-PCR or Northern blot analysis from 10 RNA and 10 cDNA samples, were also compared between eight laboratories. Results concerning solid tumors show frequent discrepancies between the results obtained by immunohistochemistry and molecular biology techniques. Moreover, inter-laboratory discrepancies concerning immunohistochemistry techniques are observed, suggesting that the interpretation of staining is critical. Results of RT-PCR and Northern blot using RNA and cDNA show that discrepancies are less frequent than those observed using immunohistochemistry. However, Northern blot is not sensitive enough to be used in routine. The problems encountered using RT-PCR are the following: positivity threshold level, reproducibility and risks of cross-contamination.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Multicentric evaluation of MDR phenotype in leukemia: intermediate analysis of the French study].
Thirty-six French centres are involved in an evaluation of the techniques used for MDR phenotype measurement. Until now, 14 samples of various kinds of leukemia (mainly acute myelogenous leukemia) and three cell lines with different levels of resistance were sent by one centre and tested. MRK16 antibody was used for flow cytometry and immunocytochemistry, RNA was measured by RT-PCR, rhodamine or anthracyclin efflux were tested for functional assay. Wide discrepancies were observed in the results, mainly with flow cytometry, specially for the samples with a probable low level of MDR1 expression. The importance of histogram interpretation was documented by the comparative analysis of results obtained on cells already marked with MRK16, fixed and sent to all centers. The use of the ratio of the mean of fluorescence, instead of percentage, should help for standardization. The use of only one control RNA (used at different dilutions) for standardisation of RT-PCR could help in decreasing the discrepancies observed. The mean of fluorescence should also be used for expressing the rhodamine cell content.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Place of in vitro models in preclinical evaluation of anticancer drugs].
In vitro models have been intensively developed for several years for selecting new anticancer agents. The National Cancer Institute has even chosen as a primary screen of new molecules a panel of 60 human tumor cell lines. However, it may seem hazardous to rely too much on in vitro models for the discovery and selection of new anticancer drugs: (1 because no metabolism of the compounds occurs in cell culture; (2 because an in vitro cell line cannot be representative of an in situ tumor cell population; (3 because antiproliferative activity is only part of antitumor activity; (4 because the toxicologic properties of the molecules are not taken into account by in vitro systems; (5 because cell cultures do not allow any selectivity study between tumor cells and normal cells. With examples drawn from three different therapeutic classes, anthracyclines, taxoids and camptothecin derivatives, we show that in vitro tests are insufficiently predictive of antitumor potential. The excess of confidence allowed to these models may lead to premature decisions which are not after that justified by clinical trials.
Animals↗
Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line.
We studied the restoration of doxorubicin accumulation and sensitivity by verapamil and quinine in a variant of the human erythroleukemia cell line K562 selected for resistance to doxorubicin and presenting a multidrug-resistance (MDR) phenotype. Verapamil was able to completely restore doxorubicin accumulation in the resistant cells to the level obtained in sensitive cells, but only partially reversed doxorubicin resistance. Quinine, in contrast, had a relatively weak effect on doxorubicin accumulation but was able to completely restore doxorubicin sensitivity in the resistant cells. In addition, verapamil was able to decrease azidopine binding to P-glycoprotein, whereas quinine was not. Quinine also modified the intracellular tolerance to doxorubicin, which suggests that it is able to modify drug distribution within the cells. Confocal microscopy revealed that verapamil and quinine were able to restore nuclear fluorescence staining of doxorubicin in resistant cells; since this was obtained for quinine without significant increase of doxorubicin accumulation, this observation confirms that quinine acts principally on doxorubicin redistribution within the cells, allowing the drug to reach its nuclear targets. When used in association, verapamil and quinine reversed doxorubicin resistance in a synergistic fashion. We conclude that verapamil and quinine do not share the same targets for reversal of MDR in this cell line; whereas verapamil directly interferes with P-glycoprotein and mainly governs drug accumulation, quinine has essentially intracellular targets involved in drug redistribution from sequestration compartments.
ATP Binding Cassette Transporter, Subfamily B, Mem↗