Apport de la tomographie par émission de positons au 18F-fluorodéoxyglucose (TEP-FDG) dans la prise en charge du cancer du canal anal

ObjectiveTo evaluate the contribution of FDG-PET in the management of anal carcinoma, with special emphasis on its impact on therapeutic strategy.Materials and methodsFrom March 2005 to August 2008, 48 PET were performed on 43 patients with anal epidermoid carcinoma, in initial staging (IS: 20 exams), therapeutic response assessment (TRA: 11), and recurrence assessment (RA: 17). We compared initial therapeutic strategies defined on conventional assessment results, to final ones chosen after PET.ResultsPET revealed lesions that were undetected by conventional investigation in 23% of cases (IS: 25%; TRA: 18%; RA: 23%) and cleared suspicious lesions in 21% of cases (IS: 10%; TRA: 18%; RA: 35%). It influenced the therapeutic strategy, and sometimes even modified it radically, in 44% of cases (IS: 35%; TRA: 54%; RA: 47%). This therapeutic impact was stronger in settings with diagnostic ambiguity, in which PET allowed to specify the diagnosis and to orientate consequently the therapeutic choice.ConclusionPET is interesting in the management of anal carcinoma, especially in uncertain diagnostic settings, in which the metabolic information brought allows to influence the therapeutic choice in almost half of the cases.     

Metabolomics and In-Silico Analysis Reveal Critical Energy Deregulations in Animal Models of Parkinson’s Disease

Parkinson’s disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a complex I blocker. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level.     

Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE’s HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection.     

Molecular cloning of Xenopus fibrillarin, a conserved U3 small nuclear ribonucleoprotein recognized by antisera from humans with autoimmune disease.

Autoantibodies against U3 small nuclear ribonucleoprotein are associated with scleroderma autoimmune disease. They were shown to react with fibrillarin, a 34- to 36-kilodalton protein that has been detected in all eukaryotes tested from humans to yeasts. We isolated a 1.6-kilobase cDNA encoding fibrillarin from a Xenopus laevis cDNA library. The protein contains a 79-residue-long Gly-Arg-rich domain in its N-terminal region and a putative RNA-binding domain with ribonucleoprotein consensus sequence in its central portion. This is the first report of cloning of fibrillarin, and the deduced protein sequence is in agreement with the involvement of the protein in a ribonucleoprotein particle.     

Biochemical and pharmacologic properties of the Ca2+ channel of skeletal muscle: appearance during myogenesis and the relation between its structure and function

Two distinct and interdependent binding sites for inhibitors of voltage-dependent Ca2+ channels have been identified. They include one site for molecules of the 1,4-dihydropyridine serie such as nitrendipine, nifedipine or PN200-110 and one site for a chemically heterogenous group of compounds comprising verapamil, D600 and desmethoxyverapamil, bepridil and diltiazem. Ca2+ binds to its own coordination site which is distinct from the receptor site for organic Ca2+ channel inhibitors. The molecular size of the native [3H] nitrendipine receptor of transverse tubule membrane, brain and heart, have been determined using the radiation inactivation technique. The [3H] nitrendipine receptor is found to have a Mr of 210,000 +/- 20,000. CHAPS solubilization and purification indicate that the dihydropyridine receptor contains polypeptides of apparent molecular weights of 142,000, 32,000 and 33,000 which copurifie with (+) [3H] PN200-110 binding activity. Two stages in which there is an increased binding of [3H]nitrendipine have been observed during chick myogenesis. The first one occurs during embryonic life and has the same properties as in the in vitro development. The second stage occurs near hatching and corresponds to a large increase in the number of nitrendipine receptors. This increase is accompanied by a decrease in the affinity of nitrendipine for its receptor by a factor of 4 to 10. The second stage of development is partly under innervation control and its expression is modulated by the intracellular cyclic AMP content. The two dihydropyridines Bay K8644 and CGP 28932 work preferentially on polarized membranes. 45Ca2+ flux experiments yielded results which are in good agreement with electrophysiological, contraction and binding data obtained with rat cardiac cells and skeletal muscle cells.     

Estrogen and androgen production by purified Leydig cells of mature boars

Purified Leydig cells were obtained from testes of mature male pigs by collagenase treatment and mechanical dispersion, followed by Percoll (0-90%) density gradient centrifugation. The cells recovered at 40-45% Percoll were applied to a second gradient of 15 ml of Percoll (10-60%) to yield three bands, one major and two lesser in numbers of cells. Incubations were then made with 0.25-1.0 X 10(6) cells at 34 degrees C for 3 h in 95% O2: 5% CO2, with or without human chorionic gonadotrophin (hCG) added to the medium. Steroid concentration was determined by radioimmunoassays. The steroids measured in the media were testosterone, dehydroepiandrosterone sulfate (DHAS) and estrone sulfate (E1S). Lesser amounts of dehydroepiandrosterone (DHA) and estrone (E1) were found. Stimulation by hCG led to an increase in apparent steroid production for all steroids, including estrogens, with the greatest quantities seen with DHAS (greater than 200 ng/1 X 10(6) cells/3 h). Cells in the major band gave the best response. These results show that Leydig cells are a significant site of estrogen production in the boar testis and that this organ is a source of an abundant supply of such cells.     

The response of the skin of swine to increasing single exposures of 250-KVP X-rays

When the skin of the shoulder ("A" field) and lower back ("C" field) is irradiated through 10-cm-diameter fields with 250-kVp x-rays, having a HVL of 0.87 mm copper, a dose range is reached between approximately 1600 rads and 3000 rads in which a moist reaction is or is not formed. If a moist reaction is formed, it either heals completely, partially, or not at all. The evolution, time course, and dose dependence of the moist reaction that occurs following irradiation has been determined. The moist reaction is found at 17.5 +/- 0.6 days in the "A" field, and 20.8 +/-0.8 days in the "C" field. The reaction evolves to involve from 5 % to 100% of the field by 24.9 +/- 0.5 days in the "A" field and by 28.5 +/- 1.0 days in the "C" field. Healing is complete by 36.0 +/-1.0 days in the "A" field and by 38.0 +/- 1.3 days in the "C" field. The area of the field involved with a moist reaction at the time of maximal involvement is dose-dependent. The area of the field involved with a moist reaction at the time of complete healing is also dose-dependent. The dose at which 50 % of the fields were not healed was 2273 +/-103 rads in the "A" field, 2578 +/-141 rads in the "C" fields, and 2437 +/- 89 rads in the "A" and "C" fields. The values in the "C" field are significantly different from those in the "A" field except for the dose at which 50 % of the fields were not healed and the time at which the field was maximally healed.