Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02-98 Randomized Trial

Background Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. Methods Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. Results Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). Conclusions Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherap

Unusual clinical findings in thrombotic thrombocytopenic purpura.

International audienc

Le scanner abdominal (nouveau marqueur nutritionnel et pronostique chez le patient atteint de cirrhose inscrit sur la liste de transplantation hépatique)

OBJECTIF: Le but de ce travail est d'étudier le rôle du scanner abdominal en tant que marqueur nutritionnel et pronostique chez les patients atteints de cirrhose inscrits sur liste de transplantation hépatique. Il s'agit d'analyser la relation entre les variables clinico-biologiques classiquement utilisées pour évaluer l'état nutritionnel et les mesures tomodensitométriques évaluées, puis d'étudier l'impact des variables radiologiques sur la mortalité des patients inscrits sur liste d'attente de transplantation hépatique. PATIENTS ET METHODES: 103 patients cirrhotiques inscrits sur liste de transplantation hépatique à l'hôpital Beaujon entre le 1er janvier 1992 et le 1er janvier 2005 ont été rétrospectivement inclus dans l'étude. Les indications de la transplantation étaient parmi les suivantes : Cirrhose alcoolique, Cirrhose virale B, Cirrhose virale C, Cirrhose biliaire primitive, Cholangite sclérosante primitive, Carcinome hépato-cellulaire ou Cirrhose cryptogénétique. 39 femmes et 64 hommes, d'âge moyen égal à 45,9 ans ont été inclus. Parmi ces patients, 12 (11,6%) sont décédés dans l'attente d'une transplantation, et 19 (18,4%) sont décédés dans les suites de la transplantation hépatique. Au total, 31 des patients inclus dans l'étude sont décédés, ce qui représente un taux de mortalité globale de 30,1%. L'évaluation de l'état nutritionnel des patients était basé sur le recueil des paramètres clinico-biologiques usuels : Taille, poids, indice de masse corporelle, score subjectif " Subjective Global Assessment ", albumine et créatinine. Ces critères classiquement utilisés en vue d'évaluer l'état nutritionnel étaient complétés par la mesure des variables scannographiques suivantes : Epaisseur de graisse sous-cutanée, muscle antérieur, psoas longitudinal, psoas transversal, muscle spinal postérieur et fascia latéro-conal droit " puis comparés à ces derniers. RESULTATS: L'épaisseur du psoas transversal est significativement corrélée au score subjectif d'évaluation de l'état nutritionnel " SGA ". Cette même variable est aussi corrélée au degré de gravité du score de Child. Quelle que soit l'indication de la transplantation, l'ascite réfractaire est associée à une moindre épaisseur de graisse sous-cutanée et de muscle antérieur. De même, l'épaisseur de graisse sous-cutanée et celle du muscle antérieur sont corrélées à la mesure de l'indice de masse corporelle. La mesure radiologique de la masse musculaire a aussi une influence significative et indépendante sur le risque de décès pendant la période d'attente d'un greffon ainsi que sur la mortalité globale après inscription sur la liste d'attente. L'épaisseur du psoas transversal est statistiquement associée au risque global de décès des patients inscrits sur liste de transplantation hépatique pour cirrhose alcoolique, virale C et carcinome hépato-cellulaire. Le ratio " muscle spinal postérieur/taille " est le meilleur marqueur corrélé au décès sur liste d'attente de transplantation hépatique. Un seuil établi à 0,2 permet de distinguer un sous-groupe de patients dénutris dont le pronostic est particulièrement péjoratif en attente de transplantation hépatique. Les variables tomodensitométriques concernant la masse grasse n'ont pas d'influence indépendante sur le pronostic des patients inclus dans l'étude. Les différents paramètres musculaires et adipeux mesurés lors de l'inscription sur liste de transplantation hépatique sont sans impact significatif sur la mortalité post-opératoire. CONCLUSION: Le scanner abdominal représente une méthode simple et non invasive pour évaluer l'état nutritionnel des cirrhotiques. Elle permet de quantifier la masse musculaire et la masse adipeuse indépendamment de la rétention hydro-sodée. Si les paramètres adipeux n'ont pas d'impact pronostique, le diamètre transversal des muscles psoas et le diamètre des muscles spinaux postérieurs sont des marqueurs prédictifs indépendants de mortalité en liste d'attente et de mortalité globale après inscription sur liste d'attente de transplantation hépatique.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mineralogical and geochemical study of the rare earth element mineralization at Gakara (Burundi)

The rare earth element (REE) mineralization of Gakara (Burundi) has first been discovered in 1936 and has periodically been the subject of geological studies, at times when the exploitation of bastnäsite-(Ce) and monazite-(Ce) was economically interesting. This study focuses on the establishment of a mineral paragenesis for Gakara, with special attention to the REE-bearing phases, to understand the formation history of the deposit. The paragenesis can be subdivided into 3 stages: primary ore deposition, brecciation stage and supergene alteration. Evidence for fenitization processes (i.e. pinkish-red cathodoluminescence of K-feldpar, brecciation stage) and the strong enrichment of light REEs in bastnäsite and monazite substantiate the hypothesis of a structurally controlled hydrothermal mineralization with a strong carbonatitic affinity. This likely confirms the association of the Gakara REE deposit with the Neoproterozoic alignment of alkaline complexes and carbonatites along the present-day Western Rift. It suggests a direct link with a – currently unidentified – carbonatitic body at depth, possibly derived from a predominantly metasomatized lithospheric mantle

The effect of the protein level in a pre-starter diet on the post-hatch performance and activation of ribosomal protein S6 kinase in muscle of neonatal broilers.

The cytoplasmic serine/threonine ribosomal protein S6 kinase (S6K1) plays a critical role in controlling protein translation. There is evidence that amino acids regulate S6K1 and protein synthesis in avian species, but the effect of dietary protein level on the activation of S6K1 in neonatal chicks is unknown. Therefore, the aim of the present experiment was to investigate the effect of different protein levels, supplied during the first 5 d post-hatch, on body growth, breast muscle development and on the activation of S6K1 and its downstream target, the S6, in neonatal chicks. Chicks were fed a pre-starter diet during the first 5 d post-hatch containing low (19.6 % crude protein (CP); LP), medium (23.1 % CP; MP) or high (26.7 % CP) levels (HP) of protein. Weight gain of chicks fed the HP diet was higher (P < 0.05) compared with those fed the LP diet during day (d)3-d5 and the numerical advantage of this group was maintained from d2 to d7. On d2 and d3, greater levels of S6K1 and S6 phosphorylation and/or activity were observed in chicks receiving the HP diet compared with LP and MP diets, without differences between results of the latter two dietary treatments. In conclusion, the present results suggest that early protein nutrition impacts the development of broiler chicks

Pathological breathing patterns after pneumococcal rhombencephalitis

status: publishe

The effect of albumen removal before incubation (embryonic protein under-nutrition) on the post-hatch performance, regulators of protein translation activation and proteolysis in neonatal broilers.

Albumen was removed from broiler eggs before the start of incubation to induce prenatal protein under-nutrition in chicken embryos. With this method, the direct effect of protein deficiency was investigated, differing from mammalian models manipulating the maternal diet where indirect, hormonal effects can interfere. Based on the estimated albumen/egg weight ratio, 10 % of albumen was removed with an 18G needle, after making a hole at the sharp end of the egg with another 18G needle. Eggs were taped thereafter. The sham group underwent the same procedure, except that no albumen was removed. Control eggs did not receive any treatment. The removal of albumen decreased both embryonic and post-hatch body weight up to day 7 compared with the control group. On embryonic day 18, embryos from the albumen-deprived group had higher plasma uric acid levels compared with the sham (P= 0.016) and control (P= 0.009) groups. Moreover, a lower plasma amino acid concentration was observed at hatch compared with the sham (P= 0.038) and control (P= 0.152) groups. These findings indicate an altered protein metabolism. At hatch, a higher mRNA expression of muscle ring finger-1 (MuRF1), a gene related to proteolysis, was observed in albumen-deprived chicks compared with the control and sham chicks, together with an up-regulated expression of atrogin-1 (another atrogene) at this time point in the male protein-deficient chicks. These findings suggest that muscle proteolysis is transiently increased by the removal of albumen before the start of incubation. No evidence was found for altered protein synthesis capacity and translational efficiency in albumen-deprived chicks

IL-15 Renders Conventional Lymphocytes Resistant to Suppressive Functions of Regulatory T Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway

International audienceIL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-beta through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-beta and CD4(+) regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-beta on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-beta, IL-15 enhanced the acquisition of regulatory functions by CD4(+)CD25(-) T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-gamma production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of EL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression. The Journal of Immunology, 2009, 182: 6763-6770

Effects of sex and fasting/refeeding on hepatic AMPK signaling in chickens (Gallus gallus)

The alpha-1 isoform of chicken AMPK situates on the Z-chromosome, in contrast, the other isoforms in birds and the mammalian AMPKα1 are located on the autosomes. The present study aimed to investigate the role of hepatic AMPK signaling in adaptation to nutritional status and the potential sex-specific response in chickens. Hepatic genes and proteins were compared between the two sexes immediately after hatching. From 20d of age, chicks from each sex received feed treatments: Control was fed ad libitum; Fasted was starved for 24 h; Refed was fed for 4 h after a 24 h fasting. As a result, hepatic AMPKα1 mRNA level in males was significantly higher at both ages compared to females, due to the presence of Z-chromosomes. However, this did not make this kinase "male-bias" as it was eventually compensated at a translational level, which was not reported in previous studies. The protein levels and activation of AMPKα were even lower in newly-hatched male compared to female chicks, accompanied with a higher FAS and SREBP-1 gene expressions. Accordingly, hepatic G6PC2 mRNA levels in males were significantly lower associated with lower plasma glucose levels after hatching. Fasting activated hepatic AMPK, which in turn inhibited gene expression of GS, FAS and SREBP-1, and stimulated the downstream G6PC2 in both sexes. These changes recovered after refeeding. In conclusion, AMPK plays a role in adaptation to nutritional environment for both sexes. The Z-linked AMPK did not exert a sex-specific signaling, due to a "translational compensation" of AMPKα1.status: publishe