Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experience

Background & Aims: Protease inhibitors (PI) with peginterferon/ ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n = 18) or telaprevir (n = 19). The indication for therapy was HCV recurrence (fibrosis stage PF2 (n = 31, 83%) or fibrosing cholestatic hepatitis (n = 6, 16%). Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p = 0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p = 0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p = 0.24). Treatment was discontinued in sixteen patients (treatment failures (n = 11), adverse events (n = 5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n = 34, 92%), treated with erythropoietin and/ or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8 ± 18.2-fold with telaprevir. Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Propriétés magnétiques du sesquioxyde de fer Fe2O3α

On donne différents résultats de mesures magnétiques effectuées sur Fe2O 3α très pur. On a spécialement étudié la variation de l'aimantation avec la température et le champ et l'on signale une anomalie de la susceptibilité à basse température. Au-dessous de ce point, Fe2O3α est paramagnétique. On donne également la température de Curie et la susceptibilité au-dessus de cette température

Étude des ferrites mixtes de manganèse dans les champs alternatifs faibles

Nous donnons les propriétés magnétiques d'un ferrite mixte de manganèse dans les champs faibles sinusoïdaux, jusqu'à des fréquences de 40 Mc: s et dans un grand intervalle de température (—196°C, + 150° C). Nous nous sommes particulièrement attachés à définir les différentes pertes, ce qui permettra de comparer la valeur d'utilisation de ce matériau à celle des alliages à base de fer-nickel

Polymorphisme du composé défini Mn Bi aux températures de disparition et de réapparition de l'aimantation spontanée

On a mis en évidence, à la température de 360° C qui correspond à la disparition de l'aimantation spontanée de l'alliage MnBi, une variation brusque du paramètre c-qui passe de 6,II Å à 5,83 Å. On envisage que cette anomalie est due au passage du ferromagnétisme à l'antiferromagnétisme

Les points de transformation des composés définis MnAs, MnBi en relation avec un mécanisme probable d'antiferromagnétisme

On donne et l'on discute les principales propriétés des composés définis MnAs et MnBi qui permettent d'envisager, non pas un point de Curie, mais un point de transformation. Ce dernier pourrait être interprété comme un passage du ferromagnétisme à l'antiferromagnétisme

Les rotations dans l'aimantation (aimantation initiale, champ coercitif)

On a déterminé théoriquement, pour divers cas particuliers, les valeurs de a (aimantation initiale) et de Hc (champ coercitif) correspondant à des rotations des moments magnétiques élémentaires contre l'énergie magnétocristalline et l'énergie de tension, sous l'influence d'un champ extérieur. On compare ces résultats avec des valeurs expérimentales obtenues sur MnBi, Mn2Sb, le cobalt et les ferrites de cobalt à grand champ coercitif, ce qui permet de retenir la rotation comme mécanisme d'aimantation

Propriétés magnétiques de quelques ferrites mixtes en relation avec leur constitution ionique

On peut calculer les moments magnétiques à saturation (I = 0° K, H = ∞) des ferrites mixtes à partir de ceux des ferrites simples. Les résultats concordent très bien (à trois pour nulle près) avec les mesures