Cellular and molecular effects of the mTOR inhibitor everolimus.

mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.

UNLABELLED Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction. CONCLUSION Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

BACKGROUND VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING Eli Lilly and Co.

Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT

Abstract We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (P = 0·02).The 2-year event-free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0·02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD. © 2015 John Wiley & Sons Ltd.

Modelling the impact of deferring HCV treatment on liver-related complications in HIV coinfected men who have sex with men

BACKGROUND AND AIMS Hepatitis C (HCV) is a leading cause of morbidity and mortality in people who live with HIV. In many countries, access to direct acting antiviral agents to treat HCV is restricted to individuals with advanced liver disease (METAVIR stage F3 or F4). Our goal was to estimate the long term impact of deferring HCV treatment for men who have sex with men (MSM) who are coinfected with HIV and often have multiple risk factors for liver disease progression. METHODS We developed an individual-based model of liver disease progression in HIV/HCV coinfected men who have sex with men. We estimated liver-related morbidity and mortality as well as the median time spent with replicating HCV infection when individuals were treated in liver fibrosis stages F0, F1, F2, F3 or F4 on the METAVIR scale. RESULTS The percentage of individuals who died of liver-related complications was 2% if treatment was initiated in F0 or F1. It increased to 3% if treatment was deferred until F2, 7% if it was deferred until F3 and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5 years if treatment was initiated in F2 to almost 15 years if it was deferred until F4. CONCLUSIONS Deferring HCV therapy until advanced liver fibrosis is established could increase liver-related morbidity and mortality in HIV/HCV coinfected individuals, and substantially prolong the time individuals spend with replicating HCV infection.

Beiträge zur Imbibitionstheorie

Von Dr. Jean Dufour

La evaluación en el proceso de diseño

La presente investigación en desarrollo tiene como objetivos hacer un aporte a la teoría del diseño gráfico y optimizar su práctica profesional a través de la obtención de una metodología de evaluación que mida la calidad de afiches callejeros de propaganda y/o culturales. Los productos gráficos estudiados se han medido cuantitativa y cualitativamente a través de distintas técnicas, tanto en las instancias anterior y posterior a su implementación como en los niveles funcional, operativo y contextual y en sus efectos sobre el público receptor. En estos momentos se está elaborando una grilla de evaluación para orientar los respectivos resultados.

La evaluación en el proceso de diseño : una propuesta metodológica para la medición de la calidad en productos de comunicación gráfica : afiches callejeros : segunda parte

El objetivo de nuestra propuesta es realizar un aporte al desarrollo de la Teoría del Diseño Gráfico y optimizar su práctica profesional a través de la obtención de una metodología de evaluación que mida la calidad de los afiches callejeros de propaganda y/o culturales. Ésta ha permitido la evaluación de la calidad del producto gráfico en las instancias anterior y posterior a su implementación en el medio local. Asimismo, ha incorporado nuevos criterios de realidad a la teoría y práctica del Diseño, contribuyendo a su mejora en los niveles funcional, operativo, contextual, así como en sus efectos en el público receptor.

Endometriosis vulvar : presentación de un caso clínico

Fil: Comerio, Carlos. Hospital Luis Lagomaggiore (Mendoza, Argentina). Servicio de Dermatología

Villefranche sur Mer: multistressors experiment March 2012

The effect of ocean warming and acidification was investigated on a natural plankton assemblage from an oligotrophic area, the bay of Villefranche (NW Mediterranean Sea). The assemblage was sampled in March 2012 and exposed to the following four treatments for 12 days: control ( 360 µatm, 14°C), elevated pCO2 ( 610 µatm, 14°C), elevated temperature ( 410 µatm, 17°C), and elevated pCO2 and temperature ( 690 µatm, 17°C). Nutrients were already depleted at the beginning of the experiment and the concentrations of chlorophyll a (chl a), heterotrophic prokaryotes and viruses decreased, under all treatments, throughout the experiment. There were no statistically significant effects of ocean warming and acidification, whether in isolation or combined, on the concentrations of nutrients, particulate organic matter, chl a and most of the photosynthetic pigments. Furthermore, 13C labelling showed that the carbon transfer rates from 13C-sodium bicarbonate into particulate organic carbon were not affected by seawater warming nor acidification. Rates of gross primary production followed the general decreasing trend of chl a concentrations and were significantly higher under elevated temperature, an effect exacerbated when combined to elevated pCO2 level. In contrast to the other algal groups, the picophytoplankton population (cyanobacteria, mostly Synechococcus) increased throughout the experiment and was more abundant in the warmer treatment though to a lesser extent when combined to high pCO2 level. These results suggest that under nutrient-depleted conditions in the Mediterranean Sea, ocean acidification has a very limited impact on the plankton community and that small species will benefit from warming with a potential decrease of the export and energy transfer to higher trophic levels.

Fulminant hepatic and multiple organ failure following acute viral tonsillitis: a case report.

BACKGROUND Pyogenic tonsillitis may often be observed in the general Western population. In severe cases, it may require antibiotic treatment or even hospitalization and often a prompt clinical response will be noted. Here we present an unusual case of progressive multiple organ failure including fulminant liver failure following acute tonsillitis initially mistaken for "classic" pyogenic (that is bacterial) tonsillitis. CASE PRESENTATION A 68-year-old previously healthy white man was referred with suspicion of pyogenic angina. After tonsillectomy, he developed acute liver failure and consecutive multiple organ failure including acute hemodynamic, pulmonary and dialysis-dependent renal failure. Immunohistopathological analysis of his tonsils and liver as well as serum polymerase chain reaction analyses revealed herpes simplex virus-2 to be the causative pathogen. Treatment included high-dose acyclovir and multiorgan supportive intensive care therapy. His final outcome was favorable. CONCLUSIONS Fulminant herpes simplex virus-2-induced multiple organ failure is rarely observed in the Western hemisphere and should be considered a potential diagnosis in patients with tonsillitis and multiple organ failure including acute liver failure. From a clinical perspective, it seems important to note that fulminant herpes simplex virus-2 infection may masquerade as "routine" bacterial severe sepsis/septic shock. This persevering condition should be diagnosed early and treated goal-oriented in order to gain control of this life-threatening condition.

Decomposition driven interface evolution for layers of binary mixtures: I. Model dirivation and base states

A dynamical model is proposed to describe the coupled decomposition and profile evolution of a free surfacefilm of a binary mixture. An example is a thin film of a polymer blend on a solid substrate undergoing simultaneous phase separation and dewetting. The model is based on model-H describing the coupled transport of the mass of one component (convective Cahn-Hilliard equation) and momentum (Navier-Stokes-Korteweg equations) supplemented by appropriate boundary conditions at the solid substrate and the free surface. General transport equations are derived using phenomenological nonequilibrium thermodynamics for a general nonisothermal setting taking into account Soret and Dufour effects and interfacial viscosity for the internal diffuse interface between the two components. Focusing on an isothermal setting the resulting model is compared to literature results and its base states corresponding to homogeneous or vertically stratified flat layers are analyzed.

Code assessment and modelling for Design Basis Accident Analysis of the European sodium fast reactor design. Part I: System description, modelling and benchmarking

The new reactor concepts proposed in the Generation IV International Forum (GIF) are conceived to improve the use of natural resources, reduce the amount of high-level radioactive waste and excel in their reliability and safe operation. Among these novel designs sodium fast reactors (SFRs) stand out due to their technological feasibility as demonstrated in several countries during the last decades. As part of the contribution of EURATOM to GIF the CP-ESFR is a collaborative project with the objective, among others, to perform extensive analysis on safety issues involving renewed SFR demonstrator designs. The verification of computational tools able to simulate the plant behaviour under postulated accidental conditions by code-to-code comparison was identified as a key point to ensure reactor safety. In this line, several organizations employed coupled neutronic and thermal-hydraulic system codes able to simulate complex and specific phenomena involving multi-physics studies adapted to this particular fast reactor technology. In the “Introduction” of this paper the framework of this study is discussed, the second section describes the envisaged plant design and the commonly agreed upon modelling guidelines. The third section presents a comparative analysis of the calculations performed by each organisation applying their models and codes to a common agreed transient with the objective to harmonize the models as well as validating the implementation of all relevant physical phenomena in the different system codes.

Code assessment and modelling for Design Basis Accident analysis of the European Sodium Fast Reactor design. Part II: Optimised core and representative transients analysis

The new reactor concepts proposed in the Generation IV International Forum require the development and validation of computational tools able to assess their safety performance. In the first part of this paper the models of the ESFR design developed by several organisations in the framework of the CP-ESFR project were presented and their reliability validated via a benchmarking exercise. This second part of the paper includes the application of those tools for the analysis of design basis accident (DBC) scenarios of the reference design. Further, this paper also introduces the main features of the core optimisation process carried out within the project with the objective to enhance the core safety performance through the reduction of the positive coolant density reactivity effect. The influence of this optimised core design on the reactor safety performance during the previously analysed transients is also discussed. The conclusion provides an overview of the work performed by the partners involved in the project towards the development and enhancement of computational tools specifically tailored to the evaluation of the safety performance of the Generation IV innovative nuclear reactor designs.

Mémoires du Muséum d'histoire naturelle.

t. 12 (1825)