Advances in Human-Protein Interaction - Interactive and Immersive Molecular Simulations

International audienc

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer

International audienceBackground: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. Methods/Design: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.Discussion: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. Trial registration: STRATEGIC-1 is registered a

Acute partial Budd-Chiari syndrome and portal vein thrombosis in cytomegalovirus primary infection: a case report

BACKGROUND: Splanchnic vein thrombosis may complicate inherited thrombotic disorders. Acute cytomegalovirus infection is a rare cause of acquired venous thrombosis in the portal or mesenteric territory, but has never been described extending into a main hepatic vein. CASE PRESENTATION: A 36-year-old immunocompetent woman presented with acute primary cytomegalovirus infection in association with extensive thrombosis in the portal and splenic vein. In addition, a fresh thrombus was evident in the right hepatic vein. A thorough evaluation for a hypercoagulable state was negative. The clinical course, biological evolution, radiological and histological findings were consistent with cytomegalovirus hepatitis complicated by a partial acute Budd-Chiari syndrome and portal thrombosis. Therapeutic anticoagulation was associated with a slow clinical improvement and partial vascular recanalization. CONCLUSION: We described in details a new association between cytomegalovirus infection and acute venous thrombosis both in the portal vein and in the right hepatic vein, realizing a partial Budd-Chiari syndrome. One should be aware that this rare thrombotic event may be complicated by partial venous outflow block

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer A Secondary Analysis of the AVANT Trial

IMPORTANCE: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. OBJECTIVE: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. INTERVENTION: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. MAIN OUTCOMES AND MEASURES The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. RESULTS The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. CONCLUSIONS AND RELEVANCE: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited

Commercially Available Outbred Mice for Genome-Wide Association Studies

Genome-wide association studies using commercially available outbred mice can detect genes involved in phenotypes of biomedical interest. Useful populations need high-frequency alleles to ensure high power to detect quantitative trait loci (QTLs), low linkage disequilibrium between markers to obtain accurate mapping resolution, and an absence of population structure to prevent false positive associations. We surveyed 66 colonies for inbreeding, genetic diversity, and linkage disequilibrium, and we demonstrate that some have haplotype blocks of less than 100 Kb, enabling gene-level mapping resolution. The same alleles contribute to variation in different colonies, so that when mapping progress stalls in one, another can be used in its stead. Colonies are genetically diverse: 45% of the total genetic variation is attributable to differences between colonies. However, quantitative differences in allele frequencies, rather than the existence of private alleles, are responsible for these population differences. The colonies derive from a limited pool of ancestral haplotypes resembling those found in inbred strains: over 95% of sequence variants segregating in outbred populations are found in inbred strains. Consequently it is possible to impute the sequence of any mouse from a dense SNP map combined with inbred strain sequence data, which opens up the possibility of cataloguing and testing all variants for association, a situation that has so far eluded studies in completely outbred populations. We demonstrate the colonies' potential by identifying a deletion in the promoter of H2-Ea as the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes

Caractérisation par spectroscopie photoélectronique a rayonnement x (xps) de matériaux amorphes massifs et sous forme de couches minces, utilisables dans les microgénérateurs électrochimiques

De nouveaux matériaux d'électrode positive, des couches minces TiOySz et MoOySz, ont été analysés par xps. Les caractéristiques intrinsèques de ces matériaux ont été déterminées et les processus rédox mis en jeu lors du cyclage de générateurs expérimentaux ont été précisés. Parallèlement, des études ont été effectuées en XPS sur des matériaux d'électrolyte ((1-x) B2S3-xLi2S et (1-x) As2S3-xLi2S) sur leurs domaines vitreux respectifs ; en utilisant comme sonde principale le pic de coeur S2p, l'influence du modificateur sur le formateur de réseau a été analysée.Non disponibl

Étude de l'anesthésie générale à l'échelle atomique par modélisation d'un homologue bactérien du récepteur nicotinique humain

The discovery of anesthetic molecules represents a notable advance in medecine, mostly enabled by empirically observing their effect. In vitro experiments uncovered neuroreceptors as possible target for anesthetic molecules. Those are membrane-bound ion channels located on the target cells at nervous endings. In the last few years, bacterial neuroreceptor homologs were identified. The GLIC receptor, a homopentamer homologue to the human nicotinic receptor, was co-crystallized with bound general anesthetics, including bromoform, desflurane and propofol. In this thesis, I use molecular dynamics simulations and software programming to characterize interactions of general anesthetics with the wild type form of GLIC as well as with several mutants. In 2011, propofol and desflurane were co-crystallized in an intrasubunit binding site located in GLIC's transmembrane domain. More recently, bromoform was shown to bind this site as well as an intersubunit site. In this work I describe simulations of a new crystal structure displaying an additional binding site located in the channel's pore. Simulations in which GLIC is flooded by bromoform demonstrate the spontaneous accessibility of crystallographic binding sites in a non-crystalline environment. Exhaustive free energy calculations corroborate this data highlighting differences of binding energy between sites and between GLIC variants. Extensive sampling of binding pockets allowed me to detect a second intersubunit binding site, the accessibility of which is possibly modulated by a specific residue. Alltogether, data accumulated in this project provide a growing picture of anesthetic action at the atomic scale.La découverte des anesthésiques représente un progrès majeur de la médecine, rendu possible par l'observation empirique de leurs effets. Des expériences ont révélées les neurorécepteurs comme cibles possibles des anesthésiques, des canaux localisés sur la membrane des cellules cibles aux terminaisons nerveuses. Le récepteur GLIC, un homologue bactérien du récepteur nicotinique humain, a été co-cristallisé en 2011 avec des anesthésiques généraux liés à lui. Dans cette thèse, j'utilise les simulations de dynamique moléculaire pour caractériser les interactions entre des anesthésiques généraux et différentes formes de GLIC. En 2011, le propofol et le desflurane ont été co-cristallisés dans un site de liaison intra-sous-unité localisé dans le domaine transmembranaire de GLIC. En 2013, il a été montré que le bromoforme se lie à ce site ainsi qu'à un site inter-sous-unités. Dans ce travail, je décris des simulations d'une nouvelle structure cristalline montrant un site de liaison situé dans le pore du canal. Des simulations d'innondation de GLIC par le bromoforme ont démontré l'accessibilité spontanée des sites expérimentaux dans un environnement non cristallin. Des calculs d'énergie libre mettent en évidence des différences d'énergie de liaison entre les sites et entre des mutants de GLIC. Un échantillonnage complet des poches de liaison m'a permis de détecter un autre site de liaison inter-sous-unité duquel l'accessibilité est semble modulée par un résidu en particulier. Les données accumulées au cours de ce projet fournissent une image grandissante de l'action des anesthésiques à l'échelle atomique

X-ray photoelectron spectroscopic characterization of amorphous bulk materials and thin films, used in microbatteries

De nouveaux matériaux d'électrode positive, des couches minces TiOySz et MoOySz, ont été analysés par xps. Les caractéristiques intrinsèques de ces matériaux ont été déterminées et les processus rédox mis en jeu lors du cyclage de générateurs expérimentaux ont été précisés. Parallèlement, des études ont été effectuées en XPS sur des matériaux d'électrolyte ((1-x) B2S3-xLi2S et (1-x) As2S3-xLi2S) sur leurs domaines vitreux respectifs ; en utilisant comme sonde principale le pic de coeur S2p, l'influence du modificateur sur le formateur de réseau a été analysée.Non disponibl