Randomized phase 2 trial of intravenous oncolytic virus JX-594 combined with low-dose cyclophosphamide in patients with advanced soft-tissue sarcoma

JX-594 is an oncolytic vaccinia virus genetically modified to replicate selectively in tumor cells. Metronomic chemotherapy has shown preclinical synergy with oncolytic viruses. We report here the results of the METROMAJX which is a randomized phase II clinical trial investigating the combination of JX-594 combined with metronomic cyclophosphamide (arm 1) or metronomic cyclophosphamide (arm 2) in patients with advanced STS. A two-stage Simon design was used. JX-594 was administered intra-venously at the dose 1.109 every 2 weeks for the first 3 injections and then every 3 weeks. Cyclophosphamide was given orally at the dose of 50 mg BID 1 week on 1 week off. The primary endpoint was the 6-month non progression rate. 20 patients were included (arm 1:15, arm 2:5). The two most frequent toxicities were grade 1 fatigue and fever and grade 2 fatigue and grade 2 lymphopenia in arms 1 and 2, respectively. In arm 1, 12 patients were assessable for the efficacy analysis. None of them were progression-free at 6 months indicating that the first stage of the Simon's design was not satisfied. One patient out 4 assessable for efficacy was progression-free at 6 months in arm 2. High throughput analysis of sequential plasma samples revealed an upregulation of protein biomarkers reflecting immune induction such as CXCL10 and soluble CD8 antigen in arm 1. Systemic treatment with JX-594 is safe in patients with advanced STS. Further investigations are needed to improve immune response to oncolytic viruses and define their therapeutic potential in patients with STS

Correction: Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

[This corrects the article DOI: 10.5334/tohm.464.]

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder

Spécificités fonctionnelles des MAP kinases MEK/ERK dans la prolifération et suivie des hépatocytes transformés

La voie de signalisation ERK1/2 occupe une place centrale dans la régulation d'un grand nombre de processus physiologiques. Par conséquent, ses dérégulations sont liées au développement de diverses pathologies, dont le carcinome hépatocellulaire (CHC), 3ème cause de mortalité par cancer à travers le monde. Au sein de cette signalisation, les protéines kinases MEK1 et MEK2, comme ERK1 et ERK2, présentent une forte homologie de séquence et ont ainsi été largement considérées comme redondantes. Cependant, un nombre grandissant d'études montre que ces protéines ne sont pas totalement interchangeables. Au cours de ce travail, notre objectif fut de progresser dans la compréhension des mécanismes régulant la voie ERK1/2, en focalisant notre étude sur l'existence ou non d'une spécificité fonctionnelle entre les kinases. Nous montrons ici que malgré leur forte redondance, ces protéines peuvent également remplir certaines fonctions de façon spécifique. Par l'utilisation d'ARN interférents et de souris ERK1-/-, nous démontrons en effet un rôle prépondérant de la kinase ERK1 dans la survie des hépatocytes tumoraux. Son inhibition protège les cellules de la toxicité de l'agent chimiothérapeutique cisplatine et l'augmentation de son activité, causée par l'extinction de l'isoforme ERK2, les sensibilise à l'action de la drogue. Nous montrons aussi que la prolifération des cellules de CHC est uniquement dépendante de l'activité de MEK1. Son inhibition spécifique bloque la croissance cellulaire et ce défaut n'est corrigé que par la réexpression de MEK1, non par celle de MEK2. Ces travaux supportent ainsi l'intérêt d'une inhibition ciblée de la voie MAPK dans le traitement du CHC.The ERK1/2 signaling pathway plays a pivotal role in the regulation of numerous physiological processes. Therefore, its deregulations are linked to the development of various human diseases including hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide. Within the MAPK pathway, the kinases MEK1 and MEK2, as well as ERK1 and ERK2, share a high sequence homology and have been widely regarded as redundant isoform. However, a growing number of studies show that these kinases are not completely interchangeable. In order to improve our understanding of the molecular mechanisms regulating the MAPK pathway, we focused our study on the existence of functional specificity between the kinases. Here, we ascertained that despite their high redundancy, the protein kinases could also perform certain functions in a specific manner. Using RNA interference and ERK1-/- mice, we show a predominant role of the kinase ERK1 in tumor hepatocyte survival. Indeed, ERK1 specific targeting protects cells from the cytotoxicity of the chemotherapeutic drug cisplatin, whereas its increased activity, caused by ERK2 specific extinction, sensitizes them to the drug. In addition, we show that HCC cell proliferation solely depends on MEK1 activity. MEK1 specific inhibition impairs cell growth and this defect can only be reversed by MEK1 re-expression, not by MEK2. In conclusion, this work supports that targeted inhibition of the MAPK pathway could represent an interesting strategy for HCC treatment.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Maîtrise de l'oral en grande section de maternelle et conceptualisation de la langue écrite en début de cours préparatoire

This paper reports the first results of a current longitudinal study which aims at assessing effects of an oral skills psychoeducational training in kindergarten on oral and written language abilities at beginning first grade. Teachers carried out, during second and third term of Kindergarten school year, the training of 238 children of high, average and low speaking abilities. Cognitive and linguistic abilities and evaluation of school adaptation were assessed at the beginning of kindergarten year. School adaptation and level of school language participation were evaluated at the end of kindergarten year and level of conceptualization of written language at the beginning of first grade. Results show a training effect on school language participation and level of conceptualization of written language, in particular within a group of children who were low speakers at the beginning of kindergarten year.L'objectif est de présenter les premiers résultats d'une recherche longitudinale en cours visant à mesurer les effets d'un entraînement psychopédagogique centré sur la maîtrise de l'oral en grande section de maternelle sur les compétences orales et écrites en début de CP. Cet entraînement a été mis en œuvre par les enseignants au cours des second et troisième trimestres de l'année de GSM auprès de 238 enfants répartis en petits groupes de grands, moyens et petits parleurs. Les compétences cognitives, langagières et l'adaptation scolaire des enfants ont été évaluées au début de l'année de GSM. On dispose également, pour la fin de GSM, d'informations sur l'évolution de l'adaptation scolaire des enfants et de leur niveau de participation à la conversation scolaire et, pour le début du CP, d'une mesure de leur niveau de conceptualisation de l'écrit. Les résultats montrent un effet de l'entraînement en termes d'évolution de la quantité de participation à la conversation scolaire et du niveau de conceptualisation de l'écrit, notamment pour une partie des enfants petits parleurs de début d'année.Florin Agnès, Khomsi Abdelhamid, Guimard Philippe, Ecalle Jean, Guegan Jean-François. Maîtrise de l'oral en grande section de maternelle et conceptualisation de la langue écrite en début de cours préparatoire. In: Revue française de pédagogie, volume 126, 1999. L'acquisition/apprentissage de l'orthographe. pp. 71-82

Fungal Colonization of the Airways of Patients with Cystic Fibrosis: the Role of the Environmental Reservoirs

International audienceFilamentous fungi frequently colonize the airways of patients with cystic fibrosis and may cause severe diseases, such as the allergic bronchopulmonary aspergillosis. The most common filamentous fungi capable to chronically colonize the respiratory tract of the patients are Aspergillus fumigatus and Scedosporium species. Defining the treatment strategy may be challenging, the number of available drugs being limited and some of the causative agents being multiresistant microorganisms. The knowledge of the fungal niches in the outdoor and indoor environment is needed for understanding the origin of the contamination of the patients. In light of the abundance of some of the causative molds in compost, agricultural and flower fields, occupational activities related to such environments should be discouraged for patients with cystic fibrosis (CF). In addition, the microbiological monitoring of their indoor environment, including analysis of air and dust on surfaces, is essential to propose preventive measures aiming to reduce the exposure to environmental molds. Nevertheless, some specific niches were also identified in the indoor environment, in relation with humidity which favors the growth of thermotolerant molds. Potted plants were reported as indoor reservoirs for Scedosporium species. Likewise, Exophiala dermatitidis may be spread in the kitchen via dishwashers. However, genotype studies are still required to establish the link between dishwashers and colonization of the airways of CF patients by this black yeast. Moreover, as nothing is known regarding the other filamentous fungi associated with CF, further studies should be conducted to identify other potential specific niches in the habitat

Author Correction: Fungal Colonization of the Airways of Patients with Cystic Fibrosis: The Role of the Environmental Reservoirs

International audienc

Probing the side chain tolerance for inhibitors of the CD95/PLCγ1 interaction

International audienceProceeding our effort to study protein-protein interaction between the death receptor CD95 and phospholipase PLCγ1, we present in the current work chameleon-like traits of peptidomimetic inhibitors. Minute analysis of the interaction suggests that most of the binding energy relies on van der Waals contacts rather than more specific features, such as hydrogen bonds or salt bridges. The two most important positions of the peptoid for its interaction with PLCγ1 (Arg184 and Arg187) were modified to test this hypothesis. While Arg184 proves to be exchangeable for Trp, with no alteration in affinity, the nature of the amino acid replacing Arg187 is more dependent on its positive charge. However, affinity can be partially recovered by increasing van der Waals interactions. Overall, this study shows that for both positions, a subtle balance exists between hydrophobicity, surface contacts and affinity for CD95/PLCγ1, and provides information for the generation of new therapeutic compounds toward this druggable target

Exp Hematol Oncol

Breast cancer is one the most common cause of cancer death in women worldwide. We report here the first phase II study investigating a virus genetically engineered for tumor-selective replication in patients with breast cancer. Ten patients were treated with a combination of low-dose oral cyclophosphamide and intra-venous JX-594, a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF) and β-galactosidase. Best response as per RECIST criteria was stable disease for 2 patients and progressive disease for 8 patients. Median progression-free and overall survival were 1.6 months (95% CI: [1.1-1.9]) and 14.4 months (95% CI: [2.0 - NA]) respectively. High throughput analysis of sequential plasma samples revealed an upregulation of protein biomarkers reflecting immune induction such as IFN gamma. Whether the combination of JX-594 with an immune checkpoint inhibitor is associated with meaningful clinical activity is therefore worth to investigate

Ultrasensitive QRS made by supramolecular assembly of functionalized cyclodextrins and graphene for the detection of lung cancer VOC biomarkers

International audienceA novel electronic nose system comprising functionalized β-cyclodextrin wrapped reduced graphene oxide (RGO) sensors with distinct ability of discrimination of a set of volatile organic compounds has been developed. Non-covalent modification of chemically functionalized cyclodextrin with RGO is carried out by using pyrene adamantane as a linker wherever necessary, in order to construct a supramolecular assembly. The chemical functionality on cyclodextrin is varied utilising the principle of selective chemical modification of cyclodextrin. In the present study, the combined benefits of the host–guest inclusion complex formation ability and tunable chemical functionality of cyclodextrin, as well as the high surface area and electrical conductivity of graphene, are utilized for the development of a set of highly selective quantum resistive chemical vapour sensors (QRS), which can be assembled in an electronic nose