Netrin-1 acts as a survival factor for aggressive neuroblastoma

Neuroblastoma (NB), the most frequent solid tumor of early childhood, is diagnosed as a disseminated disease in >60% of cases, and several lines of evidence support the resistance to apoptosis as a prerequisite for NB progression. We show that autocrine production of netrin-1, a multifunctional laminin-related molecule, conveys a selective advantage in tumor growth and dissemination in aggressive NB, as it blocks the proapoptotic activity of the UNC5H netrin-1 dependence receptors. We show that such netrin-1 up-regulation is a potential marker for poor prognosis in stage 4S and, more generally, in NB stage 4 diagnosed infants. Moreover, we propose that interference with the netrin-1 autocrine loop in malignant neuroblasts could represent an alternative therapeutic strategy, as disruption of this loop triggers in vitro NB cell death and inhibits NB metastasis in avian and mouse models

Migraine-associated photophobia: A new mice model for light aversion study

International audiencePhotophobia is an abnormal intolerance of light that inducespain or discomfort in eyes. It is associated to a large number of neu-rologic and ophthalmic diseases, as headaches, dry eye or cornealneuropathy. Despite social and human impact of this disablingdisorder, neuropathogenic mechanisms of photophobia remainunknown, making it difficult to treat. Animal models are thereforefundamental to progress in our knowledge. Because photopho-bia affects 80% of patients suffering migraine, we have developeda mice model of migraine to investigate photophobia. Single orrepeated injections of isosorbide dinitrate (ISDN, a nitric oxidedonor) in C57BL/6 mice were administrated to induce migraine.Cephalic mechanical allodynia was tested by von Frey filaments tothe forehead. Light aversion was assessed by using modified ele-vated plus-maze and light/dark box tests coupled to a LED-lightingsystem. Anxiety-like behaviour was measured by the open-fieldtest. All of the animals injected developed acute or persistentmigraine-like pain. Threshold of light photosensibility was reducedafter the first ISDN injection and remained constant until 72 hafter last injection. Anxiety-like behaviour was not observed. Then,sumatriptan (only one dose 5 min after acute ISDN) or propranolol(30 min before each ISDN dose) usually used to respectively treat orprevent migraine, were administrated. Cephalic mechanical allody-nia and light aversion were abolished after sumatriptan treatment.However, propranolol prevented facial allodynia development butnot the photohypersensitivity. These findings demonstrate that (i)this model mimics migraine human features, included cephalicpain and photophobia, and (ii) the neurobiological mechanismsinvolved in the persistence of migraine and photophobia aredifferent. Our model opens up new opportunities to elucidate pho-tosensitivity mechanisms and research new therapeutic strategies

Individual co-variation between viral RNA load and gene expression reveals novel host factors during early dengue virus infection of the Aedes aegypti midgut.

Dengue virus (DENV) causes more human infections than any other mosquito-borne virus. The current lack of antiviral strategies has prompted genome-wide screens for host genes that are required for DENV infectivity. Earlier transcriptomic studies that identified DENV host factors in the primary vector Aedes aegypti used inbred laboratory colonies and/or pools of mosquitoes that erase individual variation. Here, we performed transcriptome sequencing on individual midguts in a field-derived Ae. aegypti population to identify new candidate host factors modulating DENV replication. We analyzed the transcriptomic data using an approach that accounts for individual co-variation between viral RNA load and gene expression. This approach generates a prediction about the agonist or antagonist effect of candidate genes on DENV replication based on the sign of the correlation between gene expression and viral RNA load. Using this method, we identified 39 candidate genes that went undetected by conventional pairwise comparison of gene expression levels between DENV-infected midguts and uninfected controls. Only four candidate genes were detected by both methods, emphasizing their complementarity. We demonstrated the value of our approach by functional validation of a candidate agonist gene encoding a sterol regulatory element-binding protein (SREBP), which was identified by correlation analysis but not by pairwise comparison. We confirmed that SREBP promotes DENV infection in the midgut by RNAi-mediated gene knockdown in vivo. We suggest that our approach for transcriptomic analysis can empower genome-wide screens for potential agonist or antagonist factors by leveraging inter-individual variation in gene expression. More generally, this method is applicable to a wide range of phenotypic traits displaying inter-individual variation

Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy aimed at avoiding radiotherapy during first-line treatment of children with progressive optic pathway tumors (OPT), by exclusively administering multiagent chemotherapy during 16 months. PATIENTS AND METHODS: Between 1990 and 1998, 85 children with progressive OPT were enrolled onto this multicenter nationwide trial. Chemotherapy alternating procarbazine plus carboplatin, etoposide plus cisplatin, and vincristine plus cyclophosphamide was given every 3 weeks. At the time of relapse or progression, second-line chemotherapy was authorized before recourse to radiotherapy. RESULTS: Objective response rate (partial response [PR] + complete response [CR]) to chemotherapy was 42%. Five-year progression-free survival (PFS) and overall survival rates were 34% and 89%, respectively. The 5-year radiotherapy-free survival rate was 61%. In the multivariate analysis of the 85 patients that entered onto the study, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.047) and absence of neurofibromatosis type 1 (P =.035). In the multivariate analysis of the 74 patients that remained on study after the first cycle of chemotherapy, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.0053) and no objective response to chemotherapy (P =.0029). Three-year PFS was 44% in infants < or = 1 year versus 66% in children older than 1 year. Three-year PFS was 53% in the absence of an objective response to chemotherapy versus 68% after a PR or CR. CONCLUSION: A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function.Journal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

<i>SREBP</i> is a candidate host factor during early midgut infection.

<p>(A) <i>SREBP</i> expression levels measured by RNA-Seq (log₂-transformed normalized counts) on day 1 and day 4 post DENV exposure in the midgut of control (n = 6) and DENV-infected (n = 16) individuals. <i>P</i>-values of the pairwise t-tests are indicated. (B) Correlation of <i>SREBP</i> expression level measured by RNA-Seq (log₂-transformed normalized counts) and viral RNA load (log₁₀ RNA copies / midgut) in DENV-infected midguts on day 1 and day 4 post virus exposure. Black lines represent the linear regression and light orange shaded areas represent the 95% confidence intervals. Pearson's coefficients of determination (r) and <i>P</i>-values of the linear regression coefficient are indicated.</p