Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized. International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing. We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity. We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy

Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway

Background: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature.Methods: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X -inactiva-tion). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants.Results: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo.Conclusion: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more effi-cient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts.Genetics of disease, diagnosis and treatmen

Détection de ruptures et application à la caractérisation de signaux de Chaussée

Détecter les ruptures d'un signal information revient à effectuer un test d'hypothèse basé sur un rapport de vraisemblance et/ou un intervalle de confiance. Nous appliquons les méthodes GLR, X2 et Fisher à la variance du signal de chaussée non stationnaire, supposé aléatoire et filtré par le modèle du véhicule, et à celle de l'innovation après estimation paramétrique. Ceci permet une analyse des caractéristiques de la chaussée et des conséquences sur le confort du véhicule

D8 vapour liquid equilibrium measurement tests definiition

International audienceThe main objective of the work is the complete knowledge of the H2 production section of the S_I thermochemical cycle; thus, the ternary system HI - I2 H2O around 320DC and 50 bars is investigated total and partial pressure measurements of the species in the vapour phase. This document aims to define the measurement techniques that could be used for the HIx system vapour phase characterization, and their working domains FTIR, UV-Visible and RAMAN spectroscopies. A three step strategy has been adopted for the experimentations, and very first results are given under temperature and pressure conditions up to 120DC

Oral treatment with etoposide in small cell lung cancer - dilemmas and solution

Background. Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be atrisk for excess toxicity. Conclusions. The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.Izhodišča. Etopozid je protitumorna učinkovina, ki jo pogosto uporabljamo za zdravljenje različnih rakavih obolenj, vključno z drobnoceličnim pljučnim rakom. Ta je agresivni rak s slabo napovedjo poteka bolezni. Peroralno vnašanje etopozida ima veliko prednosti tako z vidika kakovosti življenja bolnika kakor tudi z vidika obvladovanja stroškov. Uporaba etopozida pa je omejena zaradi nepopolne absorpcije ter velike intra- in inter-individualne spremenljivosti biološke uporabnosti. To lahko pri nekaterih bolnikih privede do zmanjšane učinkovitosti ali povečane toksičnosti. Zaključki. Članek s pregledom in analizo literaturnih podatkov predstavlja dileme in rešitve gledeperoralnega zdravljenja z etopozidom. Rezultati številnih raziskav so pokazali, da na biološko uporabnost etopozida vplivajo genetski, fiziološki in okoljski dejavniki. Poznamo številne pristope za izboljšanje biološke uporabnosti in zmanjšanje farmakokinetične spremenljivosti peroralnega etopozida. To so želene in neželene interakcije (npr. s ketokonazolom), razvojustreznih dostavnih sistemov, uporaba predzdravila, ki je bolj vodotopno od etopozida in vpliv na hitrost praznjenja želodca. Etopozid je primerna zdravilna učinkovina za odmerjanje na osnovi poznavanja farmakokinetike in genotipa, kar omogoča tudi prilagajanje odmerka pri posameznemu bolniku. Ugotovili so, da se učinkovitost peroralnega in intravenskega zdravljenja z etopozidom pri bolnikih z drobnoceličnim pljučnim rakom značilno ne razlikuje, medtem ko so si rezultati primerjav toksičnosti nasprotujoči. Glavno sporočilo članka je, da boljša napovedljivost farmakokinetike peroralnega etopozida omogoča večjo uporabo le-tega v rutinski klinični praksi

D8 VAPOUR LIQUID EQUILIBRIUM MEASUREMENTS TESTS DEFINITION

International audienceThe main objective of the work is the complete knowledge of the H2 production section of the S_I thermochemical cycle; thus, the ternary system HI - I2 H2O around 320DC and 50 bars is investigated total and partial pressure measurements of the species in the vapour phase. This document aims to define the measurement techniques that could be used for the HIx system vapour phase characterization, and their working domains FTIR, UV-Visible and RAMAN spectroscopies. A three step strategy has been adopted for the experimentations, and very first results are given under temperature and pressure conditions up to 120DC