Notice NOT-CA-18-094 from the NIH Guide for Grants and Contracts

Notice NOT-RM-18-017 from the NIH Guide for Grants and Contracts

Notice NOT-AI-18-039 from the NIH Guide for Grants and Contracts

Notice NOT-DA-18-016 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-AI-18-036 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications to continue a Leadership Group (LG) for a Clinical Research Network on Antibacterial Resistance (AR), which was initiated to develop, implement, and manage a clinical research program to address key clinical research questions in AR. The LG is a cohesive program dependent on the highly integrated and complimentary activities of the four centers that comprise the network: Scientific Leadership Center (SLC), Clinical Operations Center (COC), Laboratory Center (LC) and Statistics and Data Management Center (SDMC).

Notice NOT-HL-18-621 from the NIH Guide for Grants and Contracts

Repurposing potential of 1st generation H1-specific antihistamines as anti-filovirus therapeutics.

Antiviral Res. 2018 Jul 04;:

Authors: Schafer A, Cheng H, Xiong R, Soloveva V, Retterer C, Mo F, Bavari S, Thatcher G, Rong L

Abstract
Ebola and Marburg are filoviruses and biosafety level 4 pathogens responsible for causing severe hemorrhagic fevers in humans with mortality rates up to 90%. The most recent outbreak in West Africa resulted in approximately 11,310 deaths in 28,616 reported cases. Currently there are no FDA-approved vaccines or therapeutics to treat infections of these deadly viruses. Recently we screened an FDA-approved drug library and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties. Antihistamines are attractive targets for drug repurposing because of their low cost and ease of access due to wide use. In this report we identify common over the counter antihistamines, such as diphenhydramine (Benadryl) and chlorcyclizine (Ahist) as potential candidates for repurposing as anti-filovirus agents. Furthermore, we demonstrate that this potential is wide-spread through the 1st generation of H1-specific antihistamines but is not present in newer drugs or drugs targeting H2, H3 and H4 receptors. We showed that the filovirus entry inhibition is not dependent on the classical antagonism of cell surface histamine or muscarinic acetylcholine receptors but occurs in the endosome, like the cathepsin inhibitor CA-074. Finally, using extensive docking studies we showed the potential for these drugs to bind directly to the EBOV-GP at the same site as toremifene. These findings suggest that the 1st generation antihistamines are excellent candidates for repurposing as anti-filovirus therapeutics and can be further optimized for removal of unwanted histamine or muscarinic receptor interactions without loss of anti-filovirus efficacy.

PMID: 29981374 [PubMed - as supplied by publisher]

Insights into the Pharmaceuticals and Mechanisms of Neurological Orphan Diseases: Current Status and Future Expectations.

Prog Neurobiol. 2018 Jul 04;:

Authors: Ramalho TC, de Castro AA, Tavares TS, Silva MC, Silva DR, Cesar PH, Santos LA, da Cunha EFF, Nepovimova E, Kuca K

Abstract
Several rare or orphan diseases have been characterized that singly affect low numbers of people, but cumulatively reach ∼6% - 10% of the population in Europe and in the United States. Human genetics has shown to be broadly effective when evaluating subjacent genetic defects such as orphan genetic diseases, but on the other hand, a modest progress has been achieved toward comprehending the molecular pathologies and designing new therapies. Chemical genetics, placed at the interface of chemistry and genetics, could be employed to understand the molecular mechanisms of subjacent illnesses and for the discovery of new remediation processes. This review debates current progress in chemical genetics, and how a variety of compounds and reaction mechanisms can be used to study and ultimately treat rare genetic diseases. We focus here on a study involving Amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Spinal muscular atrophy (SMA) and Familial Amyloid Polyneuropathy (FAP), approaching different treatment methods and the reaction mechanisms of several compounds, trying to elucidate new routes capable of assisting in the treatment profile.

PMID: 29981392 [PubMed - as supplied by publisher]

Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors.

Eur J Pharm Sci. 2018 Jul 04;:

Authors: Xu S, Chen Y, Zhao M, Guo Y, Wang Z, Zhao L

Abstract
Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach. For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization.

PMID: 29981400 [PubMed - as supplied by publisher]

Related Articles

CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy.

Breast Cancer Res Treat. 2018 Jul 06;:

Authors: Jansen LE, Teft WA, Rose RV, Lizotte DJ, Kim RB

Abstract
PURPOSE: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. There is paucity of prospectively collected data in terms of CYP2D6 genotype and measured tamoxifen, 4-hydroxytamoxifen and endoxifen concentrations in relation to hot flash severity during tamoxifen therapy.
METHODS: We conducted a longitudinal prospective study of breast cancer patients on tamoxifen (n = 410). At each visit, blood samples were collected, and patients completed a standardized hot flash survey (n = 1144) that reflected hot flash severity during the 7 days prior to the visit. Plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using liquid chromatography-tandem mass spectrometry and genotyping was carried out for CYP2D6. A linear mixed-effects regression analysis assessed the association of covariates in relation to the hot flash severity score (HFSS).
RESULTS: Median age at first assessment was 50 years with 61.9% of patients considered peri-menopausal. Most patients (92.2%) experienced hot flash symptoms with 51.0% having low HFSS (0-4) and 7.32% experiencing HFSS > 25. Age was significantly associated with hot flash severity, with patients aged 45-59 more likely to have higher HFSS. Neither duration of tamoxifen therapy nor observed tamoxifen, endoxifen and 4-hydroxy tamoxifen plasma concentration predicted hot flash severity. Genetic variation in CYP2D6 or CYP3A4 was not predictive of hot flash severity.
CONCLUSIONS: Hot flash severity during tamoxifen therapy can not be accounted for by CYP2D6 genotype or observed plasma concentration of tamoxifen, 4-hydroxytamoxifen, or endoxifen.

PMID: 29980881 [PubMed - as supplied by publisher]

Related Articles

Single Nucleotide Polymorphisms (SNPs) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction.

Drug Metab Dispos. 2018 Jul 06;:

Authors: Liu D, Qin S, Ray B, Kalari KR, Wang L, Weinshilboum RM

Abstract
CYP1A1 expression can be up-regulated by the ligand-activated aryl hydrocarbon receptor (AHR). Based on prior observations with estrogen receptors and estrogen response elements, we tested the hypothesis that single-nucleotide polymorphisms (SNPs) mapping hundreds of base pairs (bp) from xenobiotic response elements (XREs) might influence AHR binding and subsequent gene expression. Specifically, we analyzed DNA sequences 5 Kb up- and down-stream of the CYP1A1 gene for putative XREs. SNPs located ±500 bp of these putative XREs were studied using a genomic data-rich human lymphoblastoid cell line (LCL) model system. CYP1A1 mRNA levels were determined after treatment with varying concentrations of 3-methylcholanthrene (3MC). The rs2470893 (-1694G>A) SNP, located 196 bp from an XRE in the CYP1A1 promoter was associated with two-fold variation in AHR-XRE binding in a SNP-dependent fashion. LCLs with the AA genotype displayed significantly higher AHR-XRE binding and CYP1A1 mRNA expression after 3MC treatment than did those with the GG genotype. Electrophoretic mobility shift assay (EMSA) showed that oligonucleotides with the AA genotype displayed higher LCL nuclear extract binding after 3MC treatment than did those with the GG genotype, and mass spectrometric analysis of EMSA protein-DNA complex bands identified three candidate proteins, two of which were co-immunoprecipitated with AHR. In conclusion, we have demonstrated that the rs2470893 SNP which maps 196 bp from a CYP1A1 promoter XRE is associated with variation in 3MC-dependent AHR binding and CYP1A1 expression. Similar "distant SNP effects" on AHR binding to an XRE motif and subsequent gene expression might occur for additional AHR-regulated genes.

PMID: 29980579 [PubMed - as supplied by publisher]

Related Articles

The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients.

BMC Med Genet. 2018 Jul 06;19(1):112

Authors: Obiedat H, Alrabadi N, Sultan E, Al Shatti M, Zihlif M

Abstract
BACKGROUND: Cisplatin is one of the major drugs that used in the treatment of osteosarcoma. Cisplatin exerts its function by making cisplatin-DNA adducts culminating in cellular death. These adducts found to be repaired by nucleotide excision repair (NER) pathway. This study aimed to evaluate if polymorphisms in two main genes in the NER pathway, excision repair cross-complementing group 1 and 2 (ERCC1 and ERCC2) could affect the histological response to cisplatin based chemotherapy or clinical outcomes, particularly, event free survival (EFS) and overall survival (OS) rates.
METHOD: ERCC1 (C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms were analysed in 44 patients with osteosarcoma, who were treated with cisplatin based neoadjuvant chemotherapy. DNA was extracted from patient's formalin-fixed paraffin-embedded (FFPE) samples, patient's genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP assay. The distribution of the patients' genotype and the allele frequencies were reported. The association between each of these genotypes and many clinical and patho-histological parameters (e.g. EFS, OS and patho-histological response to treatment) was examined. The associations between gender, tumor location, presence of metastasis at diagnosis, histological subtypes, and type of neoadjuvant chemotherapy and between the histological response, EFS and OS rates were also examined.
RESULTS: This study revealed that there was a positive and significant association between ERCC1 C8092 A genotypes and median EFS rate in years; patients who were carriers of C allele (CC & CA) were found to have longer EFS rates than patients with AA genotype (P value = 0.006) and the median EFS rates were respectively as following: 2.04, 0.24 years. As well, both the presence of metastasis and the histological subtype at the time of diagnosis, were able to affect the EFS rate but not the OS. However, there was a positive correlation between OS rate and the patients' primary response to treatment.
CONCLUSIONS: Our results suggested that ERCC1 8092 C allele may play a role as a candidate prognostic marker in patients with osteosarcoma.

PMID: 29980176 [PubMed - in process]

Risk Factors and impact of Allergic Bronchopulmonary Aspergillosis in P. aeruginosa negative CF Patients.

Pediatr Allergy Immunol. 2018 Jul 07;:

Authors: De Baets F, De Keyzer L, Van Daele S, Schelstraete P, Van Biervliet S, Van Braeckel E, Thomas M, Wanyama SS

Abstract
BACKGROUND: Allergic Bronchopulmonary aspergillosis (ABPA) is a major complication in CF patients. Risk factors for ABPA and clinical deterioration in CF patients, negative for Pseudomonas aeruginosa (Pa), were explored.
METHODS: We performed a retrospective case-control study in 73 Pa-negative patients. Each patient was matched with 2 controls for age, gender, pancreas sufficiency, CFTR mutation (homozygous or heterozygous deltaF508) and Pa colonization.
RESULTS: Median FEV1 at the year of diagnosis (index year) was significantly lower in ABPA patients. The median of cumulative values of FEV1 and FVC before the index year was not significantly different. After the index year, the median of cumulative data for FEV1 and FVC was significantly lower, there were significantly more hospitalization days and more days on IV antibiotics compared to controls. Comparing pre and post index year data in ABPA patients, significantly more hospitalizations and IV antibiotic days were observed after the index year. During the period preceding the index year, significantly more ABPA patients were treated with RhDnase and inhaled corticosteroids.
CONCLUSIONS: Bronchial damage cannot be considered as a facilitating factor for ABPA. ABPA causes a significant increase in bronchial damage. In ABPA patients further bronchial damage can be controlled by an increase in hospitalization days and use of IV antibiotics.. RhDnase and inhaled corticosteroids were associated with the development of ABPA. This article is protected by copyright. All rights reserved.

PMID: 29981532 [PubMed - as supplied by publisher]

Cystic fibrosis, body composition, and health outcomes: a systematic review.

Nutrition. 2018 Apr 06;55-56:131-139

Authors: Calella P, Valerio G, Brodlie M, Donini LM, Siervo M

Abstract
OBJECTIVES: Patients with cystic fibrosis are characterized by an increased risk of nutrient malabsorption and inflammation, which may influence body composition. We examined the differences in body composition between patients with cystic fibrosis and healthy controls and how body composition differences may impact disease risk and mortality.
METHODS: Three different electronic databases (PubMed, Web of Science, and Embase) were used to find articles from inception until March 2017. The search strategy excluded articles that reported data on anthropometric measures only such as body weight, height, or waist circumference. Information on the characteristics of the study populations (e.g., age, sex, body mass index), type of study design, body composition methods, body compartments, and health outcomes was extracted.
RESULTS: Thirty-nine articles were included in the systematic review. The total number of patients with cystic fibrosis and controls that were included in these studies was 1839 and 2178, respectively. Only one study explored the association between body composition and risk of mortality whereas the majority of the studies examined the association between body composition and respiratory function (33%). Patients with cystic fibrosis had less fat-free mass and bone mineral density compared with the controls and fat-free mass was associated with decreased inspiratory muscle strength.
CONCLUSIONS: Patients with cystic fibrosis may be at an increased risk of sarcopenia and osteopenia. The measurement of body composition could improve the assessment of nutritional status and reduce the risk for respiratory and metabolic complications in patients with cystic fibrosis.

PMID: 29981489 [PubMed - as supplied by publisher]

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Evolutionary trade-offs associated with loss of PmrB function in host-adapted Pseudomonas aeruginosa.

Nat Commun. 2018 Jul 06;9(1):2635

Authors: Bricio-Moreno L, Sheridan VH, Goodhead I, Armstrong S, Wong JKL, Waters EM, Sarsby J, Panagiotou S, Dunn J, Chakraborty A, Fang Y, Griswold KE, Winstanley C, Fothergill JL, Kadioglu A, Neill DR

Abstract
Pseudomonas aeruginosa colonises the upper airway of cystic fibrosis (CF) patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We previously experimentally-evolved P. aeruginosa in a murine model of respiratory tract infection and observed early-acquired mutations in pmrB, encoding the sensor kinase of a two-component system that promoted establishment and persistence of infection. Here, using proteomics, we show downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production in pmrB mutants, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type strain LESB65. Accordingly, pmrB mutants are susceptible to antibiotic treatment but show enhanced adherence to airway epithelial cells, resistance to lysozyme treatment, and downregulate host CFTR expression. We propose that P. aeruginosa pmrB mutations in CF patients are subject to an evolutionary trade-off, leading to enhanced colonisation potential, CFTR inhibition, and resistance to host defences, but also to increased susceptibility to antibiotics.

PMID: 29980663 [PubMed - in process]

Related Articles

The N terminus of α-ENaC mediates ENaC cleavage and activation by furin.

J Gen Physiol. 2018 Jul 06;:

Authors: Kota P, Gentzsch M, Dang YL, Boucher RC, Stutts MJ

Abstract
Epithelial Na+ channels comprise three homologous subunits (α, β, and γ) that are regulated by alternative splicing and proteolytic cleavage. Here, we determine the basis of the reduced Na+ current (INa) that results from expression of a previously identified, naturally occurring splice variant of the α subunit (α-ENaC), in which residues 34-82 are deleted (αΔ34-82). αΔ34-82-ENaC expression with WT β and γ subunits in Xenopus oocytes produces reduced basal INa, which can largely be recovered by exogenous trypsin. With this αΔ34-82-containing ENaC, both α and γ subunits display decreased cleavage fragments, consistent with reduced processing by furin or furin-like convertases. Data using MTSET modification of a cysteine, introduced into the degenerin locus in β-ENaC, suggest that the reduced INa of αΔ34-82-ENaC arises from an increased population of uncleaved, near-silent ENaC, rather than from a reduced open probability spread uniformly across all channels. After treatment with brefeldin A to disrupt anterograde trafficking of channel subunits, INa in oocytes expressing αΔ34-82-ENaC is reestablished more slowly than that in oocytes expressing WT ENaC. Overnight or acute incubation of oocytes expressing WT ENaC in the pore blocker amiloride increases basal ENaC proteolytic stimulation, consistent with relief of Na+ feedback inhibition. These responses are reduced in oocytes expressing αΔ34-82-ENaC. We conclude that the α-ENaC N terminus mediates interactions that govern the delivery of cleaved and uncleaved ENaC populations to the oocyte membrane.

PMID: 29980634 [PubMed - as supplied by publisher]

Related Articles

Clinical course and significance of nontuberculous mycobacteria and its subtypes in cystic fibrosis.

BMC Infect Dis. 2018 Jul 06;18(1):311

Authors: Eikani MS, Nugent M, Poursina A, Simpson P, Levy H

Abstract
BACKGROUND: Nontuberculous mycobacteria (NTM) infections in patients with cystic fibrosis (CF) is increasing globally. However, the related epidemiology, comorbidities, and clinical impact of NTM infection remains unclear in the progress of CF lung disease and patient survival.
METHODS: We performed a retrospective, case-control, cohort study (10 years), comparing NTM culture-positive CF patients (N = 28) to matched controls (N = 26). NTM positive patients were divided in to two groups of slow-growing (N = 17) and rapid- growing NTM (N = 8). Three patients were positive for both slow and rapid NTM. For independent group comparisons, a non-parametric Mann-Whitney test (Kruskal-Wallis test for more than two groups) was used to compare the continuous variables, and a Fisher's exact test was used for the categorical variables. Paired comparisons were performed using a Wilcoxon signed-rank test.
RESULTS: The prevalence of NTM isolation was 8%. The age at CF diagnosis was significantly lower in the slow-growing NTM group compared to the rapidly growing NTM group (P = 0.04). The median percent predicted forced expiratory flow of 25% - 75% (FEF25-75) was significantly higher before NTM acquisition in slow-growing (P = 0.013) and rapidly growing NTM group (P = 0.028). The slow-growing NTM group received significantly more penicillin/beta lactamase (P = 0.010) and rifampin (P = 0.042) following isolation. Macrolide use was significantly higher after isolation in both the slow-growing NTM (P = 0.018) and rapidly growing NTM groups (P = 0.042).
CONCLUSIONS: An earlier CF diagnosis was associated with a higher isolation of slow-growing NTM and greater antimicrobial use after infection. NTM acquisition is associated with a worsening of FEF25-75. Thus, both the early diagnosis and treatment of an NTM infection in patients with CF may positively impact lung function.

PMID: 29980189 [PubMed - in process]

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

J Thorac Oncol. 2018 Jul 04;:

Authors: Liu Y, Lusk CM, Cho MH, Silverman EK, Qiao D, Zhang R, Scheurer ME, Kheradmand F, Wheeler DA, Tsavachidis S, Armstrong G, Zhu D, Wistuba II, Chow CB, Behrens C, Pikielny CW, Neslund-Dudas C, Pinney SM, Anderson M, Kupert E, Bailey-Wilson J, Gaba C, Mandal D, You M, de Andrade M, Yang P, Field JK, Liloglou T, Davies M, Lissowska J, Swiatkowska B, Zaridze D, Mukeriya A, Janout V, Holcatova I, Mates D, Milosavljevic S, Scelo G, Brennan P, McKay J, Liu G, Hung RJ, COPDGene Investigators, Christiani DC, Schwartz AG, Amos CI, Spitz MR

Abstract
BACKGROUND: Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to lung cancer (LC) susceptibility but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited causal LC variants, we performed focused exome sequencing analyses on genes located in 121 GWAS loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level and smoking behavior.
METHODS: Germline DNA from 260 LC cases and 318 controls were sequenced utilizing VCRome 2.1 exome capture. Filtering was based upon enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1,773 cases and 1,123 controls.
RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant BRCA2 K3326X (OR 2.36, 95% CI 1.38 - 3.99) and three newly identified variations: LTB p.Leu87Phe (OR 7.52, 95% CI 1.01 - 16.56), P3H2 p.Gln185His (OR 5.39, 95% CI 0.75 - 15.43), and DAAM2 p.Asp762Gly (OR 0.25, 95% CI 0.10 - 0.79). Burden tests revealed strong associations between ZNF93, DAAM2, BRD9, and LTB genes and LC susceptibility.
CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

PMID: 29981437 [PubMed - as supplied by publisher]

Related Articles

Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss).

BMJ Open. 2018 Jul 05;8(7):e023330

Authors: Fernandez A, Dor E, Maurin T, Laure G, Menard ML, Drozd M, Poinso F, Bardoni B, Askenazy F, Thümmler S

Abstract
INTRODUCTION: Early-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology. Implicated genes encode proteins involved in brain development, synapses morphology and plasticity and neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS and ASD, underlying the neurodevelopmental hypothesis of EOS.The main objective of our study is to identify disease-causing genetic mutations in a cohort of patients affected by both EOS and ASD. Special attention will be paid to genes involved in neurodevelopmental pathways.
METHODS AND ANALYSIS: We describe a multicentric study in a paediatric population. The study started in April 2014. Inclusion criteria are: age 7-22 years, diagnosis of EOS with comorbid ASD and IQ >50; Parents and siblings are also enrolled. We perform psychiatric assessments (Mini International Neuropsychiatric Interview, Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime Version, Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms) together with neurocognitive evaluations (IQ, Trail Making Test A/B and verbal fluency). Then, we study variants of the coding part of DNA (exome), using next-generation sequencing process on trio (mother, father and child). Bioinformatics tools (RVIS and PolyPhen-2) are used to prioritise disease-causing mutations in candidate genes. The inclusion period will end in November 2019.
ETHICS AND DISSEMINATION: The study protocol was approved by the Local Ethic Committee and by the French National Agency for Medicines and Health Products Safety. All patients signed informed consent on enrolment in the study. Results of the present study should help to unravel the molecular pathology of EOS, paving the way for an early therapeutic intervention.
TRIAL REGISTRATION NUMBER: NCT0256552; Pre-results.

PMID: 29980548 [PubMed - in process]

Proteome profiling in the hippocampus, medial prefrontal cortex, and striatum of aging rat.

Exp Gerontol. 2018 Jul 04;:

Authors: Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Bellier JP, Makpol S, Ngah WZW, Damanhuri HA, Tooyama I

Abstract
Decrease in multiple functions occurs in the brain with aging, all of which can contribute to age-related cognitive and locomotor impairments. Brain atrophy specifically in hippocampus, medial prefrontal cortex (mPFC), and striatum, can contribute to this age-associated decline in function. Our recent metabolomics analysis showed age-related changes in these brain regions. To further understand the aging processes, analysis using a proteomics approach was carried out. This study was conducted to identify proteome profiles in the hippocampus, mPFC, and striatum of 14-, 18-, 23-, and 27-month-old rats. Proteomics analysis using ultrahigh performance liquid chromatography coupled with Q Exactive HF Orbitrap mass spectrometry identified 1074 proteins in the hippocampus, 871 proteins in the mPFC, and 241 proteins in the striatum. Of these proteins, 97 in the hippocampus, 25 in mPFC, and 5 in striatum were differentially expressed with age. The altered proteins were classified into three ontologies (cellular component, molecular function, and biological process) containing 44, 38, and 35 functional groups in the hippocampus, mPFC, and striatum, respectively. Most of these altered proteins participate in oxidative phosphorylation (e.g. cytochrome c oxidase and ATP synthase), glutathione metabolism (e.g. peroxiredoxins), or calcium signaling pathway (e.g. protein S100B and calmodulin). The most prominent changes were observed in the oldest animals. These results suggest that alterations in oxidative phosphorylation, glutathione metabolism, and calcium signaling pathway are involved in cognitive and locomotor impairments in aging.

PMID: 29981398 [PubMed - as supplied by publisher]