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Mebendazole, an antiparasitic drug, inhibits drug transporters expression in preclinical model of gastric peritoneal carcinomatosis.

Toxicol In Vitro. 2017 Sep;43:87-91

Authors: Celestino Pinto L, de Fátima Aquino Moreira-Nunes C, Soares BM, Burbano RMR, de Lemos JAR, Montenegro RC

Abstract
The present study aimed to investigate whether MBZ down-regulates drug transporter expression (ABCB1, ABCC1, SLC47A1). mRNA expression level of ABCB1, ABCC1 and SLC47A1 was evaluated by qPCR and protein expression levels MDR-1 was performed by western blotting in malignant ascites cells (AGP-01) treated with MBZ for 24h. The mRNA expression level of ABCB1 and ABCC1 significantly decreased at a 1.0μM of MBZ compared to negative control, while SLC47A1 extremely decreased at all tested concentrations of MBZ. Protein expression levels MDR-1 significantly decreased at a 1.0μM of MBZ compared to negative control. Therefore, our results showed MBZ may play an important role in inhibiting MDR gene expression in malignant ascites cells.

PMID: 28606429 [PubMed - indexed for MEDLINE]

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High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients.

Oncotarget. 2017 May 23;8(21):34387-34397

Authors: Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X, Li GC

Abstract
Transforming growth factor beta (TGF-β) promotes the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between TGF-β1 expression and clinicopathological parameters in HCC patients from The Cancer Genome Atlas (TCGA), as well as the prognostic power of TGF-β1 expression. Eligible studies were retrieved from several databases, and effects (hazard ratios (HRs) with 95% confidence intervals (CIs)) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), metastasis-free survival (MFS), and progression-free survival (PFS) were pooled to assess the prognostic ability of TGF-β1 expression in HCC patients. Twelve qualified articles and our TCGA data comprising 2,021 HCC patients were incorporated. In the TCGA analysis, HCC patients with higher TGF-β1 expression presented a shorter OS than those with lower TGF-β1 expression (HR = 1.42, p < 0.05). In the meta-analysis, univariate analyses showed that HCC patients with higher TGF-β1 expression had a shorter OS (pooling HR = 1.71, p < 0.01) and DFS/RFS/MFS/PFS (pooling HR = 1.60, p < 0.01) than those with lower TGF-β1 expression. In conclusion, our results suggested that high TGF-β1 expression promotes a poor prognosis in HCC patients.

PMID: 28415739 [PubMed - indexed for MEDLINE]

Evaluation of surrogate measures of pulmonary function derived from electrical impedance tomography data in children with cystic fibrosis.

Physiol Meas. 2018 Mar 22;:

Authors: Muller PA, Mueller JL, Mellenthin M, Murthy R, Capps M, Wagner B, Alsaker M, Deterding R, Sagel SD, Hoppe J

Abstract
BACKGROUND: Lung function monitoring by spiromety plays a critical role in the clinical care of pediatric cystic fibrosis (CF) patients, but many young children are unable to perform spirometry, and the outputs are often normal even in the presence of lung disease. Measures derived from electrical impedance tomography (EIT) images were studied for their utility as potential surrogates for spirometry in CF patients and to assess response to intravenous antibiotic treatment for acute pulmonary exacerbations (PEx) in a subset of patients. &#13; Methods: EIT data were collected on 35 subjects (21 with CF, 14 healthy controls, 8 CF patients pre- and post-treatment for an acute PEx) ages 2 to 20 years during tidal breathing and also concurrently with spirometry on subjects over age 8. EIT-derived measures of FEV1, FVC, and FEV1/FVC were computed globally and regionally from dynamic EIT images. &#13; Results: Global EIT-derived FEV1/FVC showed good correlation with spirometry FEV1/FVC values (r=0.54, p=0.01), and were able to distinguish between the groups (p=0.01). Lung heterogeneity was assessed through the spatial coefficient of variation (CV) of EIT difference images between key time points, and the CV's for EIT-derived FEV1 and FVC showed significant correlation with the CV for tidal breathing (r=0.47, p=0.01 and r=0.50, p=0.01, respectively). Global EIT-derived FEV1/FVC was better able to distinguish between groups than spirometry FEV1 (F-values 776.5 and 146.3, respectively, p &lt; 0.01.) The same held true for the CV's for EIT-dervived FEV1, FVC, and Tidal Breathing (F-values 215.93, 193.89, 204.57, respectively, p &lt; 0.01.).

PMID: 29565263 [PubMed - as supplied by publisher]

Hepatotoxicity after paracetamol overdose in a patient with cystic fibrosis despite early acetylcysteine and utility of microRNA to predict hepatotoxicity.

Clin Toxicol (Phila). 2018 Mar 22;:1-3

Authors: Wong A, Cheung B, Nejad C, Gantier M, Graudins A

Abstract
CASE DETAILS: A 19-year-old girl presented to the emergency department following overdose of 10 g of paracetamol on a background history of cystic fibrosis. Paracetamol concentration was below the nomogram line, but was treated with acetylcysteine seven hours post-overdose given her symptomatology. Nineteen hours following her overdose she developed hepatotoxicity, despite early initiation of acetylcysteine. She was discharged well six days post-ingestion. On presentation, delta miRNA-122-miR483 was 20 times that of control patients, however, alanine aminotransferase was normal.
DISCUSSION: Patients with cystic fibrosis are more likely to have glutathione deficiency, and greater susceptibility to liver injury. Delta miRNA may be a better detector of early liver injury than hepatic aminotransferases. Empiric treatment with acetylcysteine and serial biochemical reassessment in this setting should be considered.

PMID: 29564929 [PubMed - as supplied by publisher]

Personalised CFTR Pharmacotherapeutic Response Testing and Therapy of Cystic Fibrosis.

Eur Respir J. 2018 Mar 21;:

Authors: McCarthy C, Brewington JJ, Harkness B, Clancy JP, Trapnell BC

PMID: 29563174 [PubMed - as supplied by publisher]

MPs call for fresh talks to end deadlock over cystic fibrosis drug.

BMJ. 2018 Mar 21;360:k1337

Authors: Wise J

PMID: 29563081 [PubMed - in process]

Long-term effect of monophosphoryl lipid A adjuvanted specific immunotherapy in patients with grass pollen allergy.

Immunotherapy. 2018 Mar 22;:

Authors: Zielen S, Gabrielpillai J, Herrmann E, Schulze J, Schubert R, Rosewich M

Abstract
BACKGROUND: Ultra-short course pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL) is attractive to conventional allergen-specific immunotherapy (AIT). Long term efficacy of MPL-AIT has not been evaluated.
METHODS: 68 patients (age 16.75 ± 5.3 years) with allergic rhinitis to grass pollen were investigated. Group 1: 21 controls; Group 2: 19 after complete AIT, and Group 3: 28 with AIT and treatment cessation: 4 years range 3-6 years ago.
RESULTS: The clinical symptoms (running nose, sneezing, conjunctivitis and the weekly overall score) were significantly reduced in patients group 2 and 3 compared with controls without AIT p < 0.0001. T-regulatory cells and TH1/TH2 cytokine pattern did not differ between patient groups.
CONCLUSION: The patients in our trial with grass pollen allergy exhibited significant and long-lasting improvements after MPL-AIT, however larger trials are needed to support this finding.

PMID: 29562801 [PubMed - as supplied by publisher]

Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology.

Behav Genet. 2018 Mar 21;:

Authors: Curtis D, Coelewij L, Liu SH, Humphrey J, Mott R

Abstract
A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the "FMRP targets" set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a "prioritized candidate gene". Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP = 1.7) and GRIN2B (SLP = 2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, three were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees.

PMID: 29564678 [PubMed - as supplied by publisher]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Funding Opportunity RFA-FD-18-014 from the NIH Guide for Grants and Contracts. Current product-specific bioequivalence (BE) guidance published by the Office of Generic Drugs for dry powder inhalers (DPIs) include in vitro testing recommendations for single actuation content and aerodynamic particle size distribution, as well as recommendations for a pharmacokinetic study and a pharmacodynamic or clinical endpoint study. Given the extensive nature of current DPI BE guidance, it is desirable that current in vitro testing for DPIs be more reflective of in vivo performance. Computational fluid dynamics (CFD) and discrete element modeling (DEM) have been used to predict dry powder aerosol behavior, including the effects of agglomeration and deagglomeration. The purpose of the study will be to develop a CFD-DEM model which can be used to evaluate the impact of various physicochemical properties and device performance properties on regional deposition, to identify potentially biorelevant ranges for these properties that may be useful for future BE recommendations.

Funding Opportunity RFA-FD-18-012 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity is to support the research and development necessary to advance non-invasive (e.g., spectroscopic/ imaging tomography) technologies, methods, study designs, and methods of data analysis to characterize and compare the rate and extent to which a topically applied drug becomes available at or near a site of action within the skin. The expectation is that the funded work will produce an accurate, sensitive and reproducible approach that measures the amount of drug present in the skin at a series of depths below the skin surface, which can be utilized to monitor the cutaneous pharmacokinetics (PK) of the drug at selected depths (e.g., in the epidermis or dermis) by repeated measurements over time. The ultimate intent is to support the eventual development of an alternative, scientifically valid, cutaneous PK-based approach to efficiently evaluate the bioequivalence (BE) of topical products in vivo in human subjects.

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/03/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Global analysis of primary mesenchyme cell cis-regulatory modules by chromatin accessibility profiling.

BMC Genomics. 2018 Mar 20;19(1):206

Authors: Shashikant T, Khor JM, Ettensohn CA

Abstract
BACKGROUND: The developmental gene regulatory network (GRN) that underlies skeletogenesis in sea urchins and other echinoderms is a paradigm of GRN structure, function, and evolution. This transcriptional network is deployed selectively in skeleton-forming primary mesenchyme cells (PMCs) of the early embryo. To advance our understanding of this model developmental GRN, we used genome-wide chromatin accessibility profiling to identify and characterize PMC cis-regulatory modules (CRMs).
RESULTS: ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) analysis of purified PMCs provided a global picture of chromatin accessibility in these cells. We used both ATAC-seq and DNase-seq (DNase I hypersensitive site sequencing) to identify > 3000 sites that exhibited increased accessibility in PMCs relative to other embryonic cell lineages, and provide both computational and experimental evidence that a large fraction of these sites represent bona fide skeletogenic CRMs. Putative PMC CRMs were preferentially located near genes differentially expressed by PMCs and consensus binding sites for two key transcription factors in the PMC GRN, Alx1 and Ets1, were enriched in these CRMs. Moreover, a high proportion of candidate CRMs drove reporter gene expression specifically in PMCs in transgenic embryos. Surprisingly, we found that PMC CRMs were partially open in other embryonic lineages and exhibited hyperaccessibility as early as the 128-cell stage.
CONCLUSIONS: Our work provides a comprehensive picture of chromatin accessibility in an early embryonic cell lineage. By identifying thousands of candidate PMC CRMs, we significantly enhance the utility of the sea urchin skeletogenic network as a general model of GRN architecture and evolution. Our work also shows that differential chromatin accessibility, which has been used for the high-throughput identification of enhancers in differentiated cell types, is a powerful approach for the identification of CRMs in early embryonic cells. Lastly, we conclude that in the sea urchin embryo, CRMs that control the cell type-specific expression of effector genes are hyperaccessible several hours in advance of gene activation.

PMID: 29558892 [PubMed - in process]

Immunological mutational signature in adenosquamous cancer of pancreas: an exploratory study of potentially therapeutic targets.

Expert Opin Ther Targets. 2018 Mar 21;:

Authors: Silvestris N, Brunetti O, Pinto R, Petriella D, Argentiero A, Fucci L, Tommasi S, Danza K, De Summa S

Abstract
OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP.
METHODS: We compared the mutational status of a customized gene panel, including 41 genes involved in immunity checkpoint, inflammation and control of leukocytes, B and T cells proliferation of PDAC and ASCP. Moreover, we evaluated the immunohistochemical expression of programmed death ligand 1 (PD-L1).
RESULTS: We observed a status of "hypermutation" of genes included in our panel in ASCP (22/41 mutated genes). Furthermore, PD-L1 resulted expressed only in 15% the squamous counterpart of ASCP tissue.
CONCLUSION: Due to genetic characteristics and to PD-L1 expression in ASCP compared to PDAC tissue, we can conclude that ASCP presents a potential sensitivity to immunological therapy.

PMID: 29561217 [PubMed - as supplied by publisher]

Association between Nonsteroidal Anti-inflammatory Drugs and Atrial Fibrillation among a Middle-aged Population: A Nationwide Population-based Cohort.

Br J Clin Pharmacol. 2018 Mar 20;:

Authors: Chuang SY, Hsu PF, Lin FJ, Huang YW, Wang GZ, Chang WC, Tsai HJ

Abstract
AIMS: It remains inconclusive whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of atrial fibrillation (AF), especially in middle-aged Asian populations. In this study, we evaluated the association between NSAID use and the risk of AF in a nationwide population-based study of middle-aged individuals in Taiwan.
METHODS: A nested case-control study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan. We identified the cases with a diagnosis of AF (ICD-9-CM codes: 427.31) and the matched controls from three independent Longitudinal Health Insurance Databases (LHIDs) derived from the NHIRD from data collected from 2001 to 2013. Conditional logistic regression models with covariates adjustment were performed to evaluate the association between NSAID use and the risk of AF.
RESULTS: A total of 57,058 participants (28,529 AF cases and 28,529 matched controls) were included. Participants with NSAID use had an elevated risk of AF compared to non-users (adjusted odds ratio (AOR)=1.18, 95% confidence interval (CI): 1.14-1.23). When further assessing the effects of different classes of NSAIDs on the risk of AF, the results showed that participants who used non-selective NSAIDs had a significantly elevated risk of AF (AOR=1.18, 95%CI: 1.13-1.23), as did participants with a combined use of selective and non-selective NSAIDs (AOR=1.30, 95%CI: 1.21-1.39).
CONCLUSIONS: NSAID use was associated with an increased risk of AF occurrence among the participants included in our study cohort. Closely monitoring the adverse effects of NSAID treatment on the risk of AF will be important, particularly among individuals at high risk.

PMID: 29560612 [PubMed - as supplied by publisher]

Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder.

Front Psychiatry. 2018;9:65

Authors: Amare AT, Schubert KO, Tekola-Ayele F, Hsu YH, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmöller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Kato M, Liu YL, Praphanphoj V, Stingl JC, Bobo WV, Tsai SJ, Kubo M, Klein TE, Weinshilboum RM, Biernacka JM, Baune BT

Abstract
Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.

PMID: 29559929 [PubMed]

A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.

N Engl J Med. 2018 Mar 22;378(12):1096-1106

Authors: Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, Liu Y, Kozlitina J, Stender S, Wood GC, Stepanchick AN, Still MD, McCarthy S, O'Dushlaine C, Packer JS, Balasubramanian S, Gosalia N, Esopi D, Kim SY, Mukherjee S, Lopez AE, Fuller ED, Penn J, Chu X, Luo JZ, Mirshahi UL, Carey DJ, Still CD, Feldman MD, Small A, Damrauer SM, Rader DJ, Zambrowicz B, Olson W, Murphy AJ, Borecki IB, Shuldiner AR, Reid JG, Overton JD, Yancopoulos GD, Hobbs HH, Cohen JC, Gottesman O, Teslovich TM, Baras A, Mirshahi T, Gromada J, Dewey FE

Abstract
Background Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. Methods We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. Results A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. Conclusions A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

PMID: 29562163 [PubMed - in process]

A family segregating lethal neonatal coenzyme Q10 deficiency caused by mutations in COQ9.

J Inherit Metab Dis. 2018 Mar 20;:

Authors: Smith AC, Ito Y, Ahmed A, Schwartzentruber JA, Beaulieu CL, Aberg E, Majewski J, Bulman DE, Horsting-Wethly K, Koning DV, Care4Rare Canada Consortium, Rodenburg RJ, Boycott KM, Penney LS

Abstract
Primary CoQ10 deficiency is a clinically and genetically heterogeneous, autosomal recessive disorder resulting from mutations in genes involved in the synthesis of coenzyme Q10 (CoQ10). To date, mutations in nine proteins required for the biosynthesis of CoQ10 cause CoQ10 deficiency with varying clinical presentations. In 2009 the first patient with mutations in COQ9 was reported in an infant with a neonatal-onset, primary CoQ10 deficiency with multi-system disease. Here we describe four siblings with a previously undiagnosed lethal disorder characterized by oligohydramnios and intrauterine growth restriction, variable cardiomyopathy, anemia, and renal anomalies. The first and third pregnancy resulted in live born babies with abnormal tone who developed severe, treatment unresponsive lactic acidosis after birth and died hours later. Autopsy on one of the siblings demonstrated brain changes suggestive of the subacute necrotizing encephalopathy of Leigh disease. Whole-exome sequencing (WES) revealed the siblings shared compound heterozygous mutations in the COQ9 gene with both variants predicted to affect splicing. RT-PCR on RNA from patient fibroblasts revealed that the c.521 + 2 T > C variant resulted in splicing out of exons 4-5 and the c.711 + 3G > C variant spliced out exon 6, resulting in undetectable levels of COQ9 protein in patient fibroblasts. The biochemical profile of patient fibroblasts demonstrated a drastic reduction in CoQ10 levels. An additional peak on the chromatogram may represent accumulation of demethoxy coenzyme Q (DMQ), which was shown previously to accumulate as a result of a defect in COQ9. This family expands our understanding of this rare metabolic disease and highlights the prenatal onset, clinical variability, severity, and biochemical profile associated with COQ9-related CoQ10 deficiencies.

PMID: 29560582 [PubMed - as supplied by publisher]

Nucleocytoplasmic transport defect in a North American patient with ALS8.

Ann Clin Transl Neurol. 2018 Mar;5(3):369-375

Authors: Guber RD, Schindler AB, Budron MS, Chen KL, Li Y, Fischbeck KH, Grunseich C

Abstract
Amyotrophic lateral sclerosis 8 (ALS8) is a rare progressive neurodegenerative disease resulting from mutation in the gene for vesicle-associated membrane protein-associated protein B. We evaluated a North American patient using exome sequencing, and identified a P56S mutation. The disease protein had similar subcellular localization and expression levels in the patient and control fibroblasts. Patient fibroblasts showed increased basal endoplasmic reticulum stress and dysfunction of nucleocytoplasmic transport as evidenced by impaired Ran trafficking. This finding extends the identification of ALS8 into North America, and indicates a cellular defect similar to other forms of hereditary motor neuron disease.

PMID: 29560381 [PubMed]