A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

Eur J Neurol. 2018 Mar 12;:

Authors: Rydning SL, Dudesek A, Rimmele F, Funke C, Krüger S, Biskup S, Vigeland MD, Hjorthaug HS, Sejersted Y, Tallaksen C, Selmer KK, Kamm C

Abstract
BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSP) are clinically and genetically heterogenous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families.
METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function predicted by bioinformatic prediction tools.
RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease.
CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, we describe the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP. This article is protected by copyright. All rights reserved.

PMID: 29528531 [PubMed - as supplied by publisher]

Related Articles

Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation.

Cancer Sci. 2018 Mar;109(3):581-586

Authors: Hasumi H, Yao M

Abstract
Although hereditary kidney cancer syndrome accounts for approximately five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, USA and the first kidney cancer-associated gene, VHL, was identified through kindred analysis of von Hippel-Lindau (VHL) syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided the basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at the germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of the causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms of how an alteration of each kidney cancer-associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

PMID: 29325224 [PubMed - indexed for MEDLINE]

Related Articles

Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate.

Birth Defects Res. 2017 01 20;109(1):27-37

Authors: Liu H, Busch T, Eliason S, Anand D, Bullard S, Gowans LJJ, Nidey N, Petrin A, Augustine-Akpan EA, Saadi I, Dunnwald M, Lachke SA, Zhu Y, Adeyemo A, Amendt B, Roscioli T, Cornell R, Murray J, Butali A

Abstract
BACKGROUND: Recent advances in genomics methodologies, in particular the availability of next-generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only.
METHODS: The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions. Filtering methods were applied to identify variants that are clinically relevant and present in affected individuals at minor allele frequencies (≤1%) in the 1000 Genomes Project single nucleotide polymorphism database, Exome Aggregation Consortium, and Exome Variant Server databases. The bioinformatics tool Systems Tool for Craniofacial Expression-Based Gene Discovery was used to prioritize cleft candidates in our list of variants, and Sanger sequencing was used to validate the presence of identified variants in affected and unaffected relatives.
RESULTS: Our analyses approach narrowed the candidates down to the novel missense variant in ARHGAP29 (GenBank: NM_004815.3, NP_004806.3;c.1654T>C [p.Ser552Pro]. A functional assay in zebrafish embryos showed that the encoded protein lacks the activity possessed by its wild-type counterpart, and migration assays revealed that keratinocytes transfected with wild-type ARHGAP29 migrated faster than counterparts transfected with the p.Ser552Pro ARHGAP29 variant or empty vector (control).
CONCLUSION: These findings reveal ARHGAP29 to be a regulatory protein essential for proper development of the face, identifies an amino acid that is key for this, and provides a potential new diagnostic tool.Birth Defects Research 109:27-37, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 28029220 [PubMed - indexed for MEDLINE]

25 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 2018/03/13

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.

15 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 2018/03/13

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.

Notice NOT-DE-18-011 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-FD-18-006 from the NIH Guide for Grants and Contracts. The intended outcome of this program is to advance efforts to improve and develop state drug residue prevention programs. It is necessary to provide assistance to state drug residue programs that need a stronger foundation to promote the prevention of illegal drug residues in animal derived foods through educational outreach and training. This program is intended to ensure drug residue prevention programs are developed to protect consumer exposure to drug residues in the edible products of food animals and support activities related to drug residue prevention. In addition, these awards will assist state agencies to better direct their programs to reduce the outcomes of illegal drug residues in animal derived foods. This cooperative agreement program (CAP) will focus on outreach, education and training. In addition, grantees will focus on performing targeted on-site assessments related to drug residue violations and best practice visits to industry and individuals to communicate proper drug use and promote effective management practices for drug residue prevention.

14 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 2018/03/12

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.

Pharmacogenetics and the Promise of Personalized Medicine.

JAMA Cardiol. 2018 Mar 11;:

Authors: Sabatine MS

PMID: 29525817 [PubMed - as supplied by publisher]

Ulipristal acetate decreases transforming growth factor β3 serum and tumor tissue concentrations in patients with uterine fibroids.

Fertil Steril. 2018 Mar 07;:

Authors: Ciebiera M, Włodarczyk M, Wrzosek M, Słabuszewska-Jóźwiak A, Nowicka G, Jakiel G

Abstract
OBJECTIVE: To evaluate and compare transforming growth factor β3 (TGF-β3) serum concentration in patients with uterine fibroids (UFs) without hormone treatment, treated with ulipristal acetate (UPA), and controls; to evaluate TGF-β3 concentrations in UF tissue in patients without hormone treatment and those treated with UPA; and to evaluate the correlations of age and body mass index (BMI) with TGF-β3 serum and UF tissue levels between the groups.
DESIGN: Retrospective cohort study.
SETTING: University teaching hospital.
PATIENT(S): A total of 141 patients divided into three groups: UFs non-UPA, UFs, and UPA, controls.
INTERVENTION(S): Medical history and examination, genital ultrasound scan, blood and tissue sampling, and measurement of TGF-β3 serum and tissue concentrations.
MAIN OUTCOME MEASURE(S): Evaluation of the impact of UPA (3 months treatment), age and BMI on TGF-β3 serum and UF tissue levels.
RESULT(S): The values of TGF-β3 serum and tissue concentrations statistically significantly differed between the non-UPA and UPA groups. The mean TGF-β3 serum concentrations were non-UPA group 32.24 ± 34.55 pg/mL, UPA group 10.88 ± 7.15 pg/mL, and controls 11.97 ± 10.30 pg/mL. The mean TGF-β3 tissue concentrations were non-UPA group 171.29 ± 91.81 pg/mg and UPA group 99.99 ± 60.63 pg/mg. Statistically significantly lower mean TGF-β3 serum and tissue concentrations were observed in patients treated with UPA. No statistically significant correlations between TGF-β3 concentrations and age or BMI were found.
CONCLUSION(S): Reduction of serum and tissue TGF-β3 concentrations in UFs may be an important component of the effect of UPA on UF biology. Further research in this area is necessary.

PMID: 29525690 [PubMed - as supplied by publisher]

The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy.

Cell Syst. 2018 Mar 01;:

Authors: Ye Y, Xiang Y, Ozguc FM, Kim Y, Liu CJ, Park PK, Hu Q, Diao L, Lou Y, Lin C, Guo AY, Zhou B, Wang L, Chen Z, Takahashi JS, Mills GB, Yoo SH, Han L

Abstract
Cancer chronotherapy, treatment at specific times during circadian rhythms, endeavors to optimize anti-tumor effects and to lower toxicity. However, comprehensive characterization of clock genes and their clinical relevance in cancer is lacking. We systematically characterized the alterations of clock genes across 32 cancer types by analyzing data from The Cancer Genome Atlas, Cancer Therapeutics Response Portal, and The Genomics of Drug Sensitivity in Cancer databases. Expression alterations of clock genes are associated with key oncogenic pathways, patient survival, tumor stage, and subtype in multiple cancer types. Correlations between expression of clock genes and of other genes in the genome were altered in cancerous versus normal tissues. We identified interactions between clock genes and clinically actionable genes by analyzing co-expression, protein-protein interaction, and chromatin immunoprecipitation sequencing data and also found that clock gene expression is correlated to anti-cancer drug sensitivity in cancer cell lines. Our study provides a comprehensive analysis of the circadian clock across different cancer types and highlights potential clinical utility of cancer chronotherapy.

PMID: 29525205 [PubMed - as supplied by publisher]

Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment.

J Cyst Fibros. 2018 Mar 07;:

Authors: Blanchard AC, Rooney AM, Yau Y, Zhang Y, Stapleton PJ, Horton E, Klingel M, Stanojevic S, Ratjen F, Coburn B, Waters V

Abstract
BACKGROUND: Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients.
METHODS: Pa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent).
RESULTS: Forty-seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 × 10-6 μg/mL in Eradicated cases compared to 3 × 10-5 μg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection.
CONCLUSIONS: Pediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates.

PMID: 29525410 [PubMed - as supplied by publisher]

14 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 2018/03/12

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.

Related Articles

FoxO3a mediates the inhibitory effects of the antiepileptic drug Lamotrigine on breast cancer growth.

Mol Cancer Res. 2018 Mar 09;:

Authors: Pellegrino M, Rizza P, Nigro A, Ceraldi R, Ricci E, Perrotta I, Aquila S, Lanzino M, Andò S, Morelli C, Sisci D

Abstract
Breast cancer (BC) is a complex and heterogeneous disease, with distinct histological features dictating the therapy. Although the clinical outcome of BC patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in BC therapy are needed. As a "faster" alternative to reach this aim, we evaluated if Lamotrigine (LTG), a broadly used anticonvulsivant, could be "repurposed" as an antitumoral drug in BC. Our data show that LTG inhibits the proliferation, the anchorage-dependent and independent cell growth in BC cells (BCCs), including hormone-resistant cell models. These effects were associated with cell cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27Kip1 and p21Waf1/Cip1), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. LTG also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, LTG induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, LTG significantly reduced tumor growth in vivo, increasing FoxO3a expression.
IMPLICATIONS: The anticonvulsivant drug LTG shows strong antiproliferative activity on BC, both in vitro and in vivo, thus drug repurposing could represent a valuable option for a molecularly targeted therapy in BC patients.

PMID: 29523760 [PubMed - as supplied by publisher]

Related Articles

Comparative assessment of strategies to identify similar ligand-binding pockets in proteins.

BMC Bioinformatics. 2018 Mar 09;19(1):91

Authors: Govindaraj RG, Brylinski M

Abstract
BACKGROUND: Detecting similar ligand-binding sites in globally unrelated proteins has a wide range of applications in modern drug discovery, including drug repurposing, the prediction of side effects, and drug-target interactions. Although a number of techniques to compare binding pockets have been developed, this problem still poses significant challenges.
RESULTS: We evaluate the performance of three algorithms to calculate similarities between ligand-binding sites, APoc, SiteEngine, and G-LoSA. Our assessment considers not only the capabilities to identify similar pockets and to construct accurate local alignments, but also the dependence of these alignments on the sequence order. We point out certain drawbacks of previously compiled datasets, such as the inclusion of structurally similar proteins, leading to an overestimated performance. To address these issues, a rigorous procedure to prepare unbiased, high-quality benchmarking sets is proposed. Further, we conduct a comparative assessment of techniques directly aligning binding pockets to indirect strategies employing structure-based virtual screening with AutoDock Vina and rDock.
CONCLUSIONS: Thorough benchmarks reveal that G-LoSA offers a fairly robust overall performance, whereas the accuracy of APoc and SiteEngine is satisfactory only against easy datasets. Moreover, combining various algorithms into a meta-predictor improves the performance of existing methods to detect similar binding sites in unrelated proteins by 5-10%. All data reported in this paper are freely available at https://osf.io/6ngbs/ .

PMID: 29523085 [PubMed - in process]

Eating less or more - Mindset induced changes in neural correlates of pre-meal planning.

Appetite. 2018 Mar 07;:

Authors: Hege MA, Veit R, Krumsiek J, Kullmann S, Heni M, Rogers PJ, Brunstrom JM, Fritsche A, Preissl H

Abstract
Obesity develops due to an imbalance between energy intake and expenditure. Besides the decision about what to eat, daily energy intake might be even more dependent on the decision about the portion size to be consumed. For decisions between different foods, attentional focus is considered to play a key role in the choice selection. In the current study, we investigated the attentional modulation of portion size selection during pre-meal planning. We designed a functional magnetic resonance task in which healthy participants were directed to adopt different mindsets while selecting their portion size for lunch. Compared with a free choice condition, participants reduced their portion sizes when considering eating for health or pleasure, which was accompanied by increased activity in left prefrontal cortex and left orbitofrontal cortex, respectively. When planning to be full until dinner, participants selected larger portion sizes and showed a trend for increased activity in left insula. These results provide first evidence that also the cognitive process of pre-meal planning is influenced by the attentional focus at the time of choice, which could provide an opportunity for influencing the control of meal size selection by mindset manipulation.

PMID: 29524474 [PubMed - as supplied by publisher]

Related Articles

Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients.

J Am Heart Assoc. 2018 Mar 09;7(6):

Authors: Singh S, McDonough CW, Gong Y, Alghamdi WA, Arwood MJ, Bargal SA, Dumeny L, Li WY, Mehanna M, Stockard B, Yang G, de Oliveira FA, Fredette NC, Shahin MH, Bailey KR, Beitelshees AL, Boerwinkle E, Chapman AB, Gums JG, Turner ST, Cooper-DeHoff RM, Johnson JA

Abstract
BACKGROUND: Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change.
METHODS AND RESULTS: Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with P<5×10-8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10-8). G-allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (ß=5.54; P=0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis P value of 3.71×10-8. HMGCS2, a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.
CONCLUSIONS: These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.

PMID: 29523524 [PubMed - in process]

Related Articles

Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-β-catenin pathway.

Stem Cell Res Ther. 2018 Mar 09;9(1):57

Authors: Ruan B, Zhu Z, Yan Z, Yang W, Zhai D, Wang L, Ye Z, Lu H, Xiang A, Liang J, Jiang Y, Xu C, Wang Z, Wei M, Lei X, Cao X, Lu Z

Abstract
BACKGROUND: The reciprocal fate decision of mesenchymal stem cells (MSCs) to either bone or adipocytes is determined by Wnt-related signaling and the glucagon-like peptide-1 receptor (GLP-1R). Azoramide, an ER stress alleviator, was reported to have an antidiabetic effect. In this study, we investigated the function of azoramide in regulating the lineage determination of MSCs for either adipogenic or osteogenic differentiation.
METHODS: In this study, microcomputed tomography and histological analysis on bone morphogenetic protein (BMP)2-induced parietal periosteum bone formation assays, C3H10T1/2 and mouse bone marrow MSC-derived bone formation and adipogenesis assays, and specific staining for bone tissue and lipid droplets were used to evaluate the role of azoramide on the lineage determination of MSC differentiation. Cells were harvested for Western blot and quantitative real-time polymerase chain reaction (PCR), and immunofluorescence staining was used to explore the potential mechanism of azoramide for regulating MSC differentiation.
RESULTS: Based on MSC-derived bone formation assays both in vivo and in vitro, azoramide treatment displayed a cell fate determining ability in favor of adipogenesis over osteogenesis. Further mechanistic characterizations disclosed that both the GLP-1R agonist peptide exendin-4 (Ex-4) and GLP-1R small interfering (si)RNA abrogated azoramide dual effects. Moreover, cAMP-protein kinase A (PKA)-mediated nuclear β-catenin activity was responsible for the negative function of azoramide on bone formation in favor of adipogenesis.
CONCLUSIONS: These data provide the first evidence to show that azoramide may serve as an antagonist against GLP-1R in MSC lineage determination.

PMID: 29523188 [PubMed - in process]

Related Articles

Correction to: Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

Paediatr Drugs. 2018 Mar 09;:

Authors: Burcham P, Sarzynski L, Khalfoun S, Novak KJ, Miller JC, Tumin D, Hayes D

Abstract
In the print publication the name of the seventh author was incorrectly published.

PMID: 29524176 [PubMed - as supplied by publisher]

Related Articles

Aberrant GSH reductase and NOX activities concur with defective CFTR to pro-oxidative imbalance in cystic fibrosis airways.

J Bioenerg Biomembr. 2018 Mar 09;:

Authors: de Bari L, Favia M, Bobba A, Lassandro R, Guerra L, Atlante A

Abstract
Cystic fibrosis (CF) is associated to impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel also causing decreased glutathione (GSH) secretion, defective airway bacterial clearance and inflammation. Here we checked the main ROS-producing and ROS-scavenging enzymes as potential additional factors involved in CF pathogenesis. We found that CFBE41o-cells, expressing F508del CFTR, have increased NADPH oxidase (NOX) activity and expression level, mainly responsible of the increased ROS production, and decreased glutathione reductase (GR) activity, not dependent on GR protein level decrease. Furthermore, defective CFTR proved to cause both extracellular and intracellular GSH level decrease, probably by reducing the amount of extracellular GSH-derived cysteine required for cytosolic GSH synthesis. Importantly, we provide evidence that defective CFTR and NOX/GR activity imbalance both contribute to NADPH and GSH level decrease and ROS overproduction in CF cells.

PMID: 29524019 [PubMed - as supplied by publisher]