A Dual sgRNA Approach for Functional Genomics in Arabidopsis thaliana.

G3 (Bethesda). 2018 Jun 08;:

Authors: Pauwels L, De Clercq R, Goossens J, Iñigo S, Williams C, Ron M, Britt A, Goossens A

Abstract
Reverse genetics uses loss-of-function alleles to interrogate gene function. The advent of CRISPR/Cas9-based gene editing now allows the generation of knock-out alleles for any gene and entire gene families. Even in the model plant Arabidopsis thaliana, gene editing is welcomed as T-DNA insertion lines do not always generate null alleles. Here, we show efficient generation of heritable mutations in Arabidopsis using CRISPR/Cas9 with a workload similar to generating overexpression lines. We obtain for several different genes Cas9 null-segregants with bi-allelic mutations in the T2 generation. While somatic mutations were predominantly generated by the canonical non-homologous end joining (cNHEJ) pathway, we observed inherited mutations that were the result of synthesis-dependent microhomology-mediated end joining (SD-MMEJ), a repair pathway linked to polymerase θ (PolQ). We also demonstrate that our workflow is compatible with a dual sgRNA approach in which a gene is targeted by two sgRNAs simultaneously. This paired nuclease method results in more reliable loss-of-function alleles that lack a large essential part of the gene. The ease of the CRISPR/Cas9 workflow should help in the eventual generation of true null alleles of every gene in the Arabidopsis genome, which will advance both basic and applied plant research.

PMID: 29884615 [PubMed - as supplied by publisher]

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"systems biology"

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Connecting genetics and gene expression data for target prioritisation and drug repositioning.

BioData Min. 2018;11:7

Authors: Ferrero E, Agarwal P

Abstract
Developing new drugs continues to be a highly inefficient and costly business. By repurposing an existing compound for a different indication, drug repositioning offers an attractive alternative to traditional drug discovery. Most of these approaches work by matching transcriptional disease signatures to anti-correlated gene expression profiles of drug perturbations. Genome-wide association studies (GWASs) are of great interest to researchers in the pharmaceutical industry because drug programmes with supporting genetic evidence are more likely to successfully progress through the drug discovery pipeline. Here, we present a systematic approach to generate drug repositioning hypothesis based on disease genetics by mining public repositories of GWAS data and drug transcriptomic profiles. We find that genes genetically associated with a certain disease are more likely to be differentially expressed in the same disease (p-value = 1.54e-17 and AUC = 0.75) and that, in existing drug - disease combinations, genes significantly up- or down-regulated after drug treatment are enriched for genes genetically associated with that disease (p-value = 1.1e-79 and AUC = 0.64). Finally, we use this framework to generate and rank novel GWAS-driven drug repositioning predictions.

PMID: 29881461 [PubMed]

Emerging role of long non-coding RNAs in cisplatin resistance.

Onco Targets Ther. 2018;11:3185-3194

Authors: Hu Y, Zhu QN, Deng JL, Li ZX, Wang G, Zhu YS

Abstract
Cisplatin (CDDP) is one of the most commonly used chemotherapy drugs for the treatment of various cancers. Although platinum-based therapies are highly efficacious against rapidly proliferating malignant tumors, the development of CDDP resistance results in significant relapse as well as decreased overall survival rates, which is a significant obstacle in CDDP-based cancer therapy. Long non-coding RNAs (lncRNAs) are involved in cancer development and progression by the regulation of processes related to chromatin remodeling, transcription, and posttranscriptional processing. Emerging evidence has recently highlighted the roles of lncRNAs in the development of CDDP resistance. In this review, we discuss the roles and mechanisms of lncRNAs in CDDP chemoresistance, including changes in cellular uptake or efflux of a drug, intracellular detoxification, DNA repair, apoptosis, autophagy, cell stemness, and the related signaling pathways, aiming to provide potential lncRNA-targeted strategies for overcoming drug resistance in cancer therapy.

PMID: 29881292 [PubMed]

Is obesity related to the lung function of non-asthmatic children?

World J Clin Pediatr. 2018 May 08;7(2):67-74

Authors: Fretzayas A, Moustaki M, Loukou I, Douros K

Abstract
Overweight and obesity are highly prevalent in developed and developing countries among children and adolescents. During the last two decades, it became evident that excess weight is adversely related to respiratory health in childhood and adolescence mainly in terms of asthma occurrence. Additionally, there is a mounting body of evidence that overweight/obesity may also affect lung function in non-asthmatic subjects. The aim of this review was to present and discuss the studies that investigated this issue in non-asthmatic children and adolescents. Only a few studies have evaluated the impact of excess weight on static volumes and their results point towards an inverse relationship between overweight/obesity and functional residual capacity. More studies have been conducted on the impact of excess weight on dynamic lung volumes with inconsistent, however, results. Nevertheless, a relatively consistent finding was that the ratio of forced expiratory volume in 1 s/forced vital capacity was significantly lower among overweight/obese children compared to their counterparts with normal weight. The underlying mechanisms of these observations have not been adequately elucidated but it is believed to result from complex interaction of mechanical, developmental, and metabolic causes. There is a need for more well-designed studies in order to clarify the impact of excess weight on lung function in non-asthmatic subjects, as well as to explore the contribution of factors such as duration and degree of obesity, and fat distribution. Despite the absence of conclusive data, there are still convincing evidence to be communicated to the children and their families as part of the arguments to encourage them to adopt a healthier lifestyle.

PMID: 29881704 [PubMed]

Decoding the Heart through Next Generation Sequencing Approaches.

Genes (Basel). 2018 Jun 07;9(6):

Authors: Pawlak M, Niescierowicz K, Winata CL

Abstract
: Vertebrate organs develop through a complex process which involves interaction between multiple signaling pathways at the molecular, cell, and tissue levels. Heart development is an example of such complex process which, when disrupted, results in congenital heart disease (CHD). This complexity necessitates a holistic approach which allows the visualization of genome-wide interaction networks, as opposed to assessment of limited subsets of factors. Genomics offers a powerful solution to address the problem of biological complexity by enabling the observation of molecular processes at a genome-wide scale. The emergence of next generation sequencing (NGS) technology has facilitated the expansion of genomics, increasing its output capacity and applicability in various biological disciplines. The application of NGS in various aspects of heart biology has resulted in new discoveries, generating novel insights into this field of study. Here we review the contributions of NGS technology into the understanding of heart development and its disruption reflected in CHD and discuss how emerging NGS based methodologies can contribute to the further understanding of heart repair.

PMID: 29880785 [PubMed]

Mining Patients' Narratives in Social Media for Pharmacovigilance: Adverse Effects and Misuse of Methylphenidate.

Front Pharmacol. 2018;9:541

Authors: Chen X, Faviez C, Schuck S, Lillo-Le-Louët A, Texier N, Dahamna B, Huot C, Foulquié P, Pereira S, Leroux V, Karapetiantz P, Guenegou-Arnoux A, Katsahian S, Bousquet C, Burgun A

Abstract
Background: The Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) have recognized social media as a new data source to strengthen their activities regarding drug safety. Objective: Our objective in the ADR-PRISM project was to provide text mining and visualization tools to explore a corpus of posts extracted from social media. We evaluated this approach on a corpus of 21 million posts from five patient forums, and conducted a qualitative analysis of the data available on methylphenidate in this corpus. Methods: We applied text mining methods based on named entity recognition and relation extraction in the corpus, followed by signal detection using proportional reporting ratio (PRR). We also used topic modeling based on the Correlated Topic Model to obtain the list of the matics in the corpus and classify the messages based on their topics. Results: We automatically identified 3443 posts about methylphenidate published between 2007 and 2016, among which 61 adverse drug reactions (ADR) were automatically detected. Two pharmacovigilance experts evaluated manually the quality of automatic identification, and a f-measure of 0.57 was reached. Patient's reports were mainly neuro-psychiatric effects. Applying PRR, 67% of the ADRs were signals, including most of the neuro-psychiatric symptoms but also palpitations. Topic modeling showed that the most represented topics were related to Childhood and Treatment initiation, but also Side effects. Cases of misuse were also identified in this corpus, including recreational use and abuse. Conclusion: Named entity recognition combined with signal detection and topic modeling have demonstrated their complementarity in mining social media data. An in-depth analysis focused on methylphenidate showed that this approach was able to detect potential signals and to provide better understanding of patients' behaviors regarding drugs, including misuse.

PMID: 29881351 [PubMed]

Memantine induces manic episode in a 73-year-old patient with vascular neurocognitive disorder: a case report.

Neuropsychiatr Dis Treat. 2018;14:1395-1398

Authors: Duan J, Lao C, Chen J, Pan F, Zhang C, Xu W, Zhou W, Hu J, Shang D, Huang M, Xu Y

Abstract
Memantine, an N-methyl-d-aspartate receptor antagonist, is a well-established treatment option for moderate-to-severe cognitive impairment related to Alzheimer disease. Recently, growing evidence has indicated memantine might also be effective in treatment of affective disorders. The common drug-induced adverse events of memantine include confusion, dizziness, drowsiness, headache, insomnia, and agitation. Herein, we presented a case of a 73-year-old female patient with vascular neurocognitive disorder, who developed a manic episode after taking memantine.

PMID: 29881276 [PubMed]

Overcoming the legal and regulatory barriers to drug repurposing.

Nat Rev Drug Discov. 2018 Jun 08;:

Authors: Breckenridge A, Jacob R

Abstract
Drug repurposing has been proposed as a strategy to develop new therapies that has fewer risks, lower costs and shorter timelines than developing completely new drugs. However, the potential of this strategy has not been as widely realized as hoped, in part owing to legal and regulatory barriers. Here, we highlight these barriers and consider how they could be overcome.

PMID: 29880920 [PubMed - as supplied by publisher]

[Acute Promyelocytic Leukemia - A Rare, Life-Threatening Disease with High Healing Chance].

Dtsch Med Wochenschr. 2018 Feb;143(3):152-156

Authors: Nolte F, Lengfelder E, Hofmann WK

Abstract
The acute promyelocytic leukemia (APL) is a rare disease. However, if diagnosed early and treated immediately high cure rates can be achieved. Signs of hematopoietic insufficiency such as cytopenias or leucocytosis can be present at first presentation of the patients. Moreover, hemorrhagic diatheses due to coagulpathy are present in approximately 80 % of cases and contribute substatially to the high early death rate in APL patients, which has been reported as high as 30 % in population based studies. In case of initial suspicion of APL treatment with all-trans retinoic acid (ATRA) should be initated immediately to reduce the risk of fatal bleeding events and confirmation or exclusion of the PML-RARA transcript should not be awaited before start of ATRA treatment. While patients with a low or intermediate risk of relapse are treated with a combination of ATRA and arsenic trioxide (ATO), those with high risk of relapse still receive a combination regimen consisting of ATRA, anthracyclines and cytosine-arabinosid. However, treatment strategies are under clinical investigation aiming at reducing the administration of conventional chemotherapy in high risk APL patients. With the current treatment approaches cure rates of approximately 90 % of the patients with low or intermeditae risk APL can be achieved. Nevertheless, particularly the high initial death rate warrants further clinical and pathiobiologic studies to identify targets and means to decrease hemorrhagic complications in patients with APL.

PMID: 29409083 [PubMed - indexed for MEDLINE]

Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data.

Bioinformatics. 2017 Aug 01;33(15):2421-2423

Authors: Pontikos N, Yu J, Moghul I, Withington L, Blanco-Kelly F, Vulliamy T, Wong TLE, Murphy C, Cipriani V, Fiorentino A, Arno G, Greene D, Jacobsen JOB, Clark T, Gregory DS, Nemeth AM, Halford S, Inglehearn CF, Downes S, Black GC, Webster AR, Hardcastle AJ, UKIRDC, Plagnol V

Abstract
Summary: Phenopolis is an open-source web server providing an intuitive interface to genetic and phenotypic databases. It integrates analysis tools such as variant filtering and gene prioritization based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare genetic diseases.
Availability and Implementation: A demo of the website is available at https://phenopolis.github.io . If you wish to install a local copy, source code and installation instruction are available at https://github.com/phenopolis . The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts.
Contact: n.pontikos@ucl.ac.uk.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 28334266 [PubMed - indexed for MEDLINE]

An Observation Capability Semantic-Associated Approach to the Selection of Remote Sensing Satellite Sensors: A Case Study of Flood Observations in the Jinsha River Basin.

Sensors (Basel). 2018 May 21;18(5):

Authors: Hu C, Li J, Lin X, Chen N, Yang C

Abstract
Observation schedules depend upon the accurate understanding of a single sensor’s observation capability and the interrelated observation capability information on multiple sensors. The general ontologies for sensors and observations are abundant. However, few observation capability ontologies for satellite sensors are available, and no study has described the dynamic associations among the observation capabilities of multiple sensors used for integrated observational planning. This limitation results in a failure to realize effective sensor selection. This paper develops a sensor observation capability association (SOCA) ontology model that is resolved around the task-sensor-observation capability (TSOC) ontology pattern. The pattern is developed considering the stimulus-sensor-observation (SSO) ontology design pattern, which focuses on facilitating sensor selection for one observation task. The core aim of the SOCA ontology model is to achieve an observation capability semantic association. A prototype system called SemOCAssociation was developed, and an experiment was conducted for flood observations in the Jinsha River basin in China. The results of this experiment verified that the SOCA ontology based association method can help sensor planners intuitively and accurately make evidence-based sensor selection decisions for a given flood observation task, which facilitates efficient and effective observational planning for flood satellite sensors.

PMID: 29883425 [PubMed - in process]

Understanding the health economic burden of patients with tuberous sclerosis complex (TSC) with epilepsy: a retrospective cohort study in the UK Clinical Practice Research Datalink (CPRD).

BMJ Open. 2017 Oct 05;7(10):e015236

Authors: Shepherd C, Koepp M, Myland M, Patel K, Miglio C, Siva V, Gray E, Neary M

Abstract
INTRODUCTION: Epilepsy is highly prevalent in tuberous sclerosis complex (TSC), a multi-system genetic disorder. The clinical and economic burden of this condition is expected to be substantial due to treatment challenges, debilitating co-morbidities and the relationship between TSC-related manifestations. This study estimated healthcare resource utilisation (HCRU) and costs for patients with TSC with epilepsy (TSC+E) in the UK.
METHODS: Patients with TSC+E in the Clinical Practice Research Datalink (CPRD) linked to Hospital Episodes Statistics were identified from April 1997 to March 2012. Clinical data were extracted over the entire history, and costs were reported over the most recent 3-year period. HCRU was compared with a matched Comparator cohort, and the key cost drivers were identified by regression modelling.
RESULTS: In total, 209 patients with TSC+E were identified, of which 40% recorded ≥2 other primary organ system manifestations and 42% had learning disability. Treatment with ≥2 concomitant antiepileptic drugs (AEDs) was prevalent (60%), potentially suggesting refractory epilepsy. Notwithstanding, many patients with TSC+E (12%) had no record of AED use in their entire history, which may indicate undertreatment for these patients.Brain surgery was recorded in 12% of patients. Routine electroencephalography and MRI were infrequently performed (30% of patients), yet general practitioner visits, hospitalisations and outpatient visits were more frequent in patients with TSC+E than the Comparator. This translated to threefold higher clinical costs (£14 335 vs £4448), which significantly increased with each additional primary manifestation (p<0.0001).
CONCLUSIONS: Patients with TSC+E have increased HCRU compared with the general CPRD population, likely related to manifestations in several organ systems, substantial cognitive impairment and severe epilepsy, which is challenging to treat and may be intractable. Disease surveillance and testing appears to be inadequate with few treatments trialled.Multidisciplinary care in TSC clinics with specialist neurologist input may alleviate some of the morbidity of patients, but more innovative treatment and management options should be sought.

PMID: 28982809 [PubMed - indexed for MEDLINE]

CYP2D6 Genotype Phenotype Discordance Due to Drug-Drug Interaction.

Clin Pharmacol Ther. 2018 Jun 08;:

Authors: Monte AA, West K, McDaniel KT, Flaten HK, Saben J, Shelton S, Abdelmawla F, Bushman LR, Williamson K, Abbott D, Anderson PL

Abstract
Drug-drug interactions have been demonstrated to alter CYP2D6 enzyme phenotype due to inhibitor ingestion though it is unclear how substrate interactions affect phenotype. This was a pragmatic clinical trial examining the kinetics of a CYP2D6 enzyme probe drug with and without CYP2D6 dependent substrates. Patients were enrolled into an inpatient study unit, orally administered a 2 mg microdose of dextromethorphan to probe enzyme activity with and without CYP2D6 dependent drug-drug interactions. Thirty-nine subjects were enrolled in this trial. Twelve subjects were on no CYP2D6 dependent drugs and 27 were on one or more CYP2D6 dependent drugs. There were 1 poor metabolizer, 5 intermediate metabolizers, 31 normal metabolizers, and 2 ultra-rapid metabolizers. Those with co-ingestion of another CYP2D6 dependent drug were 9.49 (95% CI: 1.54, 186.41; p = 0.01) times more likely to have genotype-phenotype discordance based upon the 3 hours DX/DM ratio. CYP2D6 substrate co-ingestions can cause genotype-phenotype discordance. This article is protected by copyright. All rights reserved.

PMID: 29882961 [PubMed - as supplied by publisher]

OCT1 deficiency affects hepatocellular concentrations and pharmacokinetics of cycloguanil, the active metabolite of the antimalarial drug proguanil.

Clin Pharmacol Ther. 2018 Jun 07;:

Authors: Matthaei J, Seitz T, Jensen O, Tann A, Prukop T, Tadjerpisheh S, Brockmöller J, Tzvetkov MV

Abstract
Cycloguanil, the active metabolite of proguanil, acts on malaria schizonts in erythrocytes and hepatocytes. We analyzed the impact of organic cation transporter OCT1 on hepatocellular uptake and pharmacokinetics of proguanil and cycloguanil. OCT1 transported both proguanil and cycloguanil. Common variants OCT1*3 and *4 caused a substantial decrease and OCT1*5 and *6 complete abolishment of proguanil uptake. In 39 healthy subjects, low-activity variants OCT1*3 and *4 had only minor effects on proguanil pharmacokinetics. However, both, cycloguanil AUC and the cycloguanil-to-proguanil ratio were significantly dependent on number of these low-functional alleles (p=0.02 for both). Together, CYP2C19, CYP3A5, OCT1 polymorphisms, and sex accounted for 61% of the variation in the cycloguanil-to-proguanil ratio. Most importantly, in-vitro OCT1 inhibition caused a 5-fold decrease of intracellular cycloguanil concentrations in primary human hepatocytes. In conclusion, OCT1-mediated uptake is a limiting step in bioactivation of proguanil, and OCT1 polymorphisms may affect proguanil efficacy against hepatic malaria schizonts. This article is protected by copyright. All rights reserved.

PMID: 29882324 [PubMed - as supplied by publisher]

Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy.

Int J Nanomedicine. 2018;13:3223-3233

Authors: Suñé-Pou M, Prieto-Sánchez S, El Yousfi Y, Boyero-Corral S, Nardi-Ricart A, Nofrerias-Roig I, Pérez-Lozano P, García-Montoya E, Miñarro-Carmona M, Ticó JR, Suñé-Negre JM, Hernández-Munain C, Suñé C

Abstract
Background: Cationic solid lipid nanoparticles (SLNs) have been given considerable attention for therapeutic nucleic acid delivery owing to their advantages over viral and other nanoparticle delivery systems. However, poor delivery efficiency and complex formulations hinder the clinical translation of SLNs.
Aim: The aim of this study was to formulate and characterize SLNs incorporating the cholesterol derivative cholesteryl oleate to produce SLN-nucleic acid complexes with reduced cytotoxicity and more efficient cellular uptake.
Methods: Five cholesteryl oleate-containing formulations were prepared. Laser diffraction and laser Doppler microelectrophoresis were used to evaluate particle size and zeta potential, respectively. Nanoparticle morphology was analyzed using electron microscopy. Cytotoxicity and cellular uptake of lipoplexes were evaluated using flow cytometry and fluorescence microscopy. The gene inhibition capacity of the lipoplexes was assessed using siRNAs to block constitutive luciferase expression.
Results: We obtained nanoparticles with a mean diameter of approximately 150-200 nm in size and zeta potential values of 25-40 mV. SLN formulations with intermediate concentrations of cholesteryl oleate exhibited good stability and spherical structures with no aggregation. No cell toxicity of any reference SLN was observed. Finally, cellular uptake experiments with DNA-and RNA-SLNs were performed to select one reference with superior transient transfection efficiency that significantly decreased gene activity upon siRNA complexation.
Conclusion: The results indicate that cholesteryl oleate-loaded SLNs are a safe and effective platform for nonviral nucleic acid delivery.

PMID: 29881274 [PubMed - in process]

Pharmacogenomics of antioxidant supplementation to prevent age-related macular degeneration.

Proc Natl Acad Sci U S A. 2018 Jun 07;:

Authors: Vickers AJ

PMID: 29880714 [PubMed - as supplied by publisher]

Reply to Vickers: Pharmacogenetics and progression to neovascular age-related macular degeneration-Evidence supporting practice change.

Proc Natl Acad Sci U S A. 2018 Jun 07;:

Authors: Vavvas DG, Small KW, Awh C, Zanke BW, Tibshirani RJ, Kustra R

PMID: 29880713 [PubMed - as supplied by publisher]

ASHP offers pharmacogenetics resources.

Am J Health Syst Pharm. 2018 Jun 15;75(12):833

Authors: Traynor K

PMID: 29880512 [PubMed - in process]

Pharmacogenetics tools readily available for those who opt to use them.

Am J Health Syst Pharm. 2018 Jun 15;75(12):832-833

Authors: Traynor K

PMID: 29880511 [PubMed - in process]