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Virtual screening and repositioning of inconclusive molecules of beta-lactamase Bioassays-A data mining approach.

Comput Biol Chem. 2017 Oct;70:65-88

Authors: Gad A, Manuel AT, K R J, John L, R S, V G SP, U C AJ

Abstract
This study focuses on the best possible way forward in utilizing inconclusive molecules of PubChem bioassays AID 1332, AID 434987 and AID 434955, which are related to beta-lactamase inhibitors of Mycobacterium tuberculosis (Mtb). The inadequacy in the experimental methods that were observed during the invitro screening resulted in an inconclusive dataset. This could be due to certain moieties present within the molecules. In order to reconsider such molecules, insilico methods can be suggested in place of invitro methods For instance, datamining and medicinal chemistry methods: have been adopted to prioritise the inconclusive dataset into active or inactive molecules. These include the Random Forest algorithm for dataminning, Lilly MedChem rules for virtually screening out the promiscuity, and Self Organizing Maps (SOM) for clustering the active molecules and enlisting them for repositioning through the use of artificial neural networks. These repositioned molecules could then be prioritized for downstream drug discovery analysis.

PMID: 28822333 [PubMed - indexed for MEDLINE]

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The need for a next-generation public health response to rare diseases.

Genet Med. 2016 10 27;19(5):489-490

Authors: Valdez R, Grosse SD, Khoury MJ

PMID: 27787501 [PubMed - indexed for MEDLINE]

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Predicting the Future of Cystic Fibrosis Lung Disease: Gene Expression Holds Some of the Answers.

Ann Am Thorac Soc. 2018 May;15(5):556-557

Authors: Edmondson C, Davies JC

PMID: 29714098 [PubMed - in process]

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The human cathelicidin antimicrobial peptide LL-37 promotes the growth of the pulmonary pathogen Aspergillus fumigatus.

Infect Immun. 2018 Apr 30;:

Authors: Sheehan G, Bergsson G, McElvaney NG, Reeves EP, Kavanagh K

Abstract
The pulmonary mucus of cystic fibrosis (CF) patients displays elevated levels of the cathelicidin antimicrobial peptide LL-37 and the aim of this work was to assess the effect of LL-37 on the growth of Aspergillus fumigatus, a common pathogen of CF patients. Exposure of A. fumigatus to LL-37 and its derived fragment RK-31 (1.95 μg/ml) for 24 hours had a positive effect on growth (199.94 ± 6.172%, p < 0.05) and (218.20 ± 4.63%, p < 0.05) respectively, whereas scrambled LL-37 peptide did not (85.12 ± 2.92%). Exposure of 24 hour pre-formed mycelium to 5 μg/ml intact LL-37 for 48 hours increased hyphal wet weight (4.37 ± 0.23 g, p < 0.001) compared to the control (2.67 ± 0.05 g) and scrambled LL-37 (2.23 ± 0.09 g) treatments. Gliotoxin secretion was increased at 24 hours from LL-37 exposed hyphae (169.1 ± 6.36 ng/mg hyphae, p < 0.05) compared to the control (102 ± 18.81 ng/mg hyphae) and scrambled LL-37 (96.09 ± 15.15 ng/mg hyphae) treatments. Shotgun proteomic analysis of 24 hour LL-37 treated hyphae revealed an increase in the abundance of proteins associated with growth (eIF-5A (16.3 fold increased), tissue degradation (aspartic endopeptidase (4.7 fold increased)) and allergic reactions (Asp F13 (10 fold increased)). By 48 hour there was an increase in proteins indicative of cellular stress (glutathione peroxidase (9 fold increased)), growth (eIF-5A (6 fold increased)), and virulence (ribonuclease mitogillin (3.7 fold increased)). These results indicate that LL-37 stimulates A. fumigatus growth and this may result in increased fungal growth and secretion of toxins in the lungs of CF patients.

PMID: 29712727 [PubMed - as supplied by publisher]

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Cystic Fibrosis Disease Modifiers: Complex Genetics Defines the Phenotypic Diversity in a Monogenic Disease.

Annu Rev Genomics Hum Genet. 2018 Apr 25;:

Authors: O'Neal WK, Knowles MR

Abstract
In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype-phenotype relationships. The non-CFTR genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genomewide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 29709203 [PubMed - as supplied by publisher]

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Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients.

Endocr Regul. 2018 Apr 01;52(2):110-118

Authors: Danis D, Brennerova K, Skopkova M, Kurdiova T, Ukropec J, Stanik J, Kolnikova M, Gasperikova D

Abstract
OBJECTIVES: Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c-oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families.
METHODS AND RESULTS: Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of-function effect.
CONCLUSIONS: We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis.

PMID: 29715184 [PubMed - in process]

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Systematic analysis of copy number variation associated with congenital diaphragmatic hernia.

Proc Natl Acad Sci U S A. 2018 Apr 30;:

Authors: Zhu Q, High FA, Zhang C, Cerveira E, Russell MK, Longoni M, Joy MP, Ryan M, Mil-Homens A, Bellfy L, Coletti CM, Bhayani P, Hila R, Wilson JM, Donahoe PK, Lee C

Abstract
Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

PMID: 29712845 [PubMed - as supplied by publisher]

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Underdiagnoses resulting from variant misinterpretation: Time for systematic reanalysis of whole exome data?

Eur J Med Genet. 2018 Apr 27;:

Authors: Al-Murshedi F, Meftah D, Scott P

Abstract
BACKGROUND: Clinical whole exome sequencing (WES) yields a diagnosis in approximately 30% of patients evaluated for presumed genetic disorders. For unsolved cases, periodic reanalysis is usually predicated on the availability of improved bioinformatics tools or new gene discoveries.
METHODS: Exome data reanalysis was independently performed on unsolved cases that had underwent trio analysis by an external service provider. The retrieved exome data was reannotated using wANNOVAR and reanalysed following standard filtering criteria.
RESULTS: Independent reanalysis led to the identification of a disease-causing variation in two families segregating predominantly a neurological phenotype. As the causative genes were relatively well established at the time the WES referral was made, misinterpretation of the functional impact of the variant and/or underappreciation of the gene's associated phenotype are the most probable causes of the discrepancy in reporting.
CONCLUSION: Non-diagnostic clinical exome resulting from variant misinterpretation is probably under appreciated. These results emphasise the relevance of implement a policy for the reanalysis of high-throughput sequencing data, especially in a clinical context given the implications.

PMID: 29709712 [PubMed - as supplied by publisher]

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NMDA receptor signaling is important for neural tube formation and for preventing antiepileptic drug-induced neural tube defects.

J Neurosci. 2018 Apr 30;:

Authors: Sequerra EB, Goyal R, Castro PA, Levin JB, Borodinsky LN

Abstract
Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that N-methyl-D-aspartate (NMDA) receptors are important for the formation of the neural tube and loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation.SIGNIFICANCE STATEMENTNeural tube defects are one of the most common birth defects. Clinical investigations have determined that use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that are the side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy.

PMID: 29712790 [PubMed - as supplied by publisher]

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Pharmacokinetics, pharmacodynamics, and tolerability of single-dose oral LCB01-0371, a novel oxazolidinone with broad-spectrum activity, in healthy volunteers.

Antimicrob Agents Chemother. 2018 Apr 30;:

Authors: Cho YS, Lim HS, Lee SH, Cho YL, Nam HS, Bae KS

Abstract
LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses (NCT01554995). Single oral doses of 600 mg Linezolid, a placebo, or LCB01-0371 between 50 mg and 3200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, and LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and Linezolid were determined. LCB01-0371 was well tolerated up to 2400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil count, and increased total bilirubin. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose-proportional over the range of 50mg--800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for S. pneumonia, and the potency of LCB01-0371 at 800 mg was similar to that of Linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than Linezolid. Taken together, LCB01-0371 was well tolerated and exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of Linezolid. These results support the further clinical development of LCB01-0371.

PMID: 29712654 [PubMed - as supplied by publisher]

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Centaurea albonitens extract enhances the therapeutic effects of Vincristine in leukemic cells by inducing apoptosis.

Biomed Pharmacother. 2018 Mar;99:598-607

Authors: Bahmani F, Esmaeili S, Bashash D, Dehghan-Nayeri N, Mashati P, Gharehbaghian A

Abstract
Drug-induced toxicities and dose-related side effects are the major challenges in the conventional cancer therapy by the chemo drugs. On the other hand, herbal derivatives have obtained a great research interest in the field of therapeutic applications because of their more favorable specifications including less toxicity, cost-effective and more physiologically compatible than the chemical drugs. For this purpose, we evaluated methanolic extract prepared from Centaurea albonitens Turrill alone and in combination with Vincristine (VCR) for its potential cytotoxic effects in NALM-6, REH, NB4 and KMM-1 cell lines by using the various approaches. Centaurea genus is one of the current medicinal plants, which has used in traditional medicine, However, there are rare studies to examine its anticancer properties against hematologic malignant cells. In this study, we demonstrated Centaurea albonitens extract (CAE) induces cytotoxicity through G0/G1 phase arrest followed by apoptosis in a dose- and time- dependent manner, although with varying efficiency. Interestingly, normal cells didn't exhibit significant cytotoxicity after CAE treatment. Moreover, we found that low dose of CAE enhances anti-cancer effects of VCR in pre-B ALL cell lines (NALM-6 and REH). Further investigations validated synergistic anticancer activities of VCR and CAE through inducing apoptosis without significant cell cycle arrest. Taken together, our results demonstrated for the first time that the methanolic extract of Centaurea albonitens can be considered as a potential anticancer agent and/or an enhancer of chemotherapeutic sensitivity of VCR.

PMID: 29710458 [PubMed - in process]

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PhID: An Open-Access Integrated Pharmacology Interactions Database for Drugs, Targets, Diseases, Genes, Side-Effects, and Pathways.

J Chem Inf Model. 2017 Oct 23;57(10):2395-2400

Authors: Deng Z, Tu W, Deng Z, Hu QN

Abstract
The current network pharmacology study encountered a bottleneck with a lot of public data scattered in different databases. There is a lack of an open-access and consolidated platform that integrates this information for systemic research. To address this issue, we have developed PhID, an integrated pharmacology database which integrates >400 000 pharmacology elements (drug, target, disease, gene, side-effect, and pathway) and >200 000 element interactions in branches of public databases. PhID has three major applications: (1) assisting scientists searching through the overwhelming amount of pharmacology element interaction data by names, public IDs, molecule structures, or molecular substructures; (2) helping visualizing pharmacology elements and their interactions with a web-based network graph; and (3) providing prediction of drug-target interactions through two modules: PreDPI-ki and FIM, by which users can predict drug-target interactions of PhID entities or some drug-target pairs of their own interest. To get a systems-level understanding of drug action and disease complexity, PhID as a network pharmacology tool was established from the perspective of data layer, visualization layer, and prediction model layer to present information untapped by current databases.

PMID: 28906116 [PubMed - indexed for MEDLINE]

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Influence of knowledge and beliefs on consumption of performance enhancing agents in north-western Saudi Arabia.

Ann Saudi Med. 2017 Jul-Aug;37(4):317-325

Authors: Al OM, Elshatarat RA

Abstract
BACKGROUND: Consumption of performance enhancing agents (PEAs) has a wide range of negative health consequences, but knowledge of these consequences among gym users of PEAs in Saudi Arabia is not well understood.
OBJECTIVES: Identify the knowledge, awareness, beliefs and attitudes of gym users about negative health consequences of using PEAs, and the relationship between these factors and use of these agents.
DESIGN: Cross-sectional study.
SETTING: Five gyms in Madinah city, Saudi Arabia.
SUBJECTS AND METHODS: Convenience sampling was used to recruit gym users. An electronic self-administered questionnaire was used to collect data.
MAIN OUTCOME MEASURE(S): Level of knowledge about the negative health consequences of PEAs among gym users.
RESULTS: About 70% of 316 participants had used one or more of PEAs over the last six months. Of those, about 68.4% used protein powder supplements and 48.1% used energy drinks. Participants who believed that protein powder supplements (c2=52.3, P < .01) and energy drinks (c2=35.2, P < .01) had health hazards used these agents less often than others during the six months preceding data collection. Participants who had less knowledge about the negative health consequences were more likely to use protein powder supplement (t=2.38, P=.018). On the other hand, those who were more knowledgeable about the negative health consequences of insulin, were more likely to use insulin (t=2.45, P=.015).
CONCLUSION: Misuse of PEAs is widespread among gym users in Saudi Arabia. Improving the level of knowledge and awareness of possible serious health consequences would hopefully lead to reduced PEA consumption.
LIMITATIONS: The temporal sequence of cause and effect could not be determined in a cross sectional study. Convenience sampling in a single city limited the generalizability of the findings to all regions of Saudi Arabia.

PMID: 28761032 [PubMed - indexed for MEDLINE]

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Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: A meta-analysis of randomized clinical trials.

Int Immunopharmacol. 2017 Aug;49:85-94

Authors: Peng TR, Tsai FP, Wu TW

Abstract
OBJECTIVE: The purpose of this study is to evaluate the efficacy and adverse effects of nivolumab and pembrolizumab for the treatment of advanced non-small-cell lung cancer (NSCLC) by meta-analysis.
MATERIALS AND METHODS: This meta-analysis of randomized controlled trials (RCTs) was performed after searching PubMed, EMBASE, and American Society of Clinical Oncology meeting abstracts, clinicaltrial gov, and Cochrane library databases. Two reviewers independently assessed the quality of the trials. Outcomes analysis was overall response rates (ORR), overall survival (OS), progression- free survival (PFS) and major adverse effects with odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI).
RESULTS: Results reported from three RCTs involving 1,887 patients are included in this analysis. Indirect comparison between pembrolizumab and nivolumab in advanced NSCLC shows no statistically significant difference in ORR (OR: 1.14, 95% CI, 0.60-2.01), OS (HR: 0.98, 95% CI, 0.35-2.74) and PFS (HR: 1.12, 95% CI, 0.70-1.77). The incidence of grades≥3 adverse effects is higher with pembrolizumab as compared with nivolumab (OR: 3.44, 95% CI, 1.87-6.32). There are no significant statistical differences between severe adverse effects, such as pneumonitis and hypothyroidism, of the two drugs.
CONCLUSIONS: This study has demonstrated that pembrolizumab and nivolumab have similar survival outcomes in patients with advanced NSCLC, but pembrolizumab has a higher incidence of grades≥3 adverse effects than nivolumab.

PMID: 28554108 [PubMed - indexed for MEDLINE]

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