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pharmacogenomics

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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 2017/06/09

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 2017/06/09

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.

A disease similarity matrix based on the uniqueness of shared genes.

BMC Med Genomics. 2017 May 24;10(Suppl 1):26

Authors: Carson MB, Liu C, Lu Y, Jia C, Lu H

Abstract
BACKGROUND: Complex diseases involve many genes, and these genes are often associated with several different illnesses. Disease similarity measurement can be based on shared genotype or phenotype. Quantifying relationships between genes can reveal previously unknown connections and form a reference base for therapy development and drug repurposing.
METHODS: Here we introduce a method to measure disease similarity that incorporates the uniqueness of shared genes. For each disease pair, we calculated the uniqueness score and constructed disease similarity matrices using OMIM and Disease Ontology annotation.
RESULTS: Using the Disease Ontology-based matrix, we identified several interesting connections between cancer and other disease and conditions such as malaria, along with studies to support our findings. We also found several high scoring pairwise relationships for which there was little or no literature support, highlighting potentially interesting connections warranting additional study.
CONCLUSIONS: We developed a co-occurrence matrix based on gene uniqueness to examine the relationships between diseases from OMIM and DORIF data. Our similarity matrix can be used to identify potential disease relationships and to motivate further studies investigating the causal mechanisms in diseases.

PMID: 28589854 [PubMed - in process]

On the Integration of In Silico Drug Design Methods for Drug Repurposing.

Front Pharmacol. 2017;8:298

Authors: March-Vila E, Pinzi L, Sturm N, Tinivella A, Engkvist O, Chen H, Rastelli G

Abstract
Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A number of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease associations.

PMID: 28588497 [PubMed - in process]

Identification of Non-Electrophilic Nrf2 Activators from Approved Drugs.

Molecules. 2017 May 26;22(6):

Authors: Zhang QY, Chu XY, Jiang LH, Liu MY, Mei ZL, Zhang HY

Abstract
Oxidative damage can lead to a wide range of diseases. Nrf2 is an important transcription factor that regulates many of the cytoprotective enzymes involved in the oxidative stress response. Therefore, targeting the regulation of Nrf2 activation is one logical and effective strategy to prevent or lower the risk of oxidative stress-related diseases. Until now, most research has focused on electrophilic indirect Nrf2 activators, but the risk of 'off-target' effects may be associated with these activators. To find novel small non-electrophilic modulators of Nrf2, we started from chemical agents derived from a connectivity map (cMap) and identified 22 non-electrophilic potential Nrf2-activating drugs through a drug repositioning tactic. By determining the expression changes of antioxidant genes in MCF7 cells that were treated with the potential Nrf2 activators using quantitative real-time polymerase chain reaction RT-PCR (real-time polymerase chain reaction) (qRT-PCR), astemizole was found to have a greater scale of upregulating antioxidant genes NQO1, HO-1, and GCLM than the positive control d,l-sulforaphane, although the testing concentration was lower than that of the control. Astemizole is a good potential redox regulator and deserves more pharmacodynamic experimentation to test and verify its feasibility for use as an Nrf2 activator.

PMID: 28587109 [PubMed - in process]

Mutation-specific effects on thin filament length in thin filament myopathy.

Ann Neurol. 2016 Jun;79(6):959-69

Authors: Winter JM, Joureau B, Lee EJ, Kiss B, Yuen M, Gupta VA, Pappas CT, Gregorio CC, Stienen GJ, Edvardson S, Wallgren-Pettersson C, Lehtokari VL, Pelin K, Malfatti E, Romero NB, Engelen BG, Voermans NC, Donkervoort S, Bönnemann CG, Clarke NF, Beggs AH, Granzier H, Ottenheijm CA

Abstract
OBJECTIVE: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation.
METHODS: We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41.
RESULTS: Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap.
INTERPRETATION: These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. Ann Neurol 2016;79:959-969.

PMID: 27074222 [PubMed - indexed for MEDLINE]

FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

Oncotarget. 2017 May 18;:

Authors: Liu S, Zhang C, Zhang K, Gao Y, Wang Z, Li X, Cheng G, Wang S, Xue X, Li W, Zhang W, Zhang Y, Xing X, Li M, Hao Q

Abstract
Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

PMID: 28591725 [PubMed - as supplied by publisher]

Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics.

Nat Biotechnol. 2017 Jun 07;35(6):500-502

Authors: Hafner M, Niepel M, Sorger PK

PMID: 28591115 [PubMed - in process]

Associations between serum 25(OH)D concentrations and prevalent asthma among children living in communities with differing levels of urbanization: a cross-sectional study.

Asthma Res Pract. 2017;3:5

Authors: Pollard SL, Lima JJ, Romero K, Tarazona-Meza C, Mougey E, Tomaino K, Malpartida-Guzmán G, Hansel NN, Checkley W, GASP Study Investigators

Abstract
BACKGROUND: Prior evidence suggests that vitamin D deficiency may increase the risk of asthma and atopy and impair pulmonary function in children.
METHODS: In this cross-sectional analysis nested in a case-control study, we analyzed serum 25(OH)D concentrations in 413 children with asthma and 471 children without asthma living in two geographically adjacent study communities (Pampas and Villa El Salvador). We measured total and antigen-specific IgE levels, pulmonary function, asthma control, and exhaled nitric oxide.
RESULTS: Mean 25(OH)D concentrations were 25.2 ng/mL (SD 10.1) in children with asthma and 26.1 ng/mL (SD 13.7) in children without asthma (p = 0.28). Vitamin D deficiency (25(OH)D < 20 ng/ml) was more common in Pampas than in Villa El Salvador (52.7% vs. 10.5%; p < 0.001). In the overall study population, a 10 ng/ml decrease in serum 25(OH)D concentrations was not significantly associated with odds of asthma (OR 1.09, 95% CI: 0.94 to 1.25). However, vitamin D deficiency was associated with a 1.6-fold increase in odds of asthma in the overall cohort (95% CI: 1.14 to 2.25). After stratifying by site, a 10 ng/mL decrease in serum 25(OH)D concentrations was associated with 18% higher odds of having asthma in Pampas (OR = 1.18, 95% CI 1.02 to 1.38), whereas there was no significant association between 25(OH)D concentrations and asthma in Villa El Salvador (OR = 0.95, 95% CI 0.87 to 1.05). Combined data from these geographically adjacent populations suggests a possible threshold for the relationship between 25(OH)D levels and asthma at approximately 27.5 ng/ml. Serum 25(OH)D concentrations were not clearly associated with asthma control, total serum IgE, atopy, or airway inflammation.
CONCLUSION: Serum 25(OH)D concentrations were inversely associated with asthma in one study community with a high prevalence of deficiency. Studies are needed to investigate a possible threshold 25(OH)D concentration after which higher vitamin D levels show no further benefit for asthma.

PMID: 28588900 [PubMed - in process]

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment.

BMC Med Genet. 2017 Jun 06;18(1):64

Authors: Song J, Yang Y, Mauvais-Jarvis F, Wang YP, Niu T

Abstract
BACKGROUND: Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects.
METHODS: Based on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl's VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively.
RESULTS: Based on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl's VEP.
CONCLUSIONS: Our study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.

PMID: 28587604 [PubMed - in process]

Is There a Role for Genomics in the Management of Hypertension?

Int J Mol Sci. 2017 May 26;18(6):

Authors: Burrello J, Monticone S, Buffolo F, Tetti M, Veglio F, Williams TA, Mulatero P

Abstract
Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty-three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2-3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non-coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN.

PMID: 28587112 [PubMed - in process]

Development and Initial Assessment of a Patient Education Video about Pharmacogenetics.

J Pers Med. 2017 May 25;7(2):

Authors: Mills R, Ensinger M, Callanan N, Haga SB

Abstract
As few patient-friendly resources about pharmacogenetics are currently available, we aimed to create and assess a patient educational video on pharmacogenetic testing. A primary literature and resources review was conducted to inform the content and the format of the video. The educational video was then created using a commercially available animation program and pilot tested in focus groups of the general public and by an online survey of pharmacists. Emerging themes from the focus groups and survey indicate a desire for appropriate risk contextualization and specific examples when pharmacogenetic testing may be beneficial. Focus group participants also expressed a preference for a video with live action, and more text to reinforce concepts. Pharmacists generally felt that the video was understandable for patients and relevant for decision-making regarding testing. Using this initial feedback and the identification of important concepts to include in pharmacogenetics educational tools, we plan to revise the video, perform additional evaluations, and publish the video for public use in the future.

PMID: 28587070 [PubMed - in process]

Influence of vitamin D and transforming growth factor β3 serum concentrations, obesity, and family history on the risk for uterine fibroids.

Fertil Steril. 2016 Dec;106(7):1787-1792

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

Abstract
OBJECTIVE: To evaluate the influence of 25-hydroxyvitamin D and transforming growth factor β3 (TGF-β3) serum concentrations, weight, and family history on the risk of developing uterine fibroids.
DESIGN: Retrospective cohort study.
SETTING: University hospital.
PATIENT(S): A total of 188 women, including patients admitted for uterine fibroid surgery (n = 105) as the study group and healthy women of similar age (n = 83) as controls.
INTERVENTION(S): Medical history and completion of specially designed questionnaire, transvaginal or transabdominal genital ultrasound scan, blood sampling, and measurement of vitamin D and TGF-β3 serum concentrations.
MAIN OUTCOME MEASURE(S): Evaluation of the impact of family history, vitamin D, and TGF-β3 serum concentrations on the risk of developing uterine fibroids.
RESULT(S): Mean 25-hydroxyvitamin D serum concentrations were 21.9 ± 8.9 ng/mL and 26.7 ± 11.9 ng/mL in patients with uterine fibroids and controls, respectively. The difference was statistically significant. The TGF-β3 serum concentrations in the fibroid-positive group ranged from 1.20 to 436.15 pg/mL (half the patients had concentrations >16.25 pg/mL). Concentrations in the control group ranged from 0.96 to 49.08 pg/mL (half the women had concentrations of >11.80 pg/mL). The differences were statistically significant. Higher body mass index (BMI) and positive family history were also found to be among the risk factors for uterine fibroids.
CONCLUSION(S): Our study confirmed higher BMI, positive family history, and lower vitamin D and higher TGF-β3 serum concentrations as risk factors for uterine fibroids.

PMID: 27743697 [PubMed - indexed for MEDLINE]

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins update.

Pediatr Pulmonol. 2017 Jun 07;:

Authors: Zobell JT, Epps KL, Young DC

PMID: 28590594 [PubMed - as supplied by publisher]

Exercise Testing, Supplemental Oxygen and Hypoxia.

Ann Am Thorac Soc. 2017 Jun 07;:

Authors: Ward SA, Grocott MP, Levett DZ

Abstract
Cardiopulmonary exercise testing (CPET) in hyperoxia and hypoxia has several applications, stemming from characterization of abnormal physiological response profiles associated with exercise intolerance. As altered oxygenation can impact on the performance of gas-concentration and flow sensors and pulmonary gas exchange algorithms, integrated CPET system function requires validation under these conditions. Also, as oxygenation status can influence peak O2 uptake, care should be taken in the selection of work-rate incrementation rates when CPET performance is to be compared with sea-level. CPET has been used to evaluate the effects of supplemental O2 on exercise intolerance in chronic obstructive pulmonary disease, interstitial pulmonary fibrosis and cystic fibrosis at sea-level. However, identification of those CPET indices likely to be predictive of supplemental O2 outcomes for exercise tolerance at altitude in such patients is lacking. CPET performance with supplemental O2 in respiratory patients residing at high altitudes is poorly studied. Finally, CPET has the potential to give physiological and clinical information about acute and chronic mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. It can translate high-altitude acclimatization and adaptive processes in healthy individuals into intensive care medical practice.

PMID: 28590162 [PubMed - as supplied by publisher]

Challenges in Laboratory Detection of Fungal Pathogens in the Airways of Cystic Fibrosis Patients.

Mycopathologia. 2017 Jun 06;:

Authors: Chen SC, Meyer W, Pashley CH

Abstract
Study of the clinical significance of fungal colonization/infection in the airways of cystic fibrosis (CF) patients, especially by filamentous fungi, is challenged by the absence of standardized methodology for the detection and identification of an ever-broadening range of fungal pathogens. Culture-based methods remain the cornerstone diagnostic approaches, but current methods used in many clinical laboratories are insensitive and unstandardized, rendering comparative studies unfeasible. Guidelines for standardized processing of respiratory specimens and for their culture are urgently needed and should include recommendations for specific processing procedures, inoculum density, culture media, incubation temperature and duration of culture. Molecular techniques to detect fungi directly from clinical specimens include panfungal PCR assays, multiplex or pathogen-directed assays, real-time PCR, isothermal methods and probe-based assays. In general, these are used to complement culture. Fungal identification by DNA sequencing methods is often required to identify cultured isolates, but matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is increasingly used as an alternative to DNA sequencing. Genotyping of isolates is undertaken to investigate relatedness between isolates, to pinpoint the infection source and to study the population structure. Methods range from PCR fingerprinting and amplified fragment length polymorphism analysis, to short tandem repeat typing, multilocus sequencing typing (MLST) and whole genome sequencing (WGS). MLST is the current preferred method, whilst WGS offers best case resolution but currently is understudied.

PMID: 28589247 [PubMed - as supplied by publisher]

Identification of novel BCL11A variants in patients with epileptic encephalopathy: expanding the phenotypic spectrum.

Clin Genet. 2017 Jun 06;:

Authors: Yoshida M, Nakashima M, Okanishi T, Kanai S, Fujimoto A, Itomi K, Morimoto M, Saitsu H, Kato M, Matsumoto N, Chiyonobu T

Abstract
BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified two novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both patients shared major physical features characteristic of BCL11A-related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox-Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, with a p.Lys784Thr variant, presented with West syndrome followed by drug-resistant focal seizures and more severe developmental disability. These two newly described patients contribute to delineating the associated, yet uncertain phenotypic characteristics of BCL11A disease-causing variants.

PMID: 28589569 [PubMed - as supplied by publisher]

Distinguishing pathogenic mutations from background genetic noise in cardiology: the use of large genome databases for genetic interpretation.

Clin Genet. 2017 Jun 06;:

Authors: Ghouse J, Skov MW, Bigseth RS, Ahlberg G, Kanters JK, Olesen MS

Abstract
Advances in clinical genetic testing has led to increased insight into the human genome, including how challenging it is to interpret rare genetic variation. In some cases, the ability to detect genetic mutations exceeds the ability to understand their clinical impact, limiting the advantage of these technologies. Obstacles in genomic medicine are many and include: understanding the level of certainty/uncertainty behind pathogenicity determination, the numerous different variant interpretation-guidelines used by clinical laboratories, delivering the certain or uncertain result to the patient, helping patients evaluate medical decisions in light of uncertainty regarding the consequence of the findings. Through publication of large publicly available exome/genome databases, researchers and physicians are now able to highlight dubious variants previously associated with different cardiac traits. Also, continuous efforts through data sharing, international collaborative efforts to develop disease-gene specific guidelines, and computational analyses using large data, will indubitably assist in better variant interpretation and classification. This paper discusses the current, and quickly changing, state of variant interpretation resources within cardiovascular genetic research, i.e. publicly available databases and ways of how cardiovascular genetic counsellors and geneticists can aid in improving variant interpretation in cardiology.

PMID: 28589536 [PubMed - as supplied by publisher]

Syndrome of progressive bone marrow failure and pancreatic insufficiency remains cryptic despite whole exome sequencing: variant of Shwachman-Diamond syndrome or new condition?

Clin Case Rep. 2017 Jun;5(6):748-752

Authors: Fadus MC, Rush ET, Lettieri CK

Abstract
This case underscores the difficulty in diagnosis of bone marrow failure disorders, as the presentation of disease can be inconsistent, complicated by complex and ever-expanding genetic etiologies. A patient who presents with bone marrow failure and pancreatic insufficiency raises the question of Shwachman-Diamond syndrome (SDS) or a new condition which resembles SDS.

PMID: 28588803 [PubMed - in process]