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

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/02/27

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.

58 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 2018/02/27

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.

28 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 2018/02/27

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 Computational Workflow Translates a 58-Gene Signature to a Formalin-Fixed, Paraffin-Embedded Sample-Based Companion Diagnostic for Personalized Treatment of the BRAF-Mutation-Like Subtype of Colorectal Cancers.

High Throughput. 2017 Nov 06;6(4):

Authors: In 't Veld SGJG, Duong KN, Snel M, Witteveen A, Beumer IJ, Delahaye LJMJ, Wehkamp D, Bernards R, Glas AM, Tian S

Abstract
Colorectal cancer patients with the BRAF(p.V600E) mutation have poor prognosis in metastatic setting. Personalized treatment options and companion diagnostics are needed to better treat these patients. Previously, we developed a 58-gene signature to characterize the distinct gene expression pattern of BRAF-mutation-like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this BRAF-mutation-like subtype. The aim of this study is to translate this 58-gene signature from a research setting to a robust companion diagnostic that can use formalin-fixed, paraffin-embedded (FFPE) samples to select patients with the BRAF-mutation-like subtype. BRAF mutation and gene expression data of 302 FFPE samples were measured (mutants = 57, wild-type = 245). The performance of the 58-gene signature in FFPE samples showed a high sensitivity of 89.5%. In the identified BRAF-mutation-like subtype group, 50% of tumours were known BRAF mutants, and 50% were BRAF wild-type. The stability of the 58-gene signature in FFPE samples was evaluated by two control samples over 40 independent experiments. The standard deviations (SD) were within the predefined criteria (control 1: SD = 0.091, SD/Range = 3.0%; control 2: SD = 0.169, SD/Range = 5.5%). The fresh frozen version and translated FFPE version of this 58-gene signature were compared using 170 paired fresh frozen and FFPE samples and the result showed high consistency (agreement = 99.3%). In conclusion, we translated this 58-gene signature to a robust companion diagnostic that can use FFPE samples.

PMID: 29479053 [PubMed]

Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS.

Cancer Cell. 2018 Feb 08;:

Authors: Yamauchi T, Masuda T, Canver MC, Seiler M, Semba Y, Shboul M, Al-Raqad M, Maeda M, Schoonenberg VAC, Cole MA, Macias-Trevino C, Ishikawa Y, Yao Q, Nakano M, Arai F, Orkin SH, Reversade B, Buonamici S, Pinello L, Akashi K, Bauer DE, Maeda T

Abstract
To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy.

PMID: 29478914 [PubMed - as supplied by publisher]

Related Articles

Communication strategies employed by rare disease patient organizations in Spain.

Cien Saude Colet. 2016 Aug;21(8):2423-36

Authors: Castillo-Esparcia A, López-Villafranca P

Abstract
The current study focuses on communication strategies employed by rare disease patient organizations. The aims of these organizations are: educate and inform the public about rare diseases, raise awareness of the problems related to rare diseases, and achieve social legitimacy in order give visibility to their demands. We analyzed the portrayal of rare disease and patient organizations by Spain's major media organizations in terms of circulation and viewership - the press (El País, El Mundo, La Vanguardia,ABC and El Periódico), radio (CadenaSer, Onda Cero, Cope and RNE), and television (Telecinco, Antena 3, La 1, La Sexta, Cuatro) -between 2012 and 2014.We then carried out a descriptive analysis of communication activities performed via the World Wide Web and social networks by 143 national organizations. Finally, we conducted a telephone questionnaire of a representative sample of 90 organizations in order to explore the association between media presence and funding and public image. The triangulation of quantitative and qualitative methods allowed us to meet the study's objectives. Increased visibility of the organizations afforded by an increase in the coverage of the topic by the medialed to an increase in membership - but not in donations - and increased awareness of these diseases.

PMID: 27557016 [PubMed - indexed for MEDLINE]

Related Articles

HPCA-related dystonia: Too rare to be found?

Mov Disord. 2016 07;31(7):1071

Authors: Dobričić V, Kresojević N, Marjanović A, Tomić A, Svetel M, Novaković I, Kostić VS

PMID: 27145302 [PubMed - indexed for MEDLINE]

PhLeGrA: Graph Analytics in Pharmacology over the Web of Life Sciences Linked Open Data.

Proc Int World Wide Web Conf. 2017 Apr;2017:321-329

Authors: Kamdar MR, Musen MA

Abstract
Integrated approaches for pharmacology are required for the mechanism-based predictions of adverse drug reactions that manifest due to concomitant intake of multiple drugs. These approaches require the integration and analysis of biomedical data and knowledge from multiple, heterogeneous sources with varying schemas, entity notations, and formats. To tackle these integrative challenges, the Semantic Web community has published and linked several datasets in the Life Sciences Linked Open Data (LSLOD) cloud using established W3C standards. We present the PhLeGrA platform for Linked Graph Analytics in Pharmacology in this paper. Through query federation, we integrate four sources from the LSLOD cloud and extract a drug-reaction network, composed of distinct entities. We represent this graph as a hidden conditional random field (HCRF), a discriminative latent variable model that is used for structured output predictions. We calculate the underlying probability distributions in the drug-reaction HCRF using the datasets from the U.S. Food and Drug Administration's Adverse Event Reporting System. We predict the occurrence of 146 adverse reactions due to multiple drug intake with an AUROC statistic greater than 0.75. The PhLeGrA platform can be extended to incorporate other sources published using Semantic Web technologies, as well as to discover other types of pharmacological associations.

PMID: 29479581 [PubMed]

Related Articles

Tutorial on Protein Ontology Resources.

Methods Mol Biol. 2017;1558:57-78

Authors: Arighi CN, Drabkin H, Christie KR, Ross KE, Natale DA

Abstract
The Protein Ontology (PRO) is the reference ontology for proteins in the Open Biomedical Ontologies (OBO) foundry and consists of three sub-ontologies representing protein classes of homologous genes, proteoforms (e.g., splice isoforms, sequence variants, and post-translationally modified forms), and protein complexes. PRO defines classes of proteins and protein complexes, both species-specific and species nonspecific, and indicates their relationships in a hierarchical framework, supporting accurate protein annotation at the appropriate level of granularity, analyses of protein conservation across species, and semantic reasoning. In the first section of this chapter, we describe the PRO framework including categories of PRO terms and the relationship of PRO to other ontologies and protein resources. Next, we provide a tutorial about the PRO website ( proconsortium.org ) where users can browse and search the PRO hierarchy, view reports on individual PRO terms, and visualize relationships among PRO terms in a hierarchical table view, a multiple sequence alignment view, and a Cytoscape network view. Finally, we describe several examples illustrating the unique and rich information available in PRO.

PMID: 28150233 [PubMed - indexed for MEDLINE]

Downregulation of the Cl-/HCO3-Exchanger Pendrin in Kidneys of Mice with Cystic Fibrosis: Role in the Pathogenesis of Metabolic Alkalosis.

Cell Physiol Biochem. 2018 Feb 21;45(4):1551-1565

Authors: Varasteh Kia M, Barone S, McDonough AA, Zahedi K, Xu J, Soleimani M

Abstract
BACKGROUND/AIMS: Patients with cystic fibrosis (CF) are prone to the development of metabolic alkalosis; however, the pathogenesis of this life threatening derangement remains unknown. We hypothesized that altered acid base transport machinery in the kidney collecting duct underlies the mechanism of impaired bicarbonate elimination in the CF kidney.
METHODS: Balance studies in metabolic cages were performed in WT and CFTR knockout (CF) mice with the intestinal rescue in response to bicarbonate loading or salt restriction, and the expression levels and cellular distribution of acid base and electrolyte transporters in the proximal tubule, collecting duct and small intestine were examined by western blots, northern blots and/or immunofluorescence labeling.
RESULTS: Baseline parameters, including acid-base and systemic vascular volume status were comparable in WT and CF mice, as determined by blood gas, kidney renin expression and urine chloride excretion. Compared with WT animals, CF mice demonstrated a significantly higher serum HCO3- concentration (22.63 in WT vs. 26.83 mEq/l in CF mice; n=4, p=0.013) and serum pH (7.33 in WT vs. 7.42 in CF mice; n=4, p=0.00792) and exhibited impaired kidney HCO3- excretion (urine pH 8.10 in WT vs. 7.35 in CF mice; n=7, p=0.00990) following a 3-day oral bicarbonate load. When subjected to salt restriction, CF mice developed a significantly higher serum HCO3- concentration vs. WT animals (29.26 mEq/L in CF mice vs. 26.72 in WT; n=5, p=0.0291). Immunofluorescence labeling demonstrated a profound reduction in the apical expression of the Cl-/HCO3- exchanger pendrin in cortical collecting duct cells and western and northern blots indicated diminished plasma membrane abundance and mRNA expression of pendrin in CF kidneys.
CONCLUSIONS: We propose that patients with cystic fibrosis are prone to the development of metabolic alkalosis secondary to the inactivation of the bicarbonate secreting transporter pendrin, specifically during volume depletion, which is a common occurrence in CF patients.

PMID: 29482189 [PubMed - as supplied by publisher]

Chronic E-cigarette Exposure Alters the Human Bronchial Epithelial Proteome.

Am J Respir Crit Care Med. 2018 Feb 26;:

Authors: Ghosh A, Coakley RC, Mascenik T, Rowell TR, Davis ES, Rogers K, Webster MJ, Dang H, Herring LE, Sassano MF, Livraghi-Butrico A, Van Buren SK, Graves LM, Herman MA, Randell SH, Alexis NE, Tarran R

Abstract
RATIONAL: E-cigarettes vaporize propylene glycol/vegetable glycerin (PG/VG), nicotine and flavorings. However, the long-term health effects of exposing lungs to vaped e-liquids are unknown.
OBJECTIVES: To determine the effects of chronic vaping on pulmonary epithelia.
METHODS: We performed research bronchoscopies on healthy non-smokers, cigarette smokers and e-cigarettes users (vapers) and obtained bronchial brush biopsies and lavage samples from these subjects for proteomic investigation. We further employed in vitro and murine exposure models to support our human findings.
MEASUREMENTS AND MAIN RESULTS: Visual inspection by bronchoscopy revealed that vaper's airways appeared friable and erythematous. Epithelial cells from biopsy samples revealed ~300 proteins that were differentially expressed in smokers and vaper's airways, with only 78 proteins being commonly altered in both groups and 113 uniquely altered in vapers. For example, CYP1B1, MUC5AC and MUC4 levels were increased in vapers. Aerosolized PG/VG alone significantly increased MUC5AC protein in human airway epithelial cultures and in murine nasal epithelia in vivo. We also found that e-liquids rapidly entered cells and that PG/VG reduced membrane fluidity and impaired protein diffusion.
CONCLUSIONS: We conclude that chronic vaping exerts marked biological effects on the lung and that these effects may in part be mediated by the PG/VG base. These changes are likely not harmless and may have clinical implications for the development of chronic lung disease. Further studies will be required to determine the full extent of vaping on the lung.

PMID: 29481290 [PubMed - as supplied by publisher]

Impact of T2R38 Receptor Polymorphisms on Pseudomonas aeruginosa Infection in Cystic Fibrosis.

Am J Respir Crit Care Med. 2018 Feb 26;:

Authors: Turnbull AR, Murphy R, Behrends V, Lund-Palau H, Simbo A, Mariveles M, Alton EW, Bush A, Shoemark A, Davies JC

PMID: 29481289 [PubMed - as supplied by publisher]

Safety and Efficacy of Repeat Embolization for Recurrent Hemoptysis: A 16-Year Retrospective Study Including 223 Patients.

J Vasc Interv Radiol. 2018 Feb 22;:

Authors: Maleux G, Matton T, Laenen A, Bonne L, Cornelissen S, Dupont L

Abstract
PURPOSE: To assess safety, efficacy, and long-term outcome of repeat bronchial artery embolization (BAE) for recurrent hemoptysis.
MATERIALS AND METHODS: This was a retrospective study of patients referred for repeat BAE to manage recurrent hemoptysis after initial successful embolization. BAE was performed in 223 patients; 36 (16.1%) of these patients underwent 59 repeat BAE procedures because of recurring symptoms. The most frequent underlying lung diseases were bronchiectasis (n = 8; 22%), cystic fibrosis (n = 7; 19%), and idiopathic hemoptysis (n = 7; 19%).
RESULTS: Most patients (64%) underwent 2 embolization procedures owing to vessel recanalization (71%) as the most frequent pathophysiologic mechanism of recurrent hemoptysis. No serious adverse events requiring prolonged hospital stay were noted. Risk for relapse of hemoptysis was significantly lower for bronchiectasis compared with other chronic infections (P = .0022) and cystic fibrosis (P = .0004). Overall survival after 3-year and 5-year follow-up was 92% and 84%, respectively.
CONCLUSIONS: Repeat BAE for recurrent hemoptysis after initial successful BAE is safe and efficacious, especially in patients with bronchiectasis as the underlying lung disease.

PMID: 29477622 [PubMed - as supplied by publisher]

Related Articles

Why women do not ask for information on preconception health? A qualitative study.

BMC Pregnancy Childbirth. 2017 Jan 05;17(1):5

Authors: Bortolus R, Oprandi NC, Rech Morassutti F, Marchetto L, Filippini F, Agricola E, Tozzi AE, Castellani C, Lalatta F, Rusticali B, Mastroiacovo P

Abstract
BACKGROUND: Preconception care involves health promotion to reduce risk factors that might affect women and couples of childbearing age. The risk factors of adverse reproductive outcomes include recognized genetic diseases in the family or the individual, previous congenital diseases, miscarriage, prematurity, fetal growth restriction, infertility, chronic maternal diseases, lifestyle, and occupational or environmental factors. Effective preconception care involves a range of preventive, therapeutic and behavioural interventions. Although in Italy there are national preconception care recommendations concerning the general population, they are usually encouraged informally and only for single risk factors. At present there is increasing interest in offering a global intervention in this field. The aim of this study was to investigate attitudes and behaviours of Italian women of childbearing age and healthcare professionals regarding preconception health.
METHODS: We conducted a qualitative study among women of childbearing age and healthcare professionals between February 2014 and February 2015. Five focus groups were held: 2 with non-pregnant women aged 22 to 44 years and 3 with healthcare professionals. Discussion topics included women's questions about preconception health, worries and barriers regarding preconception care interventions, attitudes and behaviours of women and healthcare professionals towards preconception health, women's information sources. In the analysis of the focus groups priority was given to what was said by the women, supplemented by information from the healthcare professionals' focus groups.
RESULTS: Fourteen women of childbearing age (8 nulliparae and 6 multiparae) and 12 healthcare professionals (3 nurses, 4 midwives, 5 doctors) participated in the focus groups. The results indicate the presence of many barriers and a lack of awareness of preconception health relating to women, healthcare professionals and policies. Women's knowledge and attitudes towards primary preconception care information are described. The main reference source of information in this field for Italian women seems to be their obstetric-gynaecologist.
CONCLUSIONS: The study indicates that several barriers influence preconception care in Italy. Moreover, a lack of awareness of preconception health and care among Italian women of childbearing age and healthcare professionals emerges. The findings might contribute to strategies for the implementation of preconception care guidelines.

PMID: 28056865 [PubMed - indexed for MEDLINE]

Funding Opportunity PAR-18-681 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to encourage projects to generate fundamental knowledge of affective processes. Basic affective science projects should have key consequences for single (e.g., cancer screening) and multiple (e.g., adherence to oral chemotherapy regimen) event decisions and behaviors across the cancer prevention and control continuum. The FOA is expected to encourage collaboration among cancer control researchers and those from scientific disciplines not traditionally connected to cancer control applications (e.g., affective and cognitive neuroscience, decision science, consumer science) to elucidate perplexing and understudied problems in affective and decision sciences with downstream implications for cancer prevention and control.

Funding Opportunity PA-18-682 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages Small Business Technology Transfer (STTR) grant applications from small business concerns (SBCs) to address highly innovative methods and technologies that significantly advance the field of natural products.

16 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 2018/02/25

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.

Vitamin D receptor (VDR) non-synonymous single nucleotide polymorphisms (nsSNPs) affect the calcitriol drug response - A theoretical insight.

J Mol Graph Model. 2018 Feb 12;81:14-24

Authors: Muthusamy K, Nagamani S

Abstract
Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 Å3 in wild type Vs. 738.8 in Leu230Val, 820.7 Å3 in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), -105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies.

PMID: 29476931 [PubMed - as supplied by publisher]

Phosphorylation of AKT and ERK1/2 and mutations of PIK3CA and PTEN are predictive of breast cancer cell sensitivity to everolimus in vitro.

Cancer Chemother Pharmacol. 2018 Feb 23;:

Authors: Citi V, Del Re M, Martelli A, Calderone V, Breschi MC, Danesi R

Abstract
BACKGROUND: Everolimus is the hydroxyethyl derivative of sirolimus and a strong inhibitor of mammalian target of rapamycin (mTOR). This drug has immunosuppressive and anticancer activities and the present in vitro study was aimed at identifying the cellular and molecular profiles of breast cancer cells predictive of sensitivity to everolimus.
MATERIALS AND METHODS: MCF-7, T-47D, ZR-75-1, CAMA-1, HCC-1500 and MCF-10A cells were used and viability was assessed using WST-1 dye. Sensitivity to everolimus was correlated with phosphorylation of AKT (Ser473/Thr308), mTOR (Ser2448), and ERK1/2 (Thr202/Tyr204) and mutational profile of KRAS, NRAS, BRAF, PIK3CA, PTEN, TSC1, TSC2 and FRAP genes. Protein phosphorylation was evaluated by AlphaScreen SureFire, while the mutational status was examined by digital droplet PCR and Sanger sequencing.
RESULTS: Everolimus showed a transient growth inhibition in non-tumorigenic cells, while in tumorigenic lines the drug suppressed the proliferation in a concentration-dependent manner but with different potency (IC50) and efficacy (Emax), being ZR-75-1 the most sensitive and T47D the least sensitive. MCF-7, T47D and HCC1500 had activating mutations in PIK3CA gene, while loss-of-activity PTEN mutations were detected in sensitive cell lines, including ZR-75-1, which showed no changes or minimal increase in the amount of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204) induced by everolimus compared to the resistant cell line T47D in which phosphorylation of AKT and ERK was increased.
CONCLUSIONS: Cellular levels of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204), activating mutations of PIK3CA and inactivating mutations of PTEN may predict response to everolimus in breast cancer cells; these findings have potential applications for treatment personalization of everolimus in breast cancer patients.

PMID: 29476223 [PubMed - as supplied by publisher]

Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore.

J Biol Chem. 2018 Feb 23;:

Authors: Li MS, Cowley EA, El Hiani Y, Linsdell P

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that apparently has evolved from an ancestral active transporter. Key to CFTR's switch from pump to channel function may have been the appearance of one or more "lateral portals". Such portals connect the cytoplasm to the transmembrane channel pore, allowing a continuous pathway for the electro-diffusional movement of Cl- ions. However, these portals remain the least well-characterized part of the Cl- transport pathway; even the number of functional portals is uncertain, and if multiple portals do exist, their relative functional contributions are unknown. Here, we used patch-clamp recording to identify the contributions of positively charged amino acid side-chains located in CFTR's cytoplasmic transmembrane extensions to portal function. Mutagenesis-mediated neutralization of several charged side-chains reduced single-channel Cl- conductance. However, these same mutations differentially affected channel blockade by cytoplasmic suramin and Pt(NO2)42- anions. We considered and tested several models by which the contribution of these positively charged side-chains to one or more independent or non-independent portals to the pore could affect Cl- conductance and interactions with blockers. Overall, our results suggest the existence of a single portal that is lined by several positively charged side-chains that interact electrostatically with both Cl- and blocking anions. We further propose that mutations at other sites indirectly alter the function of this single portal. Comparison of our functional results with recent structural information on CFTR completes our picture of the overall molecular architecture of the Cl- permeation pathway.

PMID: 29475947 [PubMed - as supplied by publisher]