Development of the Virtual Physical Assessment Learning Material That Allows the Learners to Check Drug Efficacy and Early Detection of Adverse Effects through Virtual Experience.

Yakugaku Zasshi. 2016;136(10):1439-1444

Authors: Tokunaga J, Takamura N, Kourogi Y, Imada M, Kozasa A, Komori K, Ono C, Nishimura A, Ogata K, Setoguchi N, Matsuoka T, Kai M, Sato K, Arimori K

Abstract
 We utilized the information and communication technology to develop the physical assessment (PA) learning materials in the virtual experience type. This learning material consists of two parts which include case learning and basic learning. We created example scenarios about various conditions that a pharmacist may experience in medical scenes such as in a hospital ward, community pharmacy, home, and drugstore. Illustrations of a virtual patient's avatar before and after taking the medicines were incorporated in the learning materials. The virtual training includes a stethoscope that was used in examining sounds (heart, pulmonary and bowel sounds) that served as evidences in the confirmation of drug efficacy and its possible adverse effects. In addition, we included the images of each body part, the 24 format question items, the palpation (rate and rhythm) of the radial artery, brachial artery and pedal artery, the clinical data obtained from several medical equipment, the pupillary reflex, and the urine dipstick test. This way, learners are able to experience PA with reference to the subjective and objective data from patient reception and questions. The virtual patient's avatar displayed on the monitor features auscultatory sounds on the stethoscope. It also features clinical data obtained from other medical equipment that can give the learners an interactive way of learning about various medical conditions. For evaluation, we gave out questionnaires on the virtual PA to pharmacy students. As a result, a high evaluation was reflected in terms of the degree of usefulness for both case learning and basic learning.

PMID: 27725393 [PubMed - indexed for MEDLINE]

Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective.

BMJ. 2016 Oct 03;355:i5078

Authors: Lineberry N, Berlin JA, Mansi B, Glasser S, Berkwits M, Klem C, Bhattacharya A, Citrome L, Enck R, Fletcher J, Haller D, Chen TT, Laine C

PMID: 27697753 [PubMed - indexed for MEDLINE]

History repeats itself: the family medication history and pharmacogenomics.

Pharmacogenomics. 2016 05;17(7):669-78

Authors: Smith TR, Kearney E, Hulick PJ, Kisor DF

Abstract
Related to many drug gene-product interactions, application of pharmacogenomics can lead to improved medication efficacy while decreasing or avoiding adverse drug reactions. However, utilizing pharmacogenomics without other information does not allow for optimal medication therapy. Currently, there is a lack of documentation of family medication history, in other words, inefficacy and adverse reactions across family members throughout generations. The family medication history can serve as an impetus for pharmacogenomic testing to explain lack of medication efficacy or an adverse drug reaction and pre-emptive testing can drive recognition and documentation of medication response in family members. We propose combining the family medication history via pedigree construction with pharmacogenomics to further optimize medication therapy. We encourage clinicians to combine family medication history with pharmacogenomics.

PMID: 27143300 [PubMed - indexed for MEDLINE]

Activation of the NRF2-ARE signalling pathway by the Lentinula edodes polysaccharose LNT alleviates ROS-mediated cisplatin nephrotoxicity.

Int Immunopharmacol. 2016 Jul;36:1-8

Authors: Chen Q, Peng H, Dong L, Chen L, Ma X, Peng Y, Dai S, Liu Q

Abstract
The nephrotoxicity of cisplatin (cis-DDP) limits its general clinical applications. Lentinan (LNT), a dextran extracted from the mushroom Lentinula edodes, has been shown to have multiple pharmacological activities. The primary objective of the current study was to determine whether and how LNT alleviates cis-DDP- induced cytotoxicity in HK-2 cells and nephrotoxicity in mice. LNT did not interfere with cisplatin's anti-tumour efficacy in vitro and functioned cooperatively with cis-DDP to inhibit activity in HeLa and A549 tumour cells. LNT alleviated the cis-DDP-induced decrease in HK-2 cell viability, caspase-3 activation and cleavage of the DNA repair enzyme PARP, decreased HK-2 cell apoptosis and inhibited reactive oxygen species (ROS) accumulation in HK-2 cells. The inhibitor of ROS (N-acetyl-L-cysteine, NAC) could decreased the apoptosis of HK-2 cell. In addition, LNT significantly prevented cis-DDP-induced kidney injury in vivo. LNT itself could not eliminate ROS levels in vitro. Further studies demonstrated that LNT induced NF-E2 p45-related factor 2 (Nrf2) protein and mRNA expression in a time- and dose-dependent manner. LNT promoted Nrf2 translocation to the nucleus and binding to the antioxidant-response element (ARE) sequence and induced the transcription and translation of heme oxygenase 1 (HO-1), aldo-keto reductases 1C1 and 1C2 (AKR1C), and NADP(H):quinone oxidoreductase 1 (NQO1). Finally, we used hNrf2 siRNA and an Nrf2 agonist (tBHQ) to inhibit or enhance Nrf2 expression. The results demonstrated that the LNT-mediated alleviation of cis-DDP-induced nephrotoxicity was achieved by preventing the accumulation of ROS in a manner that depended on the activation of the Nrf2-ARE signalling pathway.

PMID: 27093515 [PubMed - indexed for MEDLINE]

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"systems biology"

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Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.

Cell. 2017 Mar 23;169(1):6-12

Authors: Manolio TA, Fowler DM, Starita LM, Haendel MA, MacArthur DG, Biesecker LG, Worthey E, Chisholm RL, Green ED, Jacob HJ, McLeod HL, Roden D, Rodriguez LL, Williams MS, Cooper GM, Cox NJ, Herman GE, Kingsmore S, Lo C, Lutz C, MacRae CA, Nussbaum RL, Ordovas JM, Ramos EM, Robinson PN, Rubinstein WS, Seidman C, Stranger BE, Wang H, Westerfield M, Bult C

Abstract
Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.

PMID: 28340351 [PubMed - in process]

[Not Available].

Rofo. 2016 Jul;188(7):687-9

Authors: Kunz WG, Paprottka PM, Reichelt A

PMID: 27355634 [PubMed - indexed for MEDLINE]

[Not Available].

Rofo. 2016 Jul;188(7):684-5

Authors: Peters S, Cohrs G, Larsen N

PMID: 27355632 [PubMed - indexed for MEDLINE]

Exploring Approaches for Detecting Protein Functional Similarity within an Orthology-based Framework.

Sci Rep. 2017 Mar 23;7(1):381

Authors: Weichenberger CX, Palermo A, Pramstaller PP, Domingues FS

Abstract
Protein functional similarity based on gene ontology (GO) annotations serves as a powerful tool when comparing proteins on a functional level in applications such as protein-protein interaction prediction, gene prioritization, and disease gene discovery. Functional similarity (FS) is usually quantified by combining the GO hierarchy with an annotation corpus that links genes and gene products to GO terms. One large group of algorithms involves calculation of GO term semantic similarity (SS) between all the terms annotating the two proteins, followed by a second step, described as "mixing strategy", which involves combining the SS values to yield the final FS value. Due to the variability of protein annotation caused e.g. by annotation bias, this value cannot be reliably compared on an absolute scale. We therefore introduce a similarity z-score that takes into account the FS background distribution of each protein. For a selection of popular SS measures and mixing strategies we demonstrate moderate accuracy improvement when using z-scores in a benchmark that aims to separate orthologous cases from random gene pairs and discuss in this context the impact of annotation corpus choice. The approach has been implemented in Frela, a fast high-throughput public web server for protein FS calculation and interpretation.

PMID: 28336965 [PubMed - in process]

A Novel Semantic Representation for Eligibility Criteria in Clinical Trials.

J Biomed Inform. 2017 Mar 21;:

Authors: Chondrogiannis E, Andronikou V, Tagaris A, Karanastasis E, Varvarigou T, Tsuji M

Abstract
Eligibility Criteria (EC) comprise an important part of a clinical study, being determinant of its cost, duration and overall success. Their formal, computer-processable description can significantly improve clinical trial design and conduction by enabling their intelligent processing, replicability and linkability with other data. For EC representation purposes, related standards were investigated, along with published literature. Moreover, a considerable number of clinicaltrials.gov studies was analyzed in collaboration with clinical experts for the determination and classification of parameters of clinical research importance. The outcome of this process was the EC Representation; a CDISC-compliant schema for organizing criteria along with a patient-centric model for their formal expression, properly linked with international classifications and codifications. Its evaluation against 200 randomly selected EC indicated that it can adequately serve its purpose, while it can be also combined with existing tools and components developed for both EC specification and especially application to Electronic Health Records.

PMID: 28336477 [PubMed - as supplied by publisher]

On the Prediction of Flickr Image Popularity by Analyzing Heterogeneous Social Sensory Data.

Sensors (Basel). 2017 Mar 19;17(3):

Authors: Aloufi S, Zhu S, El Saddik A

Abstract
The increase in the popularity of social media has shattered the gap between the physical and virtual worlds. The content generated by people or social sensors on social media provides information about users and their living surroundings, which allows us to access a user's preferences, opinions, and interactions. This provides an opportunity for us to understand human behavior and enhance the services provided for both the real and virtual worlds. In this paper, we will focus on the popularity prediction of social images on Flickr, a popular social photo-sharing site, and promote the research on utilizing social sensory data in the context of assisting people to improve their life on the Web. Social data are different from the data collected from physical sensors; in the fact that they exhibit special characteristics that pose new challenges. In addition to their huge quantity, social data are noisy, unstructured, and heterogeneous. Moreover, they involve human semantics and contextual data that require analysis and interpretation based on human behavior. Accordingly, we address the problem of popularity prediction for an image by exploiting three main factors that are important for making an image popular. In particular, we investigate the impact of the image's visual content, where the semantic and sentiment information extracted from the image show an impact on its popularity, as well as the textual information associated with the image, which has a fundamental role in boosting the visibility of the image in the keyword search results. Additionally, we explore social context, such as an image owner's popularity and how it positively influences the image popularity. With a comprehensive study on the effect of the three aspects, we further propose to jointly consider the heterogeneous social sensory data. Experimental results obtained from real-world data demonstrate that the three factors utilized complement each other in obtaining promising results in the prediction of image popularity on social photo-sharing site.

PMID: 28335498 [PubMed - in process]

Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl.

Pain Med. 2017 Feb 24;:

Authors: Lloyd RA, Hotham E, Hall C, Williams M, Suppiah V

Abstract
Objective. : Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl.
Method. : A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms.
Results. : Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1 , OPRM1 , and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects.
Conclusions. : Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations.

PMID: 28339912 [PubMed - as supplied by publisher]

Design and evaluation of a pharmacogenomics information resource for pharmacists.

J Am Med Inform Assoc. 2017 Feb 26;:

Authors: Romagnoli KM, Boyce RD, Empey PE, Ning Y, Adams S, Hochheiser H

Abstract
Objective: To develop and evaluate a pharmacogenomics information resource for pharmacists.
Materials and Methods: We built a pharmacogenomics information resource presenting Food and Drug Administration (FDA) drug product labelling information, refined it based on feedback from pharmacists, and conducted a comparative usability evaluation, measuring task completion time, task correctness and perceived usability. Tasks involved hypothetical clinical situations requiring interpretation of pharmacogenomics information to determine optimal prescribing for specific patients.
Results: Pharmacists were better able to perform certain tasks using the redesigned resource relative to the Pharmacogenomic Knowledgebase (PharmGKB) and the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling. On average, participants completed tasks in 107.5 s using our resource, compared to 188.9 s using PharmGKB and 240.2 s using the FDA table. Using the System Usability Scale, participants rated our resource 79.62 on average, compared to 53.27 for PharmGKB and 50.77 for the FDA table. Participants found the correct answers for 100% of tasks using our resource, compared to 76.9% using PharmGKB and 69.2% using the FDA table.
Discussion: We present structured, clinically relevant pharmacogenomic FDA drug product label information with visualizations to help explain the relationships between gene variants, drugs, and phenotypes. The results from our evaluation suggest that user-centered interfaces for pharmacogenomics information can increase ease of access and comprehension.
Conclusion: A clinician-focused pharmacogenomics information resource can answer pharmacogenomics-related medication questions faster, more correctly, and more easily than widely used alternatives, as perceived by pharmacists.

PMID: 28339805 [PubMed - as supplied by publisher]

BRIDG: a domain information model for translational and clinical protocol-driven research.

J Am Med Inform Assoc. 2017 Feb 26;:

Authors: Becnel LB, Hastak S, Ver Hoef W, Milius RP, Slack M, Wold D, Glickman ML, Brodsky B, Jaffe C, Kush R, Helton E

Abstract
Background: It is critical to integrate and analyze data from biological, translational, and clinical studies with data from health systems; however, electronic artifacts are stored in thousands of disparate systems that are often unable to readily exchange data.
Objective: To facilitate meaningful data exchange, a model that presents a common understanding of biomedical research concepts and their relationships with health care semantics is required. The Biomedical Research Integrated Domain Group (BRIDG) domain information model fulfills this need. Software systems created from BRIDG have shared meaning "baked in," enabling interoperability among disparate systems. For nearly 10 years, the Clinical Data Standards Interchange Consortium, the National Cancer Institute, the US Food and Drug Administration, and Health Level 7 International have been key stakeholders in developing BRIDG.
Methods: BRIDG is an open-source Unified Modeling Language-class model developed through use cases and harmonization with other models.
Results: With its 4+ releases, BRIDG includes clinical and now translational research concepts in its Common, Protocol Representation, Study Conduct, Adverse Events, Regulatory, Statistical Analysis, Experiment, Biospecimen, and Molecular Biology subdomains.
Interpretation: The model is a Clinical Data Standards Interchange Consortium, Health Level 7 International, and International Standards Organization standard that has been utilized in national and international standards-based software development projects. It will continue to mature and evolve in the areas of clinical imaging, pathology, ontology, and vocabulary support. BRIDG 4.1.1 and prior releases are freely available at https://bridgmodel.nci.nih.gov .

PMID: 28339791 [PubMed - as supplied by publisher]

Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects.

Clin Pharmacol Drug Dev. 2017 Mar 24;:

Authors: Nomoto M, Pastino G, Rege B, Aluri J, Ferry J, Han D

Abstract
Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated.

PMID: 28339166 [PubMed - as supplied by publisher]

Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives.

Int J Environ Res Public Health. 2017 Mar 14;14(3):

Authors: Zhang YJ, Li MP, Tang J, Chen XP

Abstract
Clopidogrel has significantly reduced the incidence of recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). However, recurrence events still remain, which may be partly due to inadequate platelet inhibition by standard clopidogrel therapy. Genetic polymorphisms involved in clopidogrel's absorption, metabolism, and the P2Y12 receptor may interfere with its antiplatelet activity. Recent evidence indicated that epigenetic modification may also affect clopidogrel response. In addition, non-genetic factors such as demographics, disease complications, and drug-drug interactions can impair the antiplatelet effect of clopidogrel. The identification of factors contributing to the variation in clopidogrel response is needed to improve platelet inhibition and to reduce risk for cardiovascular events. This review encompasses the most recent updates on factors influencing pharmacokinetic and pharmacodynamic responses to clopidogrel.

PMID: 28335443 [PubMed - in process]

Pomegranate juice does not affect the disposition of simvastatin in healthy subjects.

Eur J Drug Metab Pharmacokinet. 2016 Aug;41(4):339-44

Authors: Park SJ, Yeo CW, Shim EJ, Kim H, Liu KH, Shin JG, Shon JH

Abstract
Previous in vitro and in vivo investigations reported controversial results for the inhibitory potential of pomegranate on Cytochrome P450 (CYP) 3A activity. This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic parameters of simvastatin and simvastatin acid were compared among the study periods. In the period of grapefruit juice, the mean C max and AUCinf of simvastatin [the geometric mean ratio (90 % CI) 15.6 (11.6-21.0) and 9.1 (6.0-13.7)] were increased significantly when compared with the control period, whereas they were not significantly different in the period of pomegranate juice [C max and AUCinf 1.20 (0.89-1.62) and 1.29 (0.85-1.94)]. The mean C max and AUCinf of simvastatin acid were increased significantly after intake of grapefruit juice, but not pomegranate juice. These results suggest that pomegranate juice affects little on the disposition of simvastatin in humans. Pomegranate juice does not seem to have a clinically relevant inhibitory potential on CYP3A4 activity.

PMID: 25720525 [PubMed - indexed for MEDLINE]

Molecular Structure of the Human CFTR Ion Channel.

Cell. 2017 Mar 23;169(1):85-95.e8

Authors: Liu F, Zhang Z, Csanády L, Gadsby DC, Chen J

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function.

PMID: 28340353 [PubMed - in process]

Viruses in cystic fibrosis patients' airways.

Crit Rev Microbiol. 2017 Mar 24;:1-19

Authors: Billard L, Le Berre R, Pilorgé L, Payan C, Héry-Arnaud G, Vallet S

Abstract
Although bacteria have historically been considered to play a major role in cystic fibrosis (CF) airway damage, a strong impact of respiratory viral infections (RVI) is also now recognized. Emerging evidence confirms that respiratory viruses are associated with deterioration of pulmonary function and exacerbation and facilitation of bacterial colonization in CF patients. The aim of this review is to provide an overview of the current knowledge on respiratory viruses in CF airways, to discuss the resulting inflammation and RVI response, to determine how to detect the viruses, and to assess their clinical consequences, prevalence, and interactions with bacteria. The most predominant are Rhinoviruses (RVs), significantly associated with CF exacerbation. Molecular techniques, and especially multiplex PCR, help to diagnose viral infections, and the coming rise of metagenomics will extend knowledge of viral populations in the complex ecosystem of CF airways. Prophylaxis and vaccination are currently available only for Respiratory syncytial and Influenza virus (IV), but antiviral molecules are being tested to improve CF patients' care. All the points raised in this review highlight the importance of taking account of RVIs and their potential impact on the CF airway ecosystem.

PMID: 28340310 [PubMed - as supplied by publisher]

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

PLoS One. 2017;12(3):e0173822

Authors: Trouvé P, Génin E, Férec C

Abstract
Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

PMID: 28339466 [PubMed - in process]