DNA data bank of Japan (DDBJ) progress report.

Nucleic Acids Res. 2016 Jan 4;44(D1):D51-7

Authors: Mashima J, Kodama Y, Kosuge T, Fujisawa T, Katayama T, Nagasaki H, Okuda Y, Kaminuma E, Ogasawara O, Okubo K, Nakamura Y, Takagi T

Abstract
The DNA Data Bank of Japan Center (DDBJ Center; http://www.ddbj.nig.ac.jp) maintains and provides public archival, retrieval and analytical services for biological information. The contents of the DDBJ databases are shared with the US National Center for Biotechnology Information (NCBI) and the European Bioinformatics Institute (EBI) within the framework of the International Nucleotide Sequence Database Collaboration (INSDC). Since 2013, the DDBJ Center has been operating the Japanese Genotype-phenotype Archive (JGA) in collaboration with the National Bioscience Database Center (NBDC) in Japan. In addition, the DDBJ Center develops semantic web technologies for data integration and sharing in collaboration with the Database Center for Life Science (DBCLS) in Japan. This paper briefly reports on the activities of the DDBJ Center over the past year including submissions to databases and improvements in our services for data retrieval, analysis, and integration.

PMID: 26578571 [PubMed - indexed for MEDLINE]

DMETTM (Drug Metabolism Enzymes and Transporters): a Pharmacogenomic platform for precision medicine.

Oncotarget. 2016 Jun 9;

Authors: Arbitrio M, Di Martino MT, Scionti F, Agapito G, Guzzi PH, Cannataro M, Tassone P, Tagliaferri P

Abstract
In the era of personalized medicine, high-throughput technologies have allowed the investigation of genetic variations underlying the inter-individual variability in drug pharmacokinetics/pharmacodynamics. Several studies have recently moved from a candidate gene-based pharmacogenetic approach to genome-wide pharmacogenomic analyses to identify biomarkers for selection of patient-tailored therapies. In this aim, the identification of genetic variants affecting the individual drug metabolism is relevant for the definition of more active and less toxic treatments. This review focuses on the potentiality, reliability and limitations of the DMETTM (Drug Metabolism Enzymes and Transporters) Plus as pharmacogenomic drug metabolism multi-gene panel platform for selecting biomarkers in the final aim to optimize drugs use and characterize the individual genetic background.

PMID: 27304055 [PubMed - as supplied by publisher]

Personalized medicine. Closing the gap between knowledge and clinical practice.

Autoimmun Rev. 2016 Jun 11;

Authors: Anaya JM, Duarte-Rey C, Sarmiento-Monroy JC, Bardey D, Castiblanco J, Rojas-Villarraga A

Abstract
Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.

PMID: 27302209 [PubMed - as supplied by publisher]

Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration - experience from a pediatric tertiary care facility.

J Am Med Inform Assoc. 2016 Jun 14;

Authors: Manzi SF, Fusaro VA, Chadwick L, Brownstein C, Clinton C, Mandl KD, Wolf WA, Hawkins JB

Abstract
OBJECTIVE: This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR).
MATERIALS AND METHODS: An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy.
RESULTS: Clinical decision support rules built within an EHR provided guidance to providers for 31 patients (100%) who had actionable PGx variants and were written for interacting medications. A breakdown of the PGx alerts by practitioner service, and alert response for the initial cohort of patients tested is described. In 90% (355/394) of the cases, thiopurine methyltranferase genotyping was ordered pre-emptively.
DISCUSSION: This paper outlines one approach to implementing a clinical PGx service in a pediatric teaching hospital that cares for a heterogeneous patient population. There is a focus on incorporation of PGx clinical decision support rules and a program to standardize report text within the electronic health record with subsequent exploration of clinician behavior in response to the alerts.
CONCLUSION: The incorporation of PGx data at the time of prescribing and dispensing, if done correctly, has the potential to impact the incidence of adverse drug events, a significant cause of morbidity and mortality.

PMID: 27301749 [PubMed - as supplied by publisher]

Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children.

Pharmacogenomics. 2015;16(10):1065-76

Authors: Visscher H, Rassekh SR, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Rogers PC, Rieder MJ, Carleton BC, Hayden MR, Ross CJ, CPNDS consortium

Abstract
AIM: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model.
PATIENTS & METHODS: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes.
RESULTS: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]).
CONCLUSION: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

PMID: 26230641 [PubMed - indexed for MEDLINE]

Progress in understanding the genomic basis for adverse drug reactions: a comprehensive review and focus on the role of ethnicity.

Pharmacogenomics. 2015;16(10):1161-78

Authors: Chan SL, Jin S, Loh M, Brunham LR

Abstract
A major goal of the field of pharmacogenomics is to identify the genomic causes of serious adverse drug reactions (ADRs). Increasingly, genome-wide association studies (GWAS) have been used to achieve this goal. In this article, we review recent progress in the identification of genetic variants associated with ADRs using GWAS and discuss emerging themes from these studies. We also compare aspects of GWAS for ADRs to GWAS for common diseases. In the second part of the article, we review progress in performing pharmacogenomic research in multi-ethnic populations and discuss the challenges and opportunities of investigating genetic causes of ADRs in ethnically diverse patient populations.

PMID: 25978008 [PubMed - indexed for MEDLINE]

Partial restoration of pancreatic function in a child with cystic fibrosis.

Lancet Respir Med. 2016 May;4(5):e21-e22

Authors: Howlett C, Ronan NJ, NiChroinin M, Mullane D, Plant BJ

PMID: 27304562 [PubMed - as supplied by publisher]

The phospholipid flippase ATP8B1 mediates apical localization of the Cystic Fibrosis Transmembrane Regulator.

Biochim Biophys Acta. 2016 Jun 11;

Authors: van der Mark VA, de Jonge HR, Chang JC, Ho-Mok KS, Duijst S, Vidović D, Carlon MS, Elferink RP, Paulusma CC

Abstract
Progressive familial intrahepatic cholestasis type 1 (PFIC1) is caused by mutations in the gene encoding the phospholipid flippase ATP8B1. Apart from severe cholestatic liver disease, many PFIC1 patients develop extrahepatic symptoms characteristic of cystic fibrosis (CF), such as pulmonary infection, sweat gland dysfunction and failure to thrive. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel essential for epithelial fluid transport. Previously it was shown that CFTR transcript levels were strongly reduced in livers of PFIC1 patients. Here we have investigated the hypothesis that ATP8B1 is important for proper CFTR expression and function. We analyzed CFTR expression in ATP8B1-depleted intestinal and pulmonary epithelial cell lines and assessed CFTR function by measuring short-circuit currents across transwell-grown ATP8B1-depleted intestinal T84 cells and by a genetically-encoded fluorescent chloride sensor. In addition, we studied CFTR surface expression upon induction of CFTR transcription. We show that CFTR protein levels are strongly reduced in the apical membrane of human ATP8B1-depleted intestinal and pulmonary epithelial cell lines, a phenotype that coincided with reduced CFTR activity. Apical membrane insertion upon induction of ectopically-expressed CFTR was strongly impaired in ATP8B1-depleted cells. We conclude that ATP8B1 is essential for correct apical localization of CFTR in human intestinal and pulmonary epithelial cells, and that impaired CFTR localization underlies some of the extrahepatic phenotypes observed in ATP8B1 deficiency.

PMID: 27301931 [PubMed - as supplied by publisher]

The innate immune protein calprotectin promotes Pseudomonas aeruginosa and Staphylococcus aureus interaction.

Nat Commun. 2016;7:11951

Authors: Wakeman CA, Moore JL, Noto MJ, Zhang Y, Singleton MD, Prentice BM, Gilston BA, Doster RS, Gaddy JA, Chazin WJ, Caprioli RM, Skaar EP

Abstract
Microorganisms form biofilms containing differentiated cell populations. To determine factors driving differentiation, we herein visualize protein and metal distributions within Pseudomonas aeruginosa biofilms using imaging mass spectrometry. These in vitro experiments reveal correlations between differential protein distribution and metal abundance. Notably, zinc- and manganese-depleted portions of the biofilm repress the production of anti-staphylococcal molecules. Exposure to calprotectin (a host protein known to sequester metal ions at infectious foci) recapitulates responses occurring within metal-deplete portions of the biofilm and promotes interaction between P. aeruginosa and Staphylococcus aureus. Consistent with these results, the presence of calprotectin promotes co-colonization of the murine lung, and polymicrobial communities are found to co-exist in calprotectin-enriched airspaces of a cystic fibrosis lung explant. These findings, which demonstrate that metal fluctuations are a driving force of microbial community structure, have clinical implications because of the frequent occurrence of P. aeruginosa and S. aureus co-infections.

PMID: 27301800 [PubMed - in process]

The analysis of the antibiotic resistome offers new opportunities for therapeutic intervention.

Future Med Chem. 2016 Jun 15;

Authors: Corona F, Blanco P, Alcalde-Rico M, Hernando-Amado S, Lira F, Bernardini A, Sánchez MB, Martínez JL

Abstract
Most efforts in the development of antimicrobials have focused on the screening of lethal targets. Nevertheless, the constant expansion of antimicrobial resistance makes the antibiotic resistance determinants themselves suitable targets for finding inhibitors to be used in combination with antibiotics. Among them, inhibitors of antibiotic inactivating enzymes and of multidrug efflux pumps are suitable candidates for improving the efficacy of antibiotics. In addition, the application of systems biology tools is helping to understand the changes in bacterial physiology associated to the acquisition of resistance, including the increased susceptibility to other antibiotics displayed by some antibiotic-resistant mutants. This information is useful for implementing novel strategies based in metabolic interventions or combination of antibiotics for improving the efficacy of antibacterial therapy.

PMID: 27304087 [PubMed - as supplied by publisher]

Molecular and genetic inflammation networks in major human diseases.

Mol Biosyst. 2016 Jun 15;

Authors: Zhao Y, Forst CV, Sayegh CE, Wang IM, Yang X, Zhang B

Abstract
It has been well-recognized that inflammation alongside tissue repair and damage maintaining tissue homeostasis determines the initiation and progression of complex diseases. Albeit with the accomplishment of having captured the most critical inflammation-involved molecules, genetic susceptibilities, epigenetic factors, and environmental factors, our schemata on the role of inflammation in complex diseases remain largely patchy, in part due to the success of reductionism in terms of research methodology per se. Omics data alongside the advances in data integration technologies have enabled reconstruction of molecular and genetic inflammation networks which shed light on the underlying pathophysiology of complex diseases or clinical conditions. Given the proven beneficial role of anti-inflammation in coronary heart disease as well as other complex diseases and immunotherapy as a revolutionary transition in oncology, it becomes timely to review our current understanding of the molecular and genetic inflammation networks underlying major human diseases. In this review, we first briefly discuss the complexity of infectious diseases and then highlight recently uncovered molecular and genetic inflammation networks in other major human diseases including obesity, type II diabetes, coronary heart disease, late onset Alzheimer's disease, Parkinson's disease, and sporadic cancer. The commonality and specificity of these molecular networks are addressed in the context of genetics based on genome-wide association study (GWAS). The double-sword role of inflammation, such as how the aberrant type 1 and/or type 2 immunity leads to chronic and severe clinical conditions, remains open in terms of the inflammasome and the core inflammatome network features. Increasingly available large Omics and clinical data in tandem with systems biology approaches have offered an exciting yet challenging opportunity toward reconstruction of more comprehensive and dynamic molecular and genetic inflammation networks, which hold great promise in transiting network snapshots to video-style multi-scale interplays of disease mechanisms, in turn leading to effective clinical intervention.

PMID: 27303926 [PubMed - as supplied by publisher]

The natural defense system and the normative self model.

F1000Res. 2016;5:797

Authors: Kourilsky P

Abstract
Infectious agents are not the only agressors, and the immune system is not the sole defender of the organism. In an enlarged perspective, the 'normative self model' postulates that a 'natural defense system' protects man and other complex organisms against the environmental and internal hazards of life, including infections and cancers. It involves multiple error detection and correction mechanisms that confer robustness to the body at all levels of its organization. According to the model, the self relies on a set of physiological norms, and NONself (meaning : Non Obedient to the Norms of the self) is anything 'off-norms'. The natural defense system comprises a set of 'civil defenses' (to which all cells in organs and tissues contribute), and a 'professional army ', made of a smaller set of mobile cells. Mobile and non mobile cells differ in their tuning abilities. Tuning extends the recognition capabilities of NONself by the mobile cells, which increase their defensive function. To prevent them to drift, which would compromise self/NONself discrimination, the more plastic mobile cells need to periodically refer to the more stable non mobile cells to keep within physiological standards.

PMID: 27303629 [PubMed]

A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT.

Oncotarget. 2016 May 18;

Authors: Bown JL, Shovman M, Robertson P, Boiko A, Goltsov A, Mullen P, Harrison DJ

Abstract
Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualization toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery.

PMID: 27302920 [PubMed - as supplied by publisher]

Advances in targeted proteomics and applications to biomedical research.

Proteomics. 2016 Jun 15;

Authors: Shi T, Song E, Nie S, Rodland KD, Liu T, Qian WJ, Smith RD

Abstract
Targeted proteomics technique has emerged as a powerful protein quantification tool in systems biology, biomedical research, and increasing for clinical applications. The most widely used targeted proteomics approach, selected reaction monitoring (SRM), also known as multiple reaction monitoring (MRM), can be used for quantification of cellular signaling networks and preclinical verification of candidate protein biomarkers. As an extension to our previous review on advances in SRM sensitivity (Shi et al., Proteomics, 12, 1074-1092, 2012) herein we review recent advances in the method and technology for further enhancing SRM sensitivity (from 2012 to present), and highlighting its broad biomedical applications in human bodily fluids, tissue and cell lines. Furthermore, we also review two recently introduced targeted proteomics approaches, parallel reaction monitoring (PRM) and data-independent acquisition (DIA) with targeted data extraction on fast scanning high-resolution accurate-mass (HR/AM) instruments. Such HR/AM targeted quantification with monitoring all target product ions addresses SRM limitations effectively in specificity and multiplexing; whereas when compared to SRM, PRM and DIA are still in the infancy with a limited number of applications. Thus, for HR/AM targeted quantification we focus our discussion on method development, data processing and analysis, and its advantages and limitations in targeted proteomics. Finally, general perspectives on the potential of achieving both high sensitivity and high sample throughput for large-scale quantification of hundreds of target proteins are discussed. This article is protected by copyright. All rights reserved.

PMID: 27302376 [PubMed - as supplied by publisher]

Personalized medicine. Closing the gap between knowledge and clinical practice.

Autoimmun Rev. 2016 Jun 11;

Authors: Anaya JM, Duarte-Rey C, Sarmiento-Monroy JC, Bardey D, Castiblanco J, Rojas-Villarraga A

Abstract
Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.

PMID: 27302209 [PubMed - as supplied by publisher]

Dynamic zonation of liver polyploidy.

Cell Tissue Res. 2016 Jun 15;

Authors: Tanami S, Ben-Moshe S, Elkayam A, Mayo A, Bahar Halpern K, Itzkovitz S

Abstract
The liver is a polyploid organ, consisting of hepatocytes with one or two nuclei each containing 2, 4, 8 or more haploid chromosome sets. The dynamic changes in the spatial distributions of polyploid classes across the liver lobule, its repeating anatomical unit, have not been characterized. Identifying these spatial patterns is important for understanding liver homeostatic and regenerative turnover, as well as potential division of labor among ploidy classes. Here, we use single molecule-based tissue imaging to reconstruct the spatial zonation profiles of liver polyploid classes in mice of different ages. We find that liver polyploidy proceeds in spatial waves, advancing more rapidly in the mid-lobule zone compared to the periportal and perivenous zones. We also measure the spatial zonation profiles of S-phase entry at different ages and identify more rapid S-phase entry in the mid-lobule zone at older ages. Our findings reveal fundamental features of liver spatial heterogeneity and highlight their dynamic changes during development and aging.

PMID: 27301446 [PubMed - as supplied by publisher]

Genomic cloud computing: legal and ethical points to consider.

Eur J Hum Genet. 2015 Oct;23(10):1271-8

Authors: Dove ES, Joly Y, Tassé AM, Public Population Project in Genomics and Society (P3G) International Steering Committee, International Cancer Genome Consortium (ICGC) Ethics and Policy Committee, Knoppers BM

Abstract
The biggest challenge in twenty-first century data-intensive genomic science, is developing vast computer infrastructure and advanced software tools to perform comprehensive analyses of genomic data sets for biomedical research and clinical practice. Researchers are increasingly turning to cloud computing both as a solution to integrate data from genomics, systems biology and biomedical data mining and as an approach to analyze data to solve biomedical problems. Although cloud computing provides several benefits such as lower costs and greater efficiency, it also raises legal and ethical issues. In this article, we discuss three key 'points to consider' (data control; data security, confidentiality and transfer; and accountability) based on a preliminary review of several publicly available cloud service providers' Terms of Service. These 'points to consider' should be borne in mind by genomic research organizations when negotiating legal arrangements to store genomic data on a large commercial cloud service provider's servers. Diligent genomic cloud computing means leveraging security standards and evaluation processes as a means to protect data and entails many of the same good practices that researchers should always consider in securing their local infrastructure.

PMID: 25248396 [PubMed - indexed for MEDLINE]

Genetic and metabolic engineering of microorganisms for the development of new flavor compounds from terpenic substrates.

Crit Rev Biotechnol. 2015;35(3):313-25

Authors: Bution ML, Molina G, Abrahão MR, Pastore GM

Abstract
Throughout human history, natural products have been the basis for the discovery and development of therapeutics, cosmetic and food compounds used in industry. Many compounds found in natural organisms are rather difficult to chemically synthesize and to extract in large amounts, and in this respect, genetic and metabolic engineering are playing an increasingly important role in the production of these compounds, such as new terpenes and terpenoids, which may potentially be used to create aromas in industry. Terpenes belong to the largest class of natural compounds, are produced by all living organisms and play a fundamental role in human nutrition, cosmetics and medicine. Recent advances in systems biology and synthetic biology are allowing us to perform metabolic engineering at the whole-cell level, thus enabling the optimal design of microorganisms for the efficient production of drugs, cosmetic and food additives. This review describes the recent advances made in the genetic and metabolic engineering of the terpenes pathway with a particular focus on systems biotechnology.

PMID: 24494701 [PubMed - indexed for MEDLINE]

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