Learn about the effect of deforestation and then reforestation on river channel morphology.\n Understand the composite mathematical modelling for continuous simulations of hydro-geomorphological processes.\n Know about the process-response models for estimation of cliff erosion and its quantitative predictions.\n Grow your knowledge about various geomorphometric tools that are available in freely available GIS software.",isbn:"978-953-51-3574-6",printIsbn:"978-953-51-3573-9",pdfIsbn:"978-953-51-4625-4",doi:"10.5772/65532",price:119,priceEur:129,priceUsd:155,slug:"hydro-geomorphology-models-and-trends",numberOfPages:122,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"865bfca98cafeeb9fdcf21c9453845f6",bookSignature:"Dericks P. Shukla",publishedDate:"October 18th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5805.jpg",keywords:null,numberOfDownloads:9970,numberOfWosCitations:12,numberOfCrossrefCitations:13,numberOfDimensionsCitations:20,numberOfTotalCitations:45,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 28th 2016",dateEndSecondStepPublish:"October 19th 2016",dateEndThirdStepPublish:"January 15th 2017",dateEndFourthStepPublish:"April 15th 2017",dateEndFifthStepPublish:"June 14th 2017",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"6 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"176921",title:"Dr.",name:"Dericks",middleName:null,surname:"Shukla",slug:"dericks-shukla",fullName:"Dericks Shukla",profilePictureURL:"https://mts.intechopen.com/storage/users/176921/images/6252_n.jpg",biography:"Dr. Dericks P. Shukla, assistant professor in the School of Engineering, Indian Institute of Technology Mandi (IIT Mandi), has more than 7 years of experience in the areas of remote sensing and GIS, natural hazard assessment and mapping, climatic-tectono-geomorphology and hydro-geochemistry. He has published more than 17 research papers in peer-reviewed journals and various conference papers. He has been working in the field of landslide susceptibility/hazard zonation and prediction, groundwater pollution mainly arsenic contamination and fluvial and glacial geomorphologic studies using remote sensing and GIS techniques. He has five ongoing projects as principal investigator funded by DLR (German Aerospace Agency); Space Application Centre, Indian Space Research Organization (SAC-ISRO); and Department of Science and Technology (DST).",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Indian Institute of Technology Mandi",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"648",title:"Geomorphometry",slug:"geomorphometry"}],chapters:[{id:"57063",title:"Introductory Chapter: Geomorphology",slug:"introductory-chapter-geomorphology",totalDownloads:2647,totalCrossrefCites:1,authors:[{id:"176921",title:"Dr.",name:"Dericks",surname:"Shukla",slug:"dericks-shukla",fullName:"Dericks Shukla"}]},{id:"55152",title:"Computation of Hydro-geomorphologic Changes in Two Basins of Northeastern Greece",slug:"computation-of-hydro-geomorphologic-changes-in-two-basins-of-northeastern-greece",totalDownloads:1571,totalCrossrefCites:0,authors:[{id:"37707",title:"Prof.",name:"Vlassios",surname:"Hrissanthou",slug:"vlassios-hrissanthou",fullName:"Vlassios Hrissanthou"},{id:"200942",title:"Dr.",name:"Konstantinos",surname:"Kaffas",slug:"konstantinos-kaffas",fullName:"Konstantinos Kaffas"}]},{id:"54918",title:"Analysis of the Impacts of Changes in Streamflow and of Restoration on the Morphological Evolution of the Matambin River Channel in the St. Lawrence Lowlands (Quebec, Canada)",slug:"analysis-of-the-impacts-of-changes-in-streamflow-and-of-restoration-on-the-morphological-evolution-o",totalDownloads:1410,totalCrossrefCites:1,authors:[{id:"50312",title:"Prof.",name:"Ali",surname:"Assani",slug:"ali-assani",fullName:"Ali Assani"}]},{id:"54919",title:"The Modelling of Coastal Cliffs and Future Trends",slug:"the-modelling-of-coastal-cliffs-and-future-trends",totalDownloads:1655,totalCrossrefCites:3,authors:[{id:"196739",title:"Dr.",name:"Ricardo",surname:"Castedo",slug:"ricardo-castedo",fullName:"Ricardo Castedo"},{id:"204921",title:"Dr.",name:"Carlos",surname:"Paredes",slug:"carlos-paredes",fullName:"Carlos Paredes"},{id:"204922",title:"Dr.",name:"Rogelio",surname:"De La Vega-Panizo",slug:"rogelio-de-la-vega-panizo",fullName:"Rogelio De La Vega-Panizo"},{id:"204923",title:"Dr.",name:"Anastasio P.",surname:"Santos",slug:"anastasio-p.-santos",fullName:"Anastasio P. Santos"}]},{id:"55617",title:"Digital Elevation Models in Geomorphology",slug:"digital-elevation-models-in-geomorphology",totalDownloads:2687,totalCrossrefCites:8,authors:[{id:"196721",title:"Ph.D.",name:"Bartłomiej",surname:"Szypuła",slug:"bartlomiej-szypula",fullName:"Bartłomiej Szypuła"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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\n\t\t\t
1. Introduction
\n\t\t\t
Dynamic regulation of genes is an important part of the cell life cycle in health and disease. The regulation includes the variety and alteration of genome and gene expression, and the concept such as quality of genome will be useful to predict and assess the developmental stages of the cells, disease status and drug sensitivity. Recent technologies and worldwide sequencing projects have revealed 26,383 annotated genes in the 2.91-Gigabase human genome [1,2]. The main molecular functions of the annotated genes, as categorized by Gene Ontology (GO), are enzyme, signal transduction, nucleic acid binding, cell adhesion, chaperone, cytoskeletal structural protein, extracellular matrix, immunoglobulin, ion channel, motor, structural protein of muscle, protooncogene, select calcium binding protein, intracellular transporter, and transporter [1,3]. Despite a wealth of knowledge, the function of 42% of the annotated genes remains unknown [1]. When the human genome sequence was published in 2001 [1], there were a predicted 39,114 genes, of which 59% were of unknown function. According to the International Human Genome Sequencing Consortium, the number of identified genes is approximately 32,000, of which 51% show a match within InterPro, a database that integrates diverse information about protein families, domains, and functional sites [2-5]. In 2001, InterPro combined sequence and pattern information from four databases (PRINTS, PROSITE, Pfam, Prosite Profile); however, it now includes information from an additional eight databases (SMART, ProDom, PIRSF, SUPERFAMILY, PANTHER, CATH-Gene3D, TIGRFAM, and HAMAP) [2,4-16]. In [2], the InterPro entries are collapsed into 12 broad categories: cellular processes, metabolism, DNA replication/modification, transcription/translation, intracellular signaling, cell–cell communication, protein folding and degradation, transport, multifunctional proteins, cytoskeletal/structural, defense and immunity, and miscellaneous function. The rate of single nucleotide polymorphism (SNP) variation has been reported as 1 in 1250 base pairs [1] and more than 1.4 million SNPs have been identified [2] (Table 1).
\n\t\t\t
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\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Size of the genome
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2.91 Gbp
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Number of annotated genes
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26,383
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Main molecular functions of annotated genes
\n\t\t\t\t\t\t
enzyme, signal transduction, nucleic acid binding, cell adhesion, chaperone, cytoskeletal structural protein, extracellular matrix, immunoglobulin, ion channel, motor, structural protein of muscle, protooncogene, select calcium binding protein, intracellular transporter, transporter
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Percentage of annotated genes with unknown function
\n\t\t\t\t\t\t
42%
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Number of hypothetical and annotated genes
\n\t\t\t\t\t\t
39,114
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Percentage of hypothetical and annotated genes with unknown function
\n\t\t\t\t\t\t
59%
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Number of identified genes
\n\t\t\t\t\t\t
approx. 32,000
\n\t\t\t\t\t\t
[2]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Percentage of matches with InterPro
\n\t\t\t\t\t\t
51%
\n\t\t\t\t\t\t
[2]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Rate of SNP variation
\n\t\t\t\t\t\t
1/1250 bp
\n\t\t\t\t\t\t
[1]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
SNPs identified
\n\t\t\t\t\t\t
more than 1.4 million
\n\t\t\t\t\t\t
[2]
\n\t\t\t\t\t
\n\t\t\t\t
Table 1.
Genomic and gene characteristics revealed by the Human Genome Project.
\n\t\t\t
Among the databases combined in InterPro (Table 2), PRINTS, PROSITE, and Pfam contain protein families in which the homology between each protein is predicted by the degree of sequence similarity [8]. The others—SMART, ProDom, PIRSF, SUPERFAMILY, PANTHER, CATH-Gene3D, TIGRFAM, and HAMAP [4-16]—have unique characteristics and URLs, and have been developed sharing information among each other and incorporating information from GO. In detail, PRINTS is a collection of diagnostic protein family “fingerprints”, which are groups of conserved motifs, evident in multiple sequence alignments [6]; PROSITE is a protein domain database for functional characterization and annotation that consists of documentation entries describing protein domains, families, and functional sites as well as associated patterns and profiles to identify them [7]; Pfam contains collections of protein families, each represented by multiple sequence alignments and hidden Markov models, available via servers in the UK, the USA, and Sweden [8]; SMART (Simple Modular Architecture Research Tool) is an online resource for the identification and annotation of protein domains and the analysis of protein domain architectures [9]; ProDom is a comprehensive set of protein domain families generated automatically from the UniProt database [10]; PIRSF is a classification system that reflects evolutionary relationships among full-length proteins and domains [11]; SUPERFAMILY is a database of structural and functional annotation for all proteins and genomes [12]; PANTHER is a classification system that classifies genes by their functions using published experimental evidence and evolutionary relationships to predict function even in the absence of direct experimental evidence [13]; CATH-Gene3D is a comprehensive database of protein domain assignments for sequences from the major sequence databases [14]; TIGRFAM is a collection of protein family definitions built to aid high-throughput annotation of specific protein functions [15]; and HAMAP is composed of two databases: the proteome database and the family database, and of an automatic annotation pipeline mainly focused on microbial proteomes [16]. Hidden Markov models are usually used for the database algorithm.
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\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\tDatabase Name\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\tContext\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\tURL\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\tReference\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
InterPro
\n\t\t\t\t\t\t
integrative predictive models of protein families, domain and functional sites of multiple databases such as PRINTS, PROSITE, Pfam, SMART, ProDom, PIRSF, SUPERFAMILY, PANTHER, CATH-Gene3D, TIGRFAM, and HAMAP
\n\t\t\t\t\t\t
http://www.ebi.ac.uk/interpro/
\n\t\t\t\t\t\t
[4], [5]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
PRINTS
\n\t\t\t\t\t\t
a collection of diagnostic protein family "fingerprints" which are groups of conserved motifs, evident in multiple sequence alignments
a protein domain database for functional characterization and annotation which consists of documentation entries describing protein domains, families and functional sites as well as associated patterns and profiles to identify them
\n\t\t\t\t\t\t
http://prosite.expasy.org/
\n\t\t\t\t\t\t
[7]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Pfam
\n\t\t\t\t\t\t
a database of collection of protein families, each represented by multiple sequence alignments and hidden Markov models, available via servers in the UK, the USA and Sweden
an online resource for the identification and annotation of protein domains and the analysis of protein domain architectures, of which abbreviation is Simple Modular Architecture Research Tool
\n\t\t\t\t\t\t
http://smart.embl.de/
\n\t\t\t\t\t\t
[9]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
ProDom
\n\t\t\t\t\t\t
a comprehensive set of protein domain families automatically generated from the uniProt knowledge Database
the classification system which reflects evolutionary relationships of full-length proteins and domains
\n\t\t\t\t\t\t
http://pir.georgetown.edu/pirsf/
\n\t\t\t\t\t\t
[11]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
SUPERFAMILY
\n\t\t\t\t\t\t
a database of structural and functional annotation for all proteins and genomes
\n\t\t\t\t\t\t
http://supfam.org/SUPERFAMILY/
\n\t\t\t\t\t\t
[12]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
PANTHER
\n\t\t\t\t\t\t
the classification system which classifies genes by their functions using published scientific experimental evidence and evolutionary relationships to predict function even in the absence of direct experimental evidence
\n\t\t\t\t\t\t
http://www.pantherdb.org/
\n\t\t\t\t\t\t
[13]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CATH-Gene3D
\n\t\t\t\t\t\t
a comprehensive database of protein domain assignments for sequences from the major sequence databases
\n\t\t\t\t\t\t
http://gene3d.biochem.ucl.ac.uk/
\n\t\t\t\t\t\t
[14]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
TIGRFAM
\n\t\t\t\t\t\t
a collection of protein family definitions built to aid in high-throughput annotation of specific protein functions
\n\t\t\t\t\t\t
http://www.jcvi.org/cgi-bin/tigrfams/index.cgi
\n\t\t\t\t\t\t
[15]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
HAMAP
\n\t\t\t\t\t\t
a system which composed of two databases, the proteome database and the family database, and of an automatic annotation pipeline
\n\t\t\t\t\t\t
http://hamap.expasy.org/
\n\t\t\t\t\t\t
[16]
\n\t\t\t\t\t
\n\t\t\t\t
Table 2.
Database information.
\n\t\t
\n\t\t
\n\t\t\t
2. Gene regulation
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\n\t\t\t\t
2.1. Gene markers for cancer and cancer stem cells
\n\t\t\t\t
Several molecular markers of cancer have been identified [17]. Metastatic cancer cells can transfer into bodily fluids through the cellular epithelia, which enables the detection of cancer markers in bodily fluids such as blood plasma, urine, or saliva [17]. The different types of cancer markers include genomic DNA point mutations, microsatellite alterations, promoter hypermethylation, viral sequences, aberrant chromosomal copy number, chromosomal translocations, deletions, or loss of heterozygosity, telomere extension, alterations in RNA or protein expression, and mitochondrial DNA mutations [17].
\n\t\t\t\t
Molecular markers of cancer include TP53 (encoding p53), which has been shown to be mutated in head and neck, lung, colon, pancreatic, and bladder cancer [17,18]; colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissue, and hematopoietic tissue cancers [19]; and bladder cancer [20]. Mutation of the epidermal growth factor receptor (EGFR) gene is an important predictive/prognostic factor for EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer [21]. RAS oncogene mutations have been identified in colorectal tumors [22]. Microsatellites, which are tandem iterations of simple di-, tri-, or tetranucleotide repeats, have been reported to be unstable in some inherited diseases and in some types of cancer [23], including head and neck, lung, breast, and bladder cancer [17,23].
\n\t\t\t\t
The expression levels of the cell cycle-related proteins p21 (CDKN1A), p53 (TP53), cyclin D1 (CCND1), and aurora kinase A (AURKA) may be used as prognostic markers to predict recurrence in stage II and stage III colon cancer [24]. In addition, markers of the epithelial–mesenchymal transition (EMT)–such as reduced expression of keratins, a switch from E-Cadherin to N-Cadherin, and enhanced migration in D492M cells—might be a useful marker in breast cancer [25]. Furthermore, expression of the stem cell markers cytokeratins 15 and 19 was altered in squamous cell carcinoma: cytokeratin 15 levels were decreased and the localization of cytokeratin 19 was altered [26]. KLK3, which encodes prostate-specific antigen, a member of the kallikrein family of serine proteases, is a biomarker for prostate cancer detection and disease monitoring [27,28]. Mitochondrial DNA mutations have been associated with bladder, head and neck, lung, colorectal, and pancreatic cancer [29-32] (Table 3).
\n\t\t\t\t
Highly parallel identification of cancer-related genes using small hairpin RNA screening has revealed that the expression of known and putative oncogenes, such as EGFR, KRAS, MYC, BCR-ABL, MYB, CRKL, and CDK4 that are essential for cancer proliferation, is altered in cancer cells [33]. Other genes such as PTPN1, NF1, SMARCB1, and SMARCE1 have been identified as essential for the imatinib response of leukemia cells, and TOPOIIA expression is involved in resistance to etoposide, an anti-topoisomerase II agent, in small cell lung cancer [33-36].
lung cancer (small cell lung cancer and non-small cell lung cancer); breast, colon, esophagus, liver, bladder, ovary, and brain cancers; sarcomas, lymphomas, and leukemias
\n\t\t\t\t\t\t\t
[19]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tEGFR mutation
\n\t\t\t\t\t\t\t
non-small cell lung cancer
\n\t\t\t\t\t\t\t
[21]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tRAS mutation
\n\t\t\t\t\t\t\t
colorectal tumors
\n\t\t\t\t\t\t\t
[22]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
DNA microsatellite alterations
\n\t\t\t\t\t\t\t
bladder cancer
\n\t\t\t\t\t\t\t
[23]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
alteration in cell cycle mRNA expression
\n\t\t\t\t\t\t\t
colon cancer
\n\t\t\t\t\t\t\t
[24]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
alteration in cytokeratin mRNA expression
\n\t\t\t\t\t\t\t
squamous cell carcinoma
\n\t\t\t\t\t\t\t
[26]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
alteration in kallikrein mRNA expression
\n\t\t\t\t\t\t\t
prostate cancer
\n\t\t\t\t\t\t\t
[27]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
mitochondrial DNA mutations \n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
bladder cancer, head and neck cancer, lung cancer
\n\t\t\t\t\t\t\t
[29]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
colorectal tumors
\n\t\t\t\t\t\t\t
[30], [32]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
pancreatic cancer
\n\t\t\t\t\t\t\t
[31]
\n\t\t\t\t\t\t
\n\t\t\t\t\t
Table 3.
Genomic markers of cancer.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.2. Genes related to cell proliferation
\n\t\t\t\t
Cyclins, which regulate the cell cycle, play important roles in cell proliferation and the uncontrolled cell proliferation that is the most important factor in tumorigenesis [37]. Tumor cells accumulate mutations that result in constitutive mitogenic signaling and defective responses to anti-mitogenic signals that contribute to unscheduled proliferation [38]. In cancer, unscheduled proliferation, genomic instability, and chromosomal instability are the three major factors in cell cycle dysregulation [38]. Regulation of the cell cycle is mainly conducted by complexes of cyclins and cyclin-dependent kinases [38]. Cyclin D1 in cell migration and proliferation is temporo-spatially separated by its biphasic expression induced by thrombin, a G protein-coupled receptor agonist, which is mediated by nuclear factor of activated T cells c1 (NFATC1) and signal transducer and activator of transcription 3 (STAT3) [39]. Cyclin D1 regulates kinase activity and the G1–S phase transition in the cell cycle; deregulated cyclin D1 expression is well documented in breast, colon, and prostate cancers [39,40]. The expression of cyclin D1 is regulated by several factors including cytokines such as interleukin 3 and interleukin 6 via STAT3 and STAT5, or extracellular matrix factors such as collagen, fibronectin, and vitronectin, which activate focal adhesion kinase upon integrin clustering, and hepatocyte nuclear factor 6 [41]. Cyclin D1 is a crucial regulator of Wnt- and Notch-regulated development [41,42]. The binding of Wnt to its receptor, Frizzled, causes release of β-catenin to translocate from the cytoplasm to the nucleus, where it forms a complex with the ternary complex factor and/or the lymphoid enhancer-binding factor [41,43]. Cyclin D1 is induced by overexpression of β-catenin, which is a major component of adherens junctions that link the actin cytoskeleton to members of the cadherin family of transmembrane cell–cell adhesion receptors. It plays an important role in linking the cytoplasmic side of cadherin-mediated cell–cell contacts to the actin cytoskeleton [43]. Beta-catenin is upregulated in colorectal cancer, which is considered to trigger cyclin D1 gene expression followed by uncontrolled progression of the cell cycle [43]. In addition, β-catenin plays another role in signaling that involves transactivation, in complex with transcription factors of the lymphoid enhancing factor family in the nucleus [43]. The pathway involving β-catenin/LEF1 and elevation of cyclin D1 might be crucial for tumorigenesis [43]. Inhibiting EglN2, a member of the EglN (also called PHD or HPH) family of prolyl hydroxylases that regulates the heterodimeric transcription factor hypoxia-inducible factor (HIF), causes a decrease in the expression of its interaction partner cyclin D1 in cancer cells and impairs the cells’ ability to proliferate in vivo [44].
\n\t\t\t\t
Progression of the eukaryotic cell cycle is driven by cyclin-dependent protein kinases (CDKs), which are binding partner of cyclins. The CDK oscillator acts as the primary organizer of the cell cycle [45]. Phosphorylation of cyclin-Cdk complexes is one of the primary mechanisms of cell cycle regulation [46]. Cyclins are degraded by ubiquitin-mediated proteolysis [46]. The ubiquitylation and degradation of cyclin 1 and cyclin 2 are mediated by the SCF complex, a multi-subunit ubiquitin ligase that contains Skp1, a member of the cullin family (Cdc53) and an F-box protein, as well as a RING-finger-containing protein [46]. CDKs including CDK1, CDK2, CDK4, CDK6, and CDK11 have various functions that have been investigated using loss-of-function, target validation, and gain-of-function mouse models [38]. CDK1 is a mitotic CDK, also known as cell division control protein 2 (CDC2). It is one of the master regulators of mitosis as it controls the centrosome cycle as well as mitotic onset; deficiency in CDK1 results in embryonic lethality in the first cell divisions [38,47]. CDK2, CDK4, and CDK6 are interphase CDKs that are not essential for the mammalian cell cycle; they are, however, required for the proliferation of specific cell types [38]. Deficiency in CDK2, CDK4, and CDK6 caused mid-gestation embryonic lethality because of hematopoietic defects [38,47].
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.3. Genes related to cell differentiation
\n\t\t\t\t
Inhibitor of differentiation 1 (Id1) is associated with the induction of cell proliferation and invasion [48], as well as the invasive features of cancer and the EMT [48]. The HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis [49]. The expression of HOXA1, which plays an important role in proliferation, apoptosis, adhesion, invasion, the EMT, and anchorage-independent growth, was significantly increased in oral squamous cell carcinoma compared with in healthy oral mucosa [49], and it might be a useful prognostic marker for patients with this disease [49].
\n\t\t\t\t
Wnt/β-catenin signaling controls skeletal development and differentiation [50]. The initiating step of skeletal development is mesenchymal condensation, during which mesenchymal progenitor cells are at least bipotentiate [50]. Osteochondral progenitor cells differentiate into osteoblasts instead of chondrocytes when Wnt/β-catenin signaling is activated [50]. In vitro models using human pluripotent stem cell-derived neural progenitor cells have been used to examine whether G11778A-mutated mitochondrial DNA, which is associated with Leber’s hereditary optic neuropathy, might be involved in the differentiation of neural progenitor cells into neurons, oligodendrocytes, and astrocytes [51]. The differentiation of neural progenitor cells can be visualized by staining for the neuronal marker class III beta-tubulin [51]. Alternative splicing of exons play an important role in cellular differentiation and pathogenesis [52]. Alternative splicing in colorectal cancer and renal cell cancer samples has been analyzed by the Bioinformatics Exon Array Tool (BEAT, http://beat.ba.itb.cnr.it/) using an Affymetrix GeneChip Exon Array [52]. When the dataset was analyzed using GO terms, the cell differentiation (GO:0030154)-related gene delta-like 1 (Drosophila) (DLL1) was found to be involved in colorectal cancer [52].
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.4. Genes related to apoptosis
\n\t\t\t\t
Cell proliferation and death are regulated by various molecules. Recently, microRNAs have been revealed to play important roles during death receptor-mediated apoptosis (programmed cell death) [53]. Transfection with miR-133b caused a proapoptotic effect on tumor necrosis factor alpha (TNFα)-stimulated HeLa cells [53]: the expression of apoptosis regulatory proteins such as transgelin 2 (TAGLN2), myosin, heavy chain 9, non-muscle (MYH9), cytoskeleton-associated protein 4 (CKAP4), polypyrimidine tract binding protein 1 (PTBP1), glutathione-S-transferase pi 1 (GSTP1), and copine III (CPNE3) were down-regulated compared with in control cells [53]. The BCL protein family plays a major role in regulation of the apoptotic cascade [54]. BCL2-associated protein (BAX) promotes apoptosis and delays disease progression, and has been associated with longer disease-free survival in patients with a number of gastrointestinal cancers, such as esophageal, stomach, small intestine, and colon cancer; moreover, high BCL6 expression is correlated with worse prognosis in patients with other gastrointestinal tumors, such as esophageal adenocarcinoma [54]. There are two major cell death pathways that transduce the effects of various death inducers: the extrinsic death pathway that is mediated through cell death receptors of the TNF receptor family, such as the Fas receptor; and the intrinsic death pathway that proceeds through mitochondria [55]. The expression of apoptosis signal-regulating kinase (ASK1), which plays an important role as a mitogen-activated protein kinase kinase kinase in apoptosis signaling, is increased in gastric cancer [56]. Furthermore, the levels of cyclin D1 and phosphorylated JNK were higher in gastric cancer than in non-tumor epithelium [56]. ASK1 may play a role in the development of gastric cancer [56].
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.5. Detection of cell proliferation or apoptosis
\n\t\t\t\t
Several methods have been suggested for the diagnosis of cancer [57]. Protein markers for cancer include prostate-specific antigen for prostate cancer, CA125 for ovarian cancer, carcinoembryonic antigen for colon cancer, human chorionic gonadotropin for trophoblastic cancer, and a-fetoprotein for hepatocellular carcinoma and germ cell tumors [57]. Assays to detect telomerase activity in clinical samples include the TRAP (telomere repeat amplification protocol) assay, which involves protein extraction and subsequent primer-directed PCR amplification of telomere extensions [57].
\n\t\t\t\t
Assays for the detection of kinases that regulate cell growth, proliferation, differentiation, and metabolism have been developed [58]. The assay technology includes fluorescence polarization to detect protein phosphorylation, scintillation proximity to detect protein dephosphorylation by phosphatases, fluorescence resonance energy transfer to detect protein cleavage or modification, immunosorbent assays to detect phosphorylation state, luciferase-based ATP detection to detect the kinase-dependent depletion of ATP, luminescent oxygen channeling to detect phosphorylation, time-resolved fluorescence resonance energy transfer to detect phosphopeptide formation, and enzyme fragment complementation to detect molecular interactions with kinases [58,59]. Cell proliferation can also be determined by the tetrazolium hydroxide (XTT) cell proliferation assay, in which absorbance is measured by an ELISA reader under 490-nm-wavelength light (Biological Industries) [60].
\n\t\t\t\t
Cell proliferation assays and apoptosis assays have been used to examine the effects of inhibitors on cancer cells [61]. The cell proliferation of Neuro-2A cells, neuroblastoma cells, can be determined using the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay reagent (Promega) [61]. A colony formation assay using Neuro-2A cells was used to determine the effect of an inhibitor of GSK-3β [61]. In this experiment, colonies were allowed to form for 10 days, after which the cells were fixed with 70% ethanol and stained with 1% methylene blue. Apoptosis was then measured by flow cytometry using an Annexin V-allophycocyanin (APC) /propidium iodide (PI) detection kit (BD PharMingen) [61]. Apoptosis was also determined using 4’6-diamidino-2-phenylindole (DAPI) staining, observing apoptotic nuclear morphology, and immunoblotting with antibodies to β-catenin, X-linked inhibitor of apoptosis, and BCL2 [61]. Cell cycle analysis using PI to quantify the proportions of cells in the G1/G0 or G2–M phases was used to examine cell cycle status [61].
\n\t\t\t\t
Viable cells can be determined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assays [62]. Absorbance at 570 nm is used to detect the incorporation of MTT. Apoptosis can also be determined by caspase activation using an anti-poly ADP-ribose polymerase (PARP) antibody [62]. Viable cells can also be determined using a 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) kit (Promega) [63]. The terminal transferase dUTP nick end labeling (TUNEL) assay is commonly used to detect apoptosis [63]. Harvested cells are resuspended in DNA labeling solution consisting of TdT reaction buffer, TdT enzyme, and BrdUTP, then stained with PI to detect a fluorescein isothiocyanate-labeled anti-BrdU antibody [63]. Cell viability and proliferation assays were used to validate internal tandem duplication mutations in FLT3 as a therapeutic target for human acute myeloid leukemia [64]. Cell viability and proliferation can be determined using a Vi-cell XR automated cell viability analyzer (Beckman Coulter) [64].
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
3. Genomic variation in disease
\n\t\t\t
\n\t\t\t\t
3.1. Genome-wide association studies in cancer
\n\t\t\t\t
Despite extensive research efforts for several decades, the genetic basis of common human diseases such as cancers remains largely unknown [65]. Genome-wide association studies (GWAS) have emerged as an important tool for the discovery of genomic regions that harbor genetic variants conferring risk for various cancers [66,67]. Family-based linkage studies and studies comprising tens of thousands of gene-based SNPs can also assay genetic variation across the genome [68], but the National Institutes of Health guidelines for GWAS require a sufficient density of genetic markers to capture a large proportion of the common variants in the study population, measured in enough individuals to provide sufficient power to detect variants of modest effect [67]. The recent success of GWAS can be attributed to the convergence of new technologies that can genotype hundreds of thousands of SNPs in hundreds or thousands of samples [66,69].
\n\t\t\t\t
GWAS have been conducted in the five of the most common cancer types: breast, prostate, colorectal, lung, and melanoma (Table 4) and have identified more than 20 novel disease loci, confirming that susceptibility to these diseases is polygenic [70]. For many years, human genetics has been used to map rare mutations with large effect sizes in families or genetically homogeneous populations, such as BRCA1/BRCA2 mutations in Ashkenazi women with breast cancer and ovarian cancer [71]. A number of SNPs have now been associated with breast cancer; for example, a SNP in intron 2 of the FGFR2 gene, which encodes a receptor tyrosine kinase that is amplified and overexpressed in 5–10% of breast tumors [72,73], and SNPs on chromosomes 16q and 5q. The locus on 16q contains a gene TNRC9 and a hypothetical gene LOC643714. The function of TNRC9 is unknown but the presence of an HMG box motif suggests that it might act as a transcription factor. The 5q locus includes MAP3K1, which encodes a protein involved in signal transduction (but not previously known to be involved in cancer) and two other genes: MGC33648 and MIER3. In addition, several of the breast cancer loci appear to be associated with specific subtypes of the disease. In particular, the FGFR2 association is strongly associated with estrogen receptor-positive breast cancer, while the TNRC9 SNP is associated with both estrogen receptor-positive and -negative breast cancer [74,75]. It is surprising that none of the strongest associations map to regions harboring estrogen/progesterone genes in women of European background, particularly because a GWAS in Asian women reported a convincing association with markers near the estrogen receptor alpha (ESR1) gene [76]. In prostate cancer, the first and most important region to emerge was 8q24. This region was first associated with prostate cancer through linkage studies by the deCode group, was followed up by association analyses [77], and has been confirmed in subsequent GWAS [78-81]. Another signal, on chromosome 10q13, points to a variant in the promoter of the MSMB gene, which encodes the PSP94 protein; this is now under intense investigation as a biomarker for prostate cancer [80,81].
\n\t\t\t\t
In general, the susceptibility alleles discovered thus far are common—that is, with a frequency in one or more population of >10%, and each allele confers a small contribution to the overall risk of the disease. For nearly all regions conclusively identified by GWAS, the effect sizes per allele are estimated at <1.3. It was not anticipated that GWAS in certain cancers would yield many novel regions when other cancers strongly associated with particular environmental exposures have yielded so few regions. For example, prostate cancer, breast cancer, and colon cancer have been associated with 29, 13, and 10 regions of the genome, respectively, while there are only three associated regions for lung cancer in smokers, and three for bladder cancer despite analysis of sufficiently large data sets [67]. Several GWAS for lung cancer have identified the same locus on 15q25, suggesting that this is an important susceptibility locus for this disease [82-87]. This locus contains the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, suggesting that susceptibility may be mediated through smoking behavior [86,87].
\n\t\t\t\t
GWAS represent an important advance in discovering genetic variants influencing disease but have important limitations. There is a high potential for false-positive results, they do not yield information on gene function, they are insensitive to rare and structural variants, they require large sample sizes, and incur possible biases because of case and control selection and genotyping errors [88]. Clinicians and scientists must understand the unique aspects of these studies and be able to assess and interpret GWAS results for themselves and their patients. However, at present these studies mainly represent a valuable discovery tool for examining genomic function and clarifying pathophysiological mechanisms. However, through GWAS, the identification of variants, genes, and pathways involved in multiple cancers offers a potential route to new therapies, improved diagnosis, and better disease prevention [65].
European, Chinese, Japanese, African American, Latino, and Hawaiian
\n\t\t\t\t\t\t\t
19,879
\n\t\t\t\t\t\t\t
18,761
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[117]
\n\t\t\t\t\t\t\t
2009
\n\t\t\t\t\t\t\t
Illumina [310,520]
\n\t\t\t\t\t\t\t
Icelandic
\n\t\t\t\t\t\t\t
1,968
\n\t\t\t\t\t\t\t
35,382
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
11,806
\n\t\t\t\t\t\t\t
12,387
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[118]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [541,129]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
1,854
\n\t\t\t\t\t\t\t
1,894
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
3,268
\n\t\t\t\t\t\t\t
3,366
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[119]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [527,869]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,172
\n\t\t\t\t\t\t\t
1,157
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
3,941
\n\t\t\t\t\t\t\t
3,964
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[120]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Affymetrix & Illumina [60,275]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,235
\n\t\t\t\t\t\t\t
1,599
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,242
\n\t\t\t\t\t\t\t
917
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[121]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Affymetrix [70,897]
\n\t\t\t\t\t\t\t
Framingham
\n\t\t\t\t\t\t\t
1,345
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[122]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Illumina [316,515]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,453
\n\t\t\t\t\t\t\t
3,064
\n\t\t\t\t\t\t\t
East Asia
\n\t\t\t\t\t\t\t
1,210
\n\t\t\t\t\t\t\t
2,445
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[123]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Illumina [538,548]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,172
\n\t\t\t\t\t\t\t
1,157
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
3,124
\n\t\t\t\t\t\t\t
3,142
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Colorectal cancer
\n\t\t\t\t\t\t\t
[124]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [378,739]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
2,906
\n\t\t\t\t\t\t\t
3,416
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
8,161
\n\t\t\t\t\t\t\t
9,101
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[125]
\n\t\t\t\t\t\t\t
2010
\n\t\t\t\t\t\t\t
Illumina [~550,000] (imputed)
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
3,334
\n\t\t\t\t\t\t\t
4,628
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
14,851
\n\t\t\t\t\t\t\t
15,569
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[126]
\n\t\t\t\t\t\t\t
2010
\n\t\t\t\t\t\t\t
Affymetrix [460,945]
\n\t\t\t\t\t\t\t
German
\n\t\t\t\t\t\t\t
371
\n\t\t\t\t\t\t\t
1,263
\n\t\t\t\t\t\t\t
German Czech
\n\t\t\t\t\t\t\t
4,121 794
\n\t\t\t\t\t\t\t
7,344 815
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[127]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [~548,586]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,902
\n\t\t\t\t\t\t\t
1,929
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
4,878
\n\t\t\t\t\t\t\t
4,914
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[128]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [541,628]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
981
\n\t\t\t\t\t\t\t
1,002
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
16,476
\n\t\t\t\t\t\t\t
15,351
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[129]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [547,647]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
922
\n\t\t\t\t\t\t\t
927
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
17,872
\n\t\t\t\t\t\t\t
17,526
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[130]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Illumina [547,647]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
940
\n\t\t\t\t\t\t\t
965
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
7,473
\n\t\t\t\t\t\t\t
5,984
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[131]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Illumina [547,647]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
930
\n\t\t\t\t\t\t\t
960
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
7,334
\n\t\t\t\t\t\t\t
5,246
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[132]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Affymetrix & Illumina [99,632]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,257
\n\t\t\t\t\t\t\t
1,336
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
6,223
\n\t\t\t\t\t\t\t
6,443
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Lung cancer
\n\t\t\t\t\t\t\t
[133]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Affymetrix [906,703]
\n\t\t\t\t\t\t\t
Chinese
\n\t\t\t\t\t\t\t
2,331
\n\t\t\t\t\t\t\t
3,077
\n\t\t\t\t\t\t\t
Chinese
\n\t\t\t\t\t\t\t
6,313
\n\t\t\t\t\t\t\t
6,409
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[134]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [307,260]
\n\t\t\t\t\t\t\t
White
\n\t\t\t\t\t\t\t
327
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
587
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[135]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [620,901] (pooled)
\n\t\t\t\t\t\t\t
Italian
\n\t\t\t\t\t\t\t
600
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t\t
Italian
\n\t\t\t\t\t\t\t
317
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[136]
\n\t\t\t\t\t\t\t
2010
\n\t\t\t\t\t\t\t
Affymetrix [265,996]
\n\t\t\t\t\t\t\t
Han Chinese
\n\t\t\t\t\t\t\t
245
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t\t
Han Chinese
\n\t\t\t\t\t\t\t
305
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[137]
\n\t\t\t\t\t\t\t
2010
\n\t\t\t\t\t\t\t
Affymetrix [246,758]
\n\t\t\t\t\t\t\t
Korean
\n\t\t\t\t\t\t\t
621
\n\t\t\t\t\t\t\t
1,541
\n\t\t\t\t\t\t\t
Korean
\n\t\t\t\t\t\t\t
804
\n\t\t\t\t\t\t\t
1,470
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[138]
\n\t\t\t\t\t\t\t
2010
\n\t\t\t\t\t\t\t
Illumina [542,050]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
377
\n\t\t\t\t\t\t\t
377
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
511
\n\t\t\t\t\t\t\t
1,007
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[139]
\n\t\t\t\t\t\t\t
2009
\n\t\t\t\t\t\t\t
Illumina [515,922]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
5,739
\n\t\t\t\t\t\t\t
5,848
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
7,561
\n\t\t\t\t\t\t\t
13,818
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[140]
\n\t\t\t\t\t\t\t
2009
\n\t\t\t\t\t\t\t
Illumina [511,919]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
1,952
\n\t\t\t\t\t\t\t
1,438
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
5,608
\n\t\t\t\t\t\t\t
6,767
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[141]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [317,498]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,154
\n\t\t\t\t\t\t\t
1,138
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
2,724
\n\t\t\t\t\t\t\t
3,694
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[142]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [306,207]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
10,995 smokers
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
4,848 smokers
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[143]
\n\t\t\t\t\t\t\t
2008
\n\t\t\t\t\t\t\t
Illumina [310,023]
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
1,926
\n\t\t\t\t\t\t\t
2,522
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
2,513
\n\t\t\t\t\t\t\t
4,752
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[144]
\n\t\t\t\t\t\t\t
2007
\n\t\t\t\t\t\t\t
Affymetrix [~116,204] (pooled)
\n\t\t\t\t\t\t\t
Italian
\n\t\t\t\t\t\t\t
338
\n\t\t\t\t\t\t\t
335
\n\t\t\t\t\t\t\t
Norwegian
\n\t\t\t\t\t\t\t
265
\n\t\t\t\t\t\t\t
356
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Melanoma
\n\t\t\t\t\t\t\t
[145]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [594,997]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
2,804
\n\t\t\t\t\t\t\t
7,618
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
5,551
\n\t\t\t\t\t\t\t
7,449
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[146]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [5,480,804 (imputed)]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
2,168
\n\t\t\t\t\t\t\t
4,387
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
5,193
\n\t\t\t\t\t\t\t
15,144
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[147]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [818,977]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
1,804
\n\t\t\t\t\t\t\t
1,026
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
6,483
\n\t\t\t\t\t\t\t
23,324
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[148]
\n\t\t\t\t\t\t\t
2011
\n\t\t\t\t\t\t\t
Illumina [491,227]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
156
\n\t\t\t\t\t\t\t
2,150
\n\t\t\t\t\t\t\t
NR
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t\t
-
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
[149]
\n\t\t\t\t\t\t\t
2009
\n\t\t\t\t\t\t\t
Illumina [~317,000]
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
1,539
\n\t\t\t\t\t\t\t
3,917
\n\t\t\t\t\t\t\t
European
\n\t\t\t\t\t\t\t
2,312
\n\t\t\t\t\t\t\t
1,867
\n\t\t\t\t\t\t
\n\t\t\t\t\t
Table 4.
Summary of GWAS for the five of the most common types of cancer.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
3.2. Genetic risk score in cancer and diabetes
\n\t\t\t\t
Type 2 diabetes mellitus and cancers are major health problems worldwide [150,151]. The recent increase in the prevalence of these diseases is largely attributable to environmental factors. However, convincing evidence shows that genetic factors may play an important role in these diseases [152,153]. Recent GWAS have led to the identification of a series of SNPs that are robustly associated with either the risk of diabetes or cancers [151,154-159]. For type 2 diabetes mellitus, common SNPs have been identified in the PPARG, KCNJ11, and TCF7L2 genes, and have been widely replicated in populations of various ethnicities [160-162]. Other potential new loci include HHEX, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and WFS1 [65,155-159,163,164]. A number of SNPs have been identified as associated with breast cancer risk, including FGFR2, CASP8, ERBB4, \n\t\t\t\t\t\tTAB2\n\t\t\t\t\t, BARX2, TMEM45B, ESR1, FGFR2, TNRC9, MAP3K1, MGC33648, MIER3, and RAD51L1 [74,75,151] (Table 5).
\n\t\t\t\t
Combining multiple loci with modest effects into a global genetic risk score (GRS) might improve the identification of those at risk for common complex diseases such as type 2 diabetes and cancers [165-167]. Several studies have developed methods to predict the risk of certain diseases, such as coronary heart disease, type 2 diabetes, and breast cancer, aggregating information from multiple SNPs into a single GRS [151,168,169]. For example, in the Atherosclerosis Risk in Communities study, the aggregation of multiple SNPs into a single GRS was responsible for improving the prediction of coronary heart disease incidence [168]. In a study that used a GRS to determine the risk of type 2 diabetes in US men and women, individuals in the highest quintile of GRS had a significantly increased risk of type 2 diabetes compared with those in the lowest quintile; however, the addition of a GRS to the conventional model consisting of lifestyle risk factors only increased the area under the curve by only 1% (AUC=0.78). In this instance, the GRS was determined to be useful only when combined with the body mass index or a family history of diabetes [169]. For breast cancer, a GRS was created using 14 SNPs previously associated with breast cancer, and was substantially more predictive of estrogen receptor-positive breast cancer than of estrogen receptor-negative breast cancer, particularly for absolute risk [151]. Further studies are needed to confirm whether a GRS improves disease risk prediction.
\n\t\t\t\t
The GRS is calculated on the basis of reproducible tagging of SNP-associated loci reaching genome-wide levels of significance. The GRS can be created by two methods: a simple count method (count GRS) and a weighted method (weighted GRS) [169,170]. Both methods anticipate each SNP to be independently associated with risk. An additive genetic model is used for each SNP, applying a linear weighting of 0, 1, or 2 to genotypes containing 0, 1, or 2 risk alleles, respectively. This model is known to perform well even when the true genetic model is unknown or wrongly specified [171]. The count model assumes that each SNP in the panel contributes equally to the disease risk and is calculated by summing the values for each of the SNPs. The weighted GRS is calculated by multiplying each B-coefficient, the estimates resulting from an analysis carried out on variables that have been standardized, by the number of corresponding risk alleles (0, 1, or 2).
\n\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tDisease\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tReference\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tYear\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tEthnic group\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tParticipants\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tNo. of SNPs\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tGenes found from GWAS\n\t\t\t\t\t\t\t
Studies using a genetic risk score for cancers and diabetes, comprising SNPs identified in GWAS.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
3.3. Cancer Cell Line Encyclopedia
\n\t\t\t\t
The Cancer Cell Line Encyclopedia (CCLE) has made predictive modeling of anticancer drug sensitivity a realistic proposition, by determining genomic markers of drug sensitivity in cancer cells [172,173]. The CCLE contains information from 947 human cancer cell lines including data on gene expression, chromosomal copy number, and massively parallel sequencing data. It has been used to identify genetic, lineage-specific, and gene expression-based predictors of drug sensitivity [172]. This has revealed, for example, that the plasma cell lineage is correlated with sensitivity to IGF1 receptor inhibitors, aryl hydrocarbon receptor (AHR) expression is associated with MEK inhibitor efficacy in NRAS-mutant lines, and SLFN11 expression is associated with sensitivity to topoisomerase inhibitors [172]. Genomic markers of drug sensitivity in cancer cells have also been systematically identified using the Genomics of Drug Sensitivity in Cancer database (http://www.cancerRxgene.org) [173]. These databases will enable to overview genome quality.
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
4. Conclusion
\n\t\t\t
There are dramatic changes in the genomes of cancer cells, which vary according to cancer subtype. Integrative and wide investigations of cancer cell genomes have revealed mutations and alterations in gene expression that are associated with the disease. Databases that include abundant data related to gene and protein conformation, gene expression, and genomic mutations enable the construction of dynamic cellular simulations and disease models. New sequencing tools such as next-generation sequencing will reveal new horizons in the prediction of disease and drug sensitivity, which play an important role in personalized medicine. Appropriate translation of the abundance of information to clinical practice is one of most important future challenges for medicine. The quality of genome would be one of the important factors for detecting the development of the disease.
\n\t\t
\n\t
Acknowledgments
\n\t\t\t
The authors are grateful to all those who helped with preparation of the manuscript. In particular, we thank Jaeseong Jo for his great assistance.
\n\t\t
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/38217.pdf",chapterXML:"https://mts.intechopen.com/source/xml/38217.xml",downloadPdfUrl:"/chapter/pdf-download/38217",previewPdfUrl:"/chapter/pdf-preview/38217",totalDownloads:1908,totalViews:164,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:23,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"March 19th 2012",dateReviewed:"July 3rd 2012",datePrePublished:null,datePublished:"December 12th 2012",dateFinished:"August 10th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/38217",risUrl:"/chapter/ris/38217",book:{id:"3276",slug:"latest-research-into-quality-control"},signatures:"Shihori Tanabe and Sun Ha Jee",authors:[{id:"48635",title:"Dr.",name:"Shihori",middleName:null,surname:"Tanabe",fullName:"Shihori Tanabe",slug:"shihori-tanabe",email:"stanabe@nihs.go.jp",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/48635/images/6205_n.jpg",institution:null},{id:"153388",title:"Prof.",name:"Sun Ha",middleName:null,surname:"Jee",fullName:"Sun Ha Jee",slug:"sun-ha-jee",email:"jsunha@yuhs.ac",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Gene regulation",level:"1"},{id:"sec_2_2",title:"2.1. Gene markers for cancer and cancer stem cells",level:"2"},{id:"sec_3_2",title:"2.2. Genes related to cell proliferation",level:"2"},{id:"sec_4_2",title:"2.3. Genes related to cell differentiation",level:"2"},{id:"sec_5_2",title:"2.4. Genes related to apoptosis",level:"2"},{id:"sec_6_2",title:"2.5. Detection of cell proliferation or apoptosis",level:"2"},{id:"sec_8",title:"3. Genomic variation in disease",level:"1"},{id:"sec_8_2",title:"3.1. Genome-wide association studies in cancer",level:"2"},{id:"sec_9_2",title:"3.2. Genetic risk score in cancer and diabetes",level:"2"},{id:"sec_10_2",title:"3.3. Cancer Cell Line Encyclopedia",level:"2"},{id:"sec_12",title:"4. Conclusion",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVenter\n\t\t\t\t\t\t\tJ. 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Chem.\n\t\t\t\t\t287\n\t\t\t\t\t27\n\t\t\t\t\t22463\n\t\t\t\t\t22482\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLandis\n\t\t\t\t\t\t\tM. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPawlyk\n\t\t\t\t\t\t\tB. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSicinski\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHinds\n\t\t\t\t\t\t\tP. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tCyclin D1-dependent kinase activity in murine development and mammary tumorigenesis\n\t\t\t\t\tCancer Cell\n\t\t\t\t\t9\n\t\t\t\t\t1\n\t\t\t\t\t13\n\t\t\t\t\t22\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKlein\n\t\t\t\t\t\t\tE. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAssoian\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tTranscriptional regulation of the cyclin D1 gene at a glance\n\t\t\t\t\tJ. 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Cell Biol.\n\t\t\t\t\t155\n\t\t\t\t\t6\n\t\t\t\t\t1055\n\t\t\t\t\t1064\n\t\t\t\t\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShtutman\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhurinsky\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSimcha\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlbanese\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tD’Amico\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPestell\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tThe cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway\n\t\t\t\t\tProc. Natl. Acad. Sci.\n\t\t\t\t\tUSA\n\t\t\t\t\t96\n\t\t\t\t\t10\n\t\t\t\t\t5522\n\t\t\t\t\t5527\n\t\t\t\t\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLuo\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheung\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tControl of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase\n\t\t\t\t\tCancer Cell\n\t\t\t\t\t16\n\t\t\t\t\t5\n\t\t\t\t\t413\n\t\t\t\t\t424\n\t\t\t\t\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCoudreuse\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNurse\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tDriving the cell cycle with a minimal CDK control network\n\t\t\t\t\tNature\n\t\t\t\t\t468\n\t\t\t\t\t7327\n\t\t\t\t\t1074\n\t\t\t\t\t1079\n\t\t\t\t\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBloom\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCross\n\t\t\t\t\t\t\tF. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tMultiple levels of cyclin specificity in cell-cycle control\n\t\t\t\t\tNat. Rev. Mol. Cell Biol.\n\t\t\t\t\t8\n\t\t\t\t\t2\n\t\t\t\t\t149\n\t\t\t\t\t160\n\t\t\t\t\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSantamaría\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarrière\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCerqueira\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHunt\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTardy\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNewton\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tCdk1 is sufficient to drive the mammalian cell cycle\n\t\t\t\t\tNature\n\t\t\t\t\t448\n\t\t\t\t\t7155\n\t\t\t\t\t811\n\t\t\t\t\t815\n\t\t\t\t\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTobin\n\t\t\t\t\t\t\tN. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSims\n\t\t\t\t\t\t\tA. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLundgren\n\t\t\t\t\t\t\tK. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLehn\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLandberg\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tCyclin D1, Id1 and EMT in breast cancer\n\t\t\t\t\tBMC Cancer\n\t\t\t\t\t11\n\t\t\t\t\t417\n\t\t\t\t\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBitu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDestro\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarrera\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilva\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGraner\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKowalski\n\t\t\t\t\t\t\tL. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoares\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tHOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis\n\t\t\t\t\tBMC Cancer\n\t\t\t\t\t12\n\t\t\t\t\t146\n\t\t\t\t\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tWnt signaling in development and disease\n\t\t\t\t\tCell & Bioscience\n\t\t\t\t\t2\n\t\t\t\t\t14\n\t\t\t\t\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIyer\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlsayegh\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEroshenko\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRiggs\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBennett\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tMitochondrial gene replacement in human pluripotent stem cell-derived neural progenitors\n\t\t\t\t\tGene Ther.\n\t\t\t\t\t19\n\t\t\t\t\t5\n\t\t\t\t\t469\n\t\t\t\t\t475\n\t\t\t\t\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConsiglio\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarella\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Caro\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDelle\n\t\t\t\t\t\t\tFoglie. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGiovannelli\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrillo\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tBEAT: Bioinformatics Exon Array Tool to store, analyze and visualize Affymetrix GeneChip Human Exon Array data from disease experiments\n\t\t\t\t\tBMC Bioinformatics\n\t\t\t\t\t13\n\t\t\t\t\tSuppl 4\n\t\t\t\t\tS21\n\t\t\t\t\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPatron\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFendler\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBild\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJung\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMüller\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArntzen\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tMiR-133b targets antiapoptotic genes and enhances death receptor-induced apoptosis\n\t\t\t\t\tPLoS One\n\t\t\t\t\t7\n\t\t\t\t\t4\n\t\t\t\t\te35345\n\t\t\t\t\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlevizos\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGomatos\n\t\t\t\t\t\t\tI. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmparounis\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKonstadoulakis\n\t\t\t\t\t\t\tM. 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L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHunter\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBignell\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tPatterns of somatic mutation in human cancer genomes\n\t\t\t\t\tNature\n\t\t\t\t\t446\n\t\t\t\t\t7132\n\t\t\t\t\t153\n\t\t\t\t\t158\n\t\t\t\t\n\t\t\t'},{id:"B74",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarcia-Closas\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHall\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNevanlinna\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPooley\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorrison\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRichesson\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tHeterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics\n\t\t\t\t\tPloS Genet.\n\t\t\t\t\t4\n\t\t\t\t\t4\n\t\t\t\t\te1000054\n\t\t\t\t\n\t\t\t'},{id:"B75",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAntoniou\n\t\t\t\t\t\t\tA. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpurdle\n\t\t\t\t\t\t\tA. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSinilnikova\n\t\t\t\t\t\t\tO. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHealey\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPooley\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchmutzler\n\t\t\t\t\t\t\tR. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tCIMBA. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers\n\t\t\t\t\tAm. J. Hum. Genet.\n\t\t\t\t\t82\n\t\t\t\t\t4\n\t\t\t\t\t937\n\t\t\t\t\t948\n\t\t\t\t\n\t\t\t'},{id:"B76",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZheng\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLong\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tY. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZheng\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiang\n\t\t\t\t\t\t\tY. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tGenome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t41\n\t\t\t\t\t3\n\t\t\t\t\t324\n\t\t\t\t\t328\n\t\t\t\t\n\t\t\t'},{id:"B77",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmundadottir\n\t\t\t\t\t\t\tL. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSulem\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGudmundsson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHelgason\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaker\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAgnarsson\n\t\t\t\t\t\t\tB. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tA common variant associated with prostate cancer in European and African populations\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t38\n\t\t\t\t\t6\n\t\t\t\t\t652\n\t\t\t\t\t658\n\t\t\t\t\n\t\t\t'},{id:"B78",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYeager\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrr\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHayes\n\t\t\t\t\t\t\tR. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJacobs\n\t\t\t\t\t\t\tK. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKraft\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWacholder\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGenome-wide association study of prostate cancer identifies a second risk locus at 8q24\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t39\n\t\t\t\t\t5\n\t\t\t\t\t645\n\t\t\t\t\t649\n\t\t\t\t\n\t\t\t'},{id:"B79",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGudmundsson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSulem\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManolescu\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmundadottir\n\t\t\t\t\t\t\tL. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGudbjartsson\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHelgason\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGenome-wide association study identifies a second prostate cancer susceptibility variant at 8q24\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t39\n\t\t\t\t\t5\n\t\t\t\t\t631\n\t\t\t\t\t637\n\t\t\t\t\n\t\t\t'},{id:"B80",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEeles\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKote-Jarai\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGiles\n\t\t\t\t\t\t\tG. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOlama\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuy\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJugurnauth\n\t\t\t\t\t\t\tS. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tMultiple newly identified loci associated with prostate cancer susceptibility\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t30\n\t\t\t\t\t316\n\t\t\t\t\t321\n\t\t\t\t\n\t\t\t'},{id:"B81",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomas\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJacobs\n\t\t\t\t\t\t\tK. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYeager\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKraft\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWacholder\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrr\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tMultiple loci identified in a genome-wide association study of prostate cancer\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t3\n\t\t\t\t\t310\n\t\t\t\t\t315\n\t\t\t\t\n\t\t\t'},{id:"B82",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChanock\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHunter\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tGenomics: when the smoke clears\n\t\t\t\t\tNature\n\t\t\t\t\t452\n\t\t\t\t\t7187\n\t\t\t\t\t537\n\t\t\t\t\t538\n\t\t\t\t\n\t\t\t'},{id:"B83",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHung\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Kay\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaborieau\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoffetta\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHashibe\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZaridze\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tA susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25\n\t\t\t\t\tNature\n\t\t\t\t\t452\n\t\t\t\t\t7187\n\t\t\t\t\t633\n\t\t\t\t\t637\n\t\t\t\t\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Kay\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHung\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaborieau\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoffetta\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChabrier\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tByrnes\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tLung cancer susceptibility locus at 5p15\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t12\n\t\t\t\t\t1404\n\t\t\t\t\t1406\n\t\t\t\t\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBroderick\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWebb\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVijayakrishnan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatakidou\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tCommon 5p15and 6p21.33 variants influence lung cancer risk\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t12\n\t\t\t\t\t1407\n\t\t\t\t\t1409\n\t\t\t\t\n\t\t\t'},{id:"B86",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBierut\n\t\t\t\t\t\t\tL. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMadden\n\t\t\t\t\t\t\tP. 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Mol. Genet.\n\t\t\t\t\t20\n\t\t\t\t\t24\n\t\t\t\t\t4991\n\t\t\t\t\t4999\n\t\t\t\t\n\t\t\t'},{id:"B94",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSehrawat\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSridharan\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGhosh\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobson\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCass\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMackey\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tPotential novel candidate polymorphisms identified in genome-wide association study for breast cancer susceptibility\n\t\t\t\t\tHum. 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I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSiddiq\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJacobs\n\t\t\t\t\t\t\tK. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLindstrom\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenome-wide association study identifies new prostate cancer susceptibility loci\n\t\t\t\t\tHum. Mol. Genet.\n\t\t\t\t\t20\n\t\t\t\t\t19\n\t\t\t\t\t3867\n\t\t\t\t\t3875\n\t\t\t\t\n\t\t\t'},{id:"B112",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHaiman\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tG. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlot\n\t\t\t\t\t\t\tW. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStrom\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerndt\n\t\t\t\t\t\t\tS. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKittles\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t43\n\t\t\t\t\t6\n\t\t\t\t\t570\n\t\t\t\t\t573\n\t\t\t\t\n\t\t\t'},{id:"B113",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFitz\n\t\t\t\t\t\t\tGerald L. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKwon\n\t\t\t\t\t\t\tE. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConomos\n\t\t\t\t\t\t\tM. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKolb\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHolt\n\t\t\t\t\t\t\tS. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevine\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenome-wide association study identifies a genetic variant associated with risk for more aggressive prostate cancer\n\t\t\t\t\tCancer Epidemiol. 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Biomarkers Prev.\n\t\t\t\t\t19\n\t\t\t\t\t11\n\t\t\t\t\t2869\n\t\t\t\t\t2876\n\t\t\t\t\n\t\t\t'},{id:"B115",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakata\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkamatsu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKubo\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakahashi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHosono\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawaguchi\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tGenome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t42\n\t\t\t\t\t9\n\t\t\t\t\t751\n\t\t\t\t\t754\n\t\t\t\t\n\t\t\t'},{id:"B116",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEeles\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKote-Jarai\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAl Olama\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGiles\n\t\t\t\t\t\t\tG. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuy\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeveri\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tUK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons’ Section of Oncology; UK ProtecT Study Collaborators; PRACTICAL Consortium, Easton DF Identification of seven new prostate cancer susceptibility loci through a genome-wide association study\n\t\t\t\t\tNat. 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B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYeager\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKraft\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWacholder\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrr\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tMultiple loci identified in a genome-wide association study of prostate cancer\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t3\n\t\t\t\t\t310\n\t\t\t\t\t315\n\t\t\t\t\n\t\t\t'},{id:"B120",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDuggan\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZheng\n\t\t\t\t\t\t\tS. 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E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSplansky\n\t\t\t\t\t\t\tG. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tA genome-wide association study of breast and prostate cancer in the NHLBI’s Framingham Heart Study\n\t\t\t\t\tBMC Med. Genet.\n\t\t\t\t\t8\n\t\t\t\t\tSuppl 1\n\t\t\t\t\tS6\n\t\t\t\t\n\t\t\t'},{id:"B122",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGudmundsson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSulem\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManolescu\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmundadottir\n\t\t\t\t\t\t\tL. 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B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKraft\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWacholder\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGenome-wide association study of prostate cancer identifies a second risk locus at 8q24\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t39\n\t\t\t\t\t5\n\t\t\t\t\t645\n\t\t\t\t\t649\n\t\t\t\t\n\t\t\t'},{id:"B124",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeters\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHutter\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHsu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchumacher\n\t\t\t\t\t\t\tF. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConti\n\t\t\t\t\t\t\tD. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarlson\n\t\t\t\t\t\t\tC. 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S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWebb\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBroderick\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPittman\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Bernardo\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLubbe\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tInternational Colorectal Cancer Genetic Association Consortium\n\t\t\t\t\tMeta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t12\n\t\t\t\t\t1426\n\t\t\t\t\t1435\n\t\t\t\t\n\t\t\t'},{id:"B128",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTenesa\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFarrington\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrendergast\n\t\t\t\t\t\t\tJ. 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M.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tA genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14and 8q23.3\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t5\n\t\t\t\t\t623\n\t\t\t\t\t630\n\t\t\t\t\n\t\t\t'},{id:"B130",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBroderick\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarvajal-Carmona\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPittman\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWebb\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHowarth\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRowan\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tCORGI Consortium. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk\n\t\t\t\t\tNat. 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M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRangrej\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKustra\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTenesa\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFarrington\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGenome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t39\n\t\t\t\t\t8\n\t\t\t\t\t989\n\t\t\t\t\t994\n\t\t\t\t\n\t\t\t'},{id:"B133",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYin\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tA genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t43\n\t\t\t\t\t8\n\t\t\t\t\t792\n\t\t\t\t\t796\n\t\t\t\t\n\t\t\t'},{id:"B134",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYe\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosell\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmos\n\t\t\t\t\t\t\tC. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStewart\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMA\n\t\t\t\t\t\t\tHildebrandt\n\t\t\t\t\t\t\tet.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tal\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy\n\t\t\t\t\tJ. Natl. Cancer Inst.\n\t\t\t\t\t103\n\t\t\t\t\t10\n\t\t\t\t\t817\n\t\t\t\t\t825\n\t\t\t\t\n\t\t\t'},{id:"B135",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrullanti\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGalvan\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFalvella\n\t\t\t\t\t\t\tF. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManenti\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tColombo\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVannelli\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tMultiple genetic loci modulate lung adenocarcinoma clinical staging\n\t\t\t\t\tClin. Cancer Res.\n\t\t\t\t\t17\n\t\t\t\t\t8\n\t\t\t\t\t2410\n\t\t\t\t\t2416\n\t\t\t\t\n\t\t\t'},{id:"B136",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuan\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuan\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tGenome-wide interrogation identifies YAP1 variants associated with survival of small-cell lung cancer patients\n\t\t\t\t\tCancer Res.\n\t\t\t\t\t70\n\t\t\t\t\t23\n\t\t\t\t\t9721\n\t\t\t\t\t9729\n\t\t\t\t\n\t\t\t'},{id:"B137",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoon\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPark\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPark\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tG. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHan\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tA genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population\n\t\t\t\t\tHum. Mol. Genet.\n\t\t\t\t\t19\n\t\t\t\t\t24\n\t\t\t\t\t4948\n\t\t\t\t\t4954\n\t\t\t\t\n\t\t\t'},{id:"B138",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSheu\n\t\t\t\t\t\t\tC. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYe\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Andrade\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChang\n\t\t\t\t\t\t\tS. 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Genet.\n\t\t\t\t\t85\n\t\t\t\t\t5\n\t\t\t\t\t679\n\t\t\t\t\t691\n\t\t\t\t\n\t\t\t'},{id:"B140",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBroderick\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVijayakrishnan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatakidou\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpitz\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEisen\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tDeciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study\n\t\t\t\t\tCancer Res.\n\t\t\t\t\t69\n\t\t\t\t\t19\n\t\t\t\t\t6633\n\t\t\t\t\t6641\n\t\t\t\t\n\t\t\t'},{id:"B141",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmos\n\t\t\t\t\t\t\tC. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBroderick\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGorlov\n\t\t\t\t\t\t\tI. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEisen\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tGenome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t5\n\t\t\t\t\t616\n\t\t\t\t\t622\n\t\t\t\t\n\t\t\t'},{id:"B142",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThorgeirsson\n\t\t\t\t\t\t\tT. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeller\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSulem\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRafnar\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWiste\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMagnusson\n\t\t\t\t\t\t\tK. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tA variant associated with nicotine dependence, lung cancer and peripheral arterial disease\n\t\t\t\t\tNature\n\t\t\t\t\t452\n\t\t\t\t\t7187\n\t\t\t\t\t638\n\t\t\t\t\t642\n\t\t\t\t\n\t\t\t'},{id:"B143",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHung\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Kay\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaborieau\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoffetta\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHashibe\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZaridze\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tA susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25\n\t\t\t\t\tNature\n\t\t\t\t\t452\n\t\t\t\t\t7187\n\t\t\t\t\t633\n\t\t\t\t\t637\n\t\t\t\t\n\t\t\t'},{id:"B144",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpinola\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeoni\n\t\t\t\t\t\t\tV. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGalvan\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorsching\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tConti\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPastorino\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGenome-wide single nucleotide polymorphism analysis of lung cancer risk detects the KLF6 gene\n\t\t\t\t\tCancer Lett.\n\t\t\t\t\t251\n\t\t\t\t\t2\n\t\t\t\t\t311\n\t\t\t\t\t316\n\t\t\t\t\n\t\t\t'},{id:"B145",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarrett\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIles\n\t\t\t\t\t\t\tM. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarland\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaylor\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAitken\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAndresen\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenoMEL Consortium. Genome-wide association study identifies three new melanoma susceptibility loci\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t43\n\t\t\t\t\t11\n\t\t\t\t\t1108\n\t\t\t\t\t1113\n\t\t\t\t\n\t\t\t'},{id:"B146",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMac Gregor\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMontgomery\n\t\t\t\t\t\t\tG. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tJ. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tZ. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHenders\n\t\t\t\t\t\t\tA. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStark\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenome-wide association study identifies a new melanoma susceptibility locus at 1q21.3\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t43\n\t\t\t\t\t11\n\t\t\t\t\t1114\n\t\t\t\t\t1118\n\t\t\t\t\n\t\t\t'},{id:"B147",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmos\n\t\t\t\t\t\t\tC. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tL. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGershenwald\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tW. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFang\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tGenoMEL Investigators. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma\n\t\t\t\t\tHum. Mol. Genet.\n\t\t\t\t\t20\n\t\t\t\t\t24\n\t\t\t\t\t5012\n\t\t\t\t\t5023\n\t\t\t\t\n\t\t\t'},{id:"B148",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTeerlink\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFarnham\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAllen-Brady\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCamp\n\t\t\t\t\t\t\tN. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomas\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeachman\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tA unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q\n\t\t\t\t\tHum. Genet.\n\t\t\t\t\t131\n\t\t\t\t\t1\n\t\t\t\t\t77\n\t\t\t\t\t85\n\t\t\t\t\n\t\t\t'},{id:"B149",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBishop\n\t\t\t\t\t\t\tD. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDemenais\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIles\n\t\t\t\t\t\t\tM. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarland\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaylor\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCorda\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tGenome-wide association study identifies three loci associated with melanoma risk\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t41\n\t\t\t\t\t8\n\t\t\t\t\t920\n\t\t\t\t\t925\n\t\t\t\t\n\t\t\t'},{id:"B150",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKing\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAubert\n\t\t\t\t\t\t\tR. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHerman\n\t\t\t\t\t\t\tW. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tGlobal burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections\n\t\t\t\t\tDiabetes Care\n\t\t\t\t\t21\n\t\t\t\t\t9\n\t\t\t\t\t1414\n\t\t\t\t\t1431\n\t\t\t\t\n\t\t\t'},{id:"B151",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReeves\n\t\t\t\t\t\t\tG. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTravis\n\t\t\t\t\t\t\tR. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBull\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTipper\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaker\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tIncidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci\n\t\t\t\t\tJAMA\n\t\t\t\t\t304\n\t\t\t\t\t4\n\t\t\t\t\t426\n\t\t\t\t\t434\n\t\t\t\t\n\t\t\t'},{id:"B152",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaprio\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTuomilehto\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoskenvuo\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRomanov\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReunanen\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEriksson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1992\n\t\t\t\t\tConcordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland\n\t\t\t\t\tDiabetologia\n\t\t\t\t\t35\n\t\t\t\t\t11\n\t\t\t\t\t1060\n\t\t\t\t\t1067\n\t\t\t\t\n\t\t\t'},{id:"B153",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRisch\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1990\n\t\t\t\t\tLinkage strategies for genetically complex traits. I. Multilocus models\n\t\t\t\t\tAm. J. Hum. Genet.\n\t\t\t\t\t46\n\t\t\t\t\t2\n\t\t\t\t\t222\n\t\t\t\t\t228\n\t\t\t\t\n\t\t\t'},{id:"B154",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrant\n\t\t\t\t\t\t\tS. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThorleifsson\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReynisdottir\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManolescu\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSainz\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHelgason\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tVariant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t38\n\t\t\t\t\t3\n\t\t\t\t\t320\n\t\t\t\t\t323\n\t\t\t\t\n\t\t\t'},{id:"B155",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSladek\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRocheleau\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRung\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDina\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSerre\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tA genome-wide association study identifies novel risk loci for type 2 diabetes\n\t\t\t\t\tNature\n\t\t\t\t\t445\n\t\t\t\t\t7130\n\t\t\t\t\t881\n\t\t\t\t\t885\n\t\t\t\t\n\t\t\t'},{id:"B156",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaxena\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVoight\n\t\t\t\t\t\t\tB. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLyssenko\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurtt\n\t\t\t\t\t\t\tN. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Bakker\n\t\t\t\t\t\t\tP. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGenome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels\n\t\t\t\t\tScience\n\t\t\t\t\t316\n\t\t\t\t\t5829\n\t\t\t\t\t1331\n\t\t\t\t\t1336\n\t\t\t\t\n\t\t\t'},{id:"B157",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScott\n\t\t\t\t\t\t\tL. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMohlke\n\t\t\t\t\t\t\tK. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBonnycastle\n\t\t\t\t\t\t\tL. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWiller\n\t\t\t\t\t\t\tC. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDuren\n\t\t\t\t\t\t\tW. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tA genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants\n\t\t\t\t\tScience\n\t\t\t\t\t316\n\t\t\t\t\t5829\n\t\t\t\t\t1341\n\t\t\t\t\t1345\n\t\t\t\t\n\t\t\t'},{id:"B158",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZeggini\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeedon\n\t\t\t\t\t\t\tM. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLindgren\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrayling\n\t\t\t\t\t\t\tT. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tElliott\n\t\t\t\t\t\t\tK. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLango\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tWellcome Trust Case Control Consortium (WTCCC). Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes\n\t\t\t\t\tScience\n\t\t\t\t\t316\n\t\t\t\t\t5829\n\t\t\t\t\t1336\n\t\t\t\t\t1341\n\t\t\t\t\n\t\t\t'},{id:"B159",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZeggini\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScott\n\t\t\t\t\t\t\tL. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaxena\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVoight\n\t\t\t\t\t\t\tB. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarchini\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tMeta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t40\n\t\t\t\t\t5\n\t\t\t\t\t638\n\t\t\t\t\t645\n\t\t\t\t\n\t\t\t'},{id:"B160",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan Dam\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoebee\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeidell\n\t\t\t\t\t\t\tJ. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMM\n\t\t\t\t\t\t\tSchaap de\n\t\t\t\t\t\t\tBruin. T. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFeskens\n\t\t\t\t\t\t\tE. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tCommon variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses\n\t\t\t\t\tDiabet. Med.\n\t\t\t\t\t22\n\t\t\t\t\t5\n\t\t\t\t\t590\n\t\t\t\t\t598\n\t\t\t\t\n\t\t\t'},{id:"B161",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLudovico\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPellegrini\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Paola\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinenna\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMastroianno\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCardellini\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tHeterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk\n\t\t\t\t\tObesity (Silver Spring)\n\t\t\t\t\t15\n\t\t\t\t\t5\n\t\t\t\t\t1076\n\t\t\t\t\t1081\n\t\t\t\t\n\t\t\t'},{id:"B162",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCauchi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEl Achhab\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChoquet\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDina\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrempler\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeitgasser\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tTCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis\n\t\t\t\t\tJ. Mol. Med.\n\t\t\t\t\t85\n\t\t\t\t\t7\n\t\t\t\t\t777\n\t\t\t\t\t782\n\t\t\t\t\n\t\t\t'},{id:"B163",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteinthorsdottir\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThorleifsson\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReynisdottir\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBenediktsson\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJonsdottir\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalters\n\t\t\t\t\t\t\tG. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tA variant in CDKAL1 influences insulin response and risk of type 2 diabetes\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t39\n\t\t\t\t\t6\n\t\t\t\t\t770\n\t\t\t\t\t775\n\t\t\t\t\n\t\t\t'},{id:"B164",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSandhu\n\t\t\t\t\t\t\tM. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeedon\n\t\t\t\t\t\t\tM. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFawcett\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWasson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDebenham\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDaly\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tCommon variants in WFS1 confer risk of type 2 diabetes\n\t\t\t\t\tNat. Genet.\n\t\t\t\t\t39\n\t\t\t\t\t8\n\t\t\t\t\t951\n\t\t\t\t\t953\n\t\t\t\t\n\t\t\t'},{id:"B165",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeigs\n\t\t\t\t\t\t\tJ. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShrader\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSullivan\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Ateer\n\t\t\t\t\t\t\tJ. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFox\n\t\t\t\t\t\t\tC. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDupuis\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tGenotype score in addition to common risk factors for prediction of type 2 diabetes\n\t\t\t\t\tN. Engl. J. Med.\n\t\t\t\t\t359\n\t\t\t\t\t21\n\t\t\t\t\t2208\n\t\t\t\t\t2219\n\t\t\t\t\n\t\t\t'},{id:"B166",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeedon\n\t\t\t\t\t\t\tM. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Carthy\n\t\t\t\t\t\t\tM. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHitman\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalker\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGroves\n\t\t\t\t\t\t\tC. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZeggini\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tCombining information from common type 2 diabetes risk polymorphisms improves disease prediction\n\t\t\t\t\tPloS. Med.\n\t\t\t\t\t3\n\t\t\t\t\t10\n\t\t\t\t\te374\n\t\t\t\t\n\t\t\t'},{id:"B167",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWray\n\t\t\t\t\t\t\tN. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoddard\n\t\t\t\t\t\t\tM. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVisscher\n\t\t\t\t\t\t\tP. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tPrediction of individual genetic risk to disease from genome-wide association studies\n\t\t\t\t\tGenome Res.\n\t\t\t\t\t17\n\t\t\t\t\t10\n\t\t\t\t\t1520\n\t\t\t\t\t1528\n\t\t\t\t\n\t\t\t'},{id:"B168",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorrison\n\t\t\t\t\t\t\tA. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBare\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChambless\n\t\t\t\t\t\t\tL. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEllis\n\t\t\t\t\t\t\tS. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMalloy\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKane\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tPrediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study\n\t\t\t\t\tAm. J. Epidemiol.\n\t\t\t\t\t166\n\t\t\t\t\t1\n\t\t\t\t\t28\n\t\t\t\t\t35\n\t\t\t\t\n\t\t\t'},{id:"B169",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCornelis\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQi\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKraft\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCai\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tJoint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry\n\t\t\t\t\tAnn. Intern. Med.\n\t\t\t\t\t150\n\t\t\t\t\t8\n\t\t\t\t\t541\n\t\t\t\t\t550\n\t\t\t\t\n\t\t\t'},{id:"B170",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRipatti\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTikkanen\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrho-Melander\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAS\n\t\t\t\t\t\t\tHavulinna\n\t\t\t\t\t\t\tSilander. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tA multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses\n\t\t\t\t\tLancet\n\t\t\t\t\t376\n\t\t\t\t\t9750\n\t\t\t\t\t1393\n\t\t\t\t\t1400\n\t\t\t\t\n\t\t\t'},{id:"B171",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalding\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tA tutorial on statistical methods for population association studies\n\t\t\t\t\tNat. Rev. Genet.\n\t\t\t\t\t7\n\t\t\t\t\t10\n\t\t\t\t\t781\n\t\t\t\t\t791\n\t\t\t\t\n\t\t\t'},{id:"B172",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarretina\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaponigro\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStransky\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVenkatesan\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAA\n\t\t\t\t\t\t\tMargolin\n\t\t\t\t\t\t\tKim. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tThe Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity\n\t\t\t\t\tNature\n\t\t\t\t\t483\n\t\t\t\t\t7391\n\t\t\t\t\t603\n\t\t\t\t\t607\n\t\t\t\t\n\t\t\t'},{id:"B173",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarnett\n\t\t\t\t\t\t\tN. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdelman\n\t\t\t\t\t\t\tE. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeidorn\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreenman\n\t\t\t\t\t\t\tC. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDastur\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLau\n\t\t\t\t\t\t\tK. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tSystematic identification of genomic markers of drug sensitivity in cancer cells\n\t\t\t\t\tNature\n\t\t\t\t\t483\n\t\t\t\t\t7391\n\t\t\t\t\t570\n\t\t\t\t\t575\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Shihori Tanabe",address:"stanabe@nihs.go.jp",affiliation:'
National Institute of Health Sciences, Tokyo, Japan
'},{corresp:null,contributorFullName:"Sun Ha Jee",address:null,affiliation:'
Institute for Health Promotion, Yonsei University, Seoul, Korea
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1. Introduction
Management of blood loss throughout a burn patient’s hospital course is a critical part of global care of those with thermal injuries. Patients suffering major (20–59% Total Body Surface Area (TBSA)) or massive (>60% TBSA) burns experience coagulopathic complications similar to those reported in major trauma or septic shock [1, 2] – a reflection of the systemic impact of such massive injury burden. Burn-related endothelial injury causes the release of tissue factor from a proportionately large surface area, contributing to the generation and consumption of thrombin, fibrin, and other coagulations factors [3, 4, 5, 6, 7]. Platelet activation and consumption leads to thrombocytopenia that nadirs between 3 and 5 days after injury [8]. In addition, there are important secondary factors that contribute to coagulopathy including hemodilution from resuscitation, hypothermia, and acidosis (Figure 1) [1, 9, 10].
Figure 1.
Schematic presentation of pathophysiologic mechanisms affecting coagulation in patients who sustained severe burn injuries. Legend: SIRS = systemic inflammatory response syndrome. Schematic adopted from Glas, et al. 2016.
In general, greater burn size correlates with increased duration of surgery, number of required operative procedures, and need for blood transfusion [11, 12]. For every 1% of total body surface excised, including surface area of skin graft donor site, a patient can experience as much as 10% loss of their calculated blood volume [13]. Since intraoperative blood loss from both excision of primary wound and donor sites can account for about one-third of blood products administered during an average burn injury hospitalization, minimizing blood loss in the operating room (OR) is vital for minimizing overall transfusion requirements [14, 15]. Blood product resuscitation alone is not sufficient for hemostasis and carries significant associated risks, which opens up an important opportunity for the consideration of topical hemostatic adjuncts in the overall blood management of the burned patient [8, 16, 17]. This chapter focuses on the roles of biosurgical hemostats as they pertain to the transfusion reduction strategy in the setting of thermal injury (Table 1).
Biosurgical hemostat
Application method(s)
Utility in burn surgery
Epinephrine
Topical or tumescent; a typical solution is prepared as 1:1,000,000 epinephrine in normal saline, which constitutes a dilution of 1 mL of 1:1,000 epinephrine into 1 L of normal saline; lidocaine may be added
Long utilized in burn surgery for obtaining hemostasis, decreasing intraoperative blood loss, and substantially reducing rates of blood transfusions; generally safe, without clinically significant cardiovascular effects due to systemic absorption
Fibrin sealants (FS)
A fine spray to create a thin layer resulting in approximately 0.05–0.06 mL/cm2 material distribution
Benefits include effective graft fixation, decreased hematoma and seroma formation, and shorter operative times; graft-take may be enhanced by the fibrin clot scaffold even when wound bed is infected; can also be used on the donor site to improve the time to hemostasis; excellent safety profile; important that surgeons recognize that not all FS are the same - different formulations or products may behave in a slightly different way
Calcium alginate
Donor-site dressing
In comparison to epinephrine and fibrin-based products, not as effective as hemostatic agent; as donor-site dressing, has been observed to provide superior hemostasis for skin-graft donor sites when compared to plain sterile gauze or paraffin gauze dressings; risk of dermal calcifications
Platelet rich plasma (PRP)
Topical application
Studies on use in burn surgery are scarce; while platelets in burn patients appear to have normal functionality, further studies focusing on the quantitative hemostatic ability of PRP in the setting of thermal injury are needed
Tranexamic acid (TXA)
Administered topically or intravenously
Few studies exist evaluating the use of TXA in burn patients; however, overall available data is promising; one study demonstrated no difference in mortality or thromboembolic disease, and some improvement of graft survival in the TXA group
NuStat®
Topical dressing
While one RCT showed clinical equivalency of NuStat® compared to historic standard of care, the overall cost of wound care was significantly lower using NuStat®; further studies are needed
Recombinant tissue factor
Topical application
2017 phase II randomized parallel double-blinded study showed promising results without causing adverse events
Hydrogen peroxide
Topical (3% soak applied to the tangential excision site)
Investigators reported no complications related to corrosive damage or lipid peroxidation; needs to be sufficiently irrigated from the wound bed prior to application of the split-thickness skin graft
Oxidized regenerated cellulose (ORC)
Topical application
Limited literature exists on the use of ORC in burn surgery
Table 1.
Summary of biosurgical hemostats in burn surgery.
Abbreviations: RCT = randomized controlled trial.
2. Overview of biosurgical hemostats in burn surgery
There are different types of available biosurgical hemostats, as outlined in Table 1. For the purposes of the current chapter, it is important to recognize that a gap exists between provider awareness of this class of adjunctive hemostatic agents and their actual clinical application. Arguably, the latter is much more extensive than one might initially realize or admit. It is therefore important to bring biosurgical hemostats into focus as increasing emphasis is being placed on reduction in unnecessary blood/blood product transfusions across burn centers and critical care units.
3. Epinephrine
Epinephrine has long been used in burn surgery for obtaining hemostasis at both the wound excision site and donor site, decreasing intraoperative blood loss per area excised, and substantially reducing rates of blood transfusions (in some cases by as much as 50%) [18, 19]. When applying epinephrine to any operative site, a pre-made solution can be applied topically or injected as a tumescent solution [20]. Although exact concentrations and application modality may vary between institutions, a typical solution is prepared as 1:1,000,000 epinephrine in normal saline, which constitutes a dilution of 1 mL of 1:1,000 epinephrine into 1 L of normal saline [21, 22]. Addition of lidocaine to the above solution has also been described to help decrease postoperative pain, duration of surgery, general anesthesia, and potentially accelerate re-epithelialization of the donor site [23].
The tumescent technique significantly decreases intraoperative blood loss and has been shown to be generally safe, without clinically significant cardiovascular effects due to systemic absorption [19, 24, 25]. Typically, the diluted epinephrine is injected subcutaneously with either a long 18-gauge spinal needle or a blunt liposuction cannula with injector. When properly performed, the subcutaneous injection under the desired area causes the area to become firm (tumescent) and the overlying skin to blanch. Whether used at the donor site or the eschar excision site, the firm vasoconstricted surfaces tend to be better prepared for subsequent excision [18], both in terms of technical ease of the operation and decreased blood loss.
The same diluted epinephrine solution can also be used as a topical hemostatic agent at both the donor and wound excision sites. This is most commonly performed by soaking non-adherent gauze, such as specially coated cotton pads, in the epinephrine solution and then applying the pads directly to the freshly excised area. It should be noted that this is performed as a hemostatic maneuver only after any major or brisk surgical bleeding has first been controlled. The epinephrine solution soaked non-adherent gauze can be secured in place by lightly wrapping it with a bandage roll. Typically, these are allowed to stay in place for 10–20 minutes to allow for hemostasis to occur. Careful removal is important for preventing disruption of the newly formed clot. If any residual oozing is present, new gauze can be re-applied until adequate hemostasis is achieved. In the absence of non-adherent gauze, the epinephrine solution can alternatively be applied topically as a spray or gelatinous mixture (e.g., using water-based lubricant as an application medium) [26, 27]. Other vasoactive hemostatic agents utilized in burn surgery include terlipressin and phenylephrine, with associated literature descriptions of reportedly positive effects in terms of blood loss reduction and other operative characteristics [22, 28, 29, 30, 31, 32].
4. Fibrin sealants
Fibrin is the hemostatic product of thrombin-mediated cleavage of fibrinogen [33]. Understanding the relationship between fibrinogen and thrombin has allowed for pharmaceutical companies to develop a variety of fibrin-based products, including those designed for hemostatic applications [34, 35]. Although fibrin sealants (FS) have been used since 1909, with reported use on skin grafts as early as 1944, the first formal U.S. Food and Drug Administration (FDA) approval of a FS for use with skin grafts – including those performed in burn surgery – did not come until 2008 (Artiss®, Baxter, Westlake Village, CA) [36]. Other similar products that fall within the class of “fibrin sealants” have been effectively used in the setting of skin grafts, with similar results [37, 38, 39].
Surgeons must recognize that not all FS are the same, and that different formulations or products may not always produce identical results. There are important differences across available products that one must understand in order to optimize clinical outcomes for the burn patient. The products available provide a range of concentration ratios of fibrinogen and thrombin solutions, which are combined and “mixed” during application. For example, Artiss® (Baxter, Westlake Village, CA) contains a ratio of 67–106 mg/mL fibrinogen to 2.5–6.5 units/mL thrombin [40], whereas Tisseel® (Baxter; Deerfield, IL, US) contains a ratio of 67–106 mg/mL fibrinogen to 400–625 units/mL thrombin [41]. Although both products contain similar amount of fibrinogen, the latter has 100-fold more thrombin. Higher concentrations of thrombin will speed up the polymerization process, decreasing clotting and sealing time. With regards to the aforementioned products, increasing the thrombin concentration by 100-fold effectively shortens the polymerization time from minutes to seconds. This difference is so robust that Tisseel® is FDA approved as a hemostatic agent, while Artiss® is not. When hemostasis is less of a concern and the intended use is primarily for sealant/fixation purposes, having a slower polymerization time is better suited for manipulating a skin graft into the desired location and orientation. Similar therapeutic outcomes have been reported using a variety of component concentrations, within a pre-specified range [42].
Benefits of using FS in burn surgery include effective graft fixation, decreased hematoma and seroma formation, and shorter operative times [42, 43, 44]. There may also be an added benefit in terms of improved postoperative pain, especially when compared to alternative skin graft fixation modalities such as staples or sutures [36, 45]. When applied correctly, ideally as a fine spray to create a thin layer that is only about 0.05–0.06 mL/cm2 thick, the graft-take may be enhanced by the fibrin clot scaffold which promotes migration of fibroblasts, epithelial cells, and keratinocytes [42, 46]. Even when the wound bed is infected, FS use may improve graft take by reinforcing graft adherence to the wound bed [47]. FS can also be used on the donor site to improve the time to hemostasis [48].
Taken collectively, FS have an excellent overall safety profile [44, 49, 50]. Historically, complications from exposure to bovine-derived thrombin have been reported, including the subsequent development of anti-bovine thrombin antibodies. Associated morbidity included bleeding, thromboembolisms, hypersensitivity reactions, and prolonged activated partial thromboplastin times (aPTT) [51]. However, most currently available FS are made with recombinant thrombin, which is far less immunogenic [52]. In fact, a meta-analysis of 10 clinical trials showed that at 1 month from surgery, less than 1% of patients exposed to recombinant thrombin will develop antibodies against it [53]. Furthermore, unlike anti-bovine thrombin antibodies, anti-recombinant thrombin antibodies do not neutralize activity of native human thrombin [53, 54]. Lastly, when compared to thrombin alone, FS appear to provide significantly more effective (and generally faster) hemostasis [55].
5. Calcium alginate
The use of calcium alginate (CA) to help control hemorrhage and improve graft take has been described in burn surgery for quite some time [56]. In comparison to epinephrine applications and fibrin-based products, CA is not as effective as a hemostatic agent [57]. However, as a donor site dressing CA has been observed to provide superior hemostasis for skin-graft harvesting sites when compared to plain sterile gauze or paraffin gauze dressings [58, 59, 60]. The alginate dressing also has several other potential advantages, including excellent absorptive properties, biodegradability, ease of postoperative maintenance/wound care, improved healing time, as well as notably lower risk of infection [61]. Still, CA donor site dressings are not without potential complications, including reported instances of dermal calcifications [62].
6. Platelet rich plasma
Investigational studies on the use of platelet-rich plasma (PRP) in burn surgery are scarce overall, with further paucity of data on PRP’s hemostatic properties [63, 64]. Nevertheless, there is growing evidence that supports the use of PRP as a promoter of wound bed hemostasis prior to split thickness skin graft (STSG) placement, with the intent of decreasing the rates of hematoma formation under a STSG [65, 66]. Although PRP may have additional benefits, including pain reduction, improved skin graft adherence, and decreased skin graft healing times [67, 68], these findings have not been consistent among all available clinical reports [69]. One case–control study comparing PRP extracted from burn patients to that from matched healthy volunteers demonstrated similar platelet counts and levels of growth factors [70]. It is important to mention that PRP (and its various subcomponents) may also play a role as a regenerative medicine approach due to its rich growth factor content and non-immunogenic properties [71]. For example, this may be important in promoting skin graft donor site healing. Finally, while the platelets in burn patients appear to have normal functionality, further studies focusing on determining the quantitative hemostatic ability of PRP in the setting of thermal injury are needed to fully understand its potential [72].
7. Tranexamic acid
Tranexamic acid (TXA) is an antifibrinolytic agent, whose use topically and intravenously has been shown to decrease traumatic and perioperative blood loss, reducing the need for blood transfusions in multiple surgical applications [73, 74, 75, 76]. Despite the promising overall results from the trauma literature, there are very few studies evaluating TXA use in burn patients [77, 78]. Overall, available data show promise; however, there is also evidence of cytotoxicity in the context of wound re-epithelialization, especially with prolonged use/exposure [79]. One retrospective cohort study analyzing the effect of intraoperative intravenous TXA administration in major burn patients (>20% TBSA) undergoing primary wound excision and grafting found that intravenous TXA administration significantly decreased the amount of blood administered during and up to 24 hours after the index operation. The series of patients included in the study received a TXA infusion 15 minutes prior to surgical incision as a loading dose of 10 mg/kg given over 5 minutes, followed by continuous infusion of 1 mg/kg/h until the end of the procedure. Multivariate analysis revealed TXA to be protective against transfusion (Odds Ratio of 0.2) [77]. Secondary findings revealed no difference in mortality or thromboembolic disease, and some improvement of graft survival in the TXA group [77]. A prospective randomized trial of single dose intravenous TXA (15 mg/kg diluted to 25 ml with isotonic saline over 10 min) prior to wound excision in 50 adult patients with >20% TBSA burns found that the patients who received TXA experienced, on average, about 400 mL less intraoperative blood loss and required significantly less colloid replacement in comparison to those who received an equal volume of only isotonic saline before induction of general anesthesia [78]. Further confirmatory prospective clinical trials will be helpful in clarifying intravenous TXA’s place in burn surgery blood management protocols. In terms of TXA use as a topical agent, one case report concluded that such application of TXA, in addition to standard methods, is a safe and effective way of controlling bleeding during burn surgery [80]. Future well-designed, adequately powered comparative studies analyzing blood loss, graft survival, epithelialization rate, and infections are warranted.
8. NuStat topical hemostat: clinical equivalency with lower cost
One prospective randomized control trial compared NuStat® (a product containing patented Hemafiber Technology™ by Beeken Miomedical, Stoughton, MA) to the institutional standard of care for controlling bleeding at both burn and donor sites. Briefly, NuStat® is a two-component product consisting of continuous filament silica and bamboo cellulose, a combination that when used together promotes hemostasis by activating the clotting cascade. Though potentially underpowered, hemostasis provided by the NuStat® dressing was found to be at least comparable to other currently utilized approaches (epinephrine- and thrombin-soaked non-adherent dressings, saline-soaked laparotomy sponges, and elastic bandage wraps) [81]. While the reported results show clinical equivalency of NuStat® compared to historic standard of care, the overall cost of wound care was significantly lower using the novel hemostatic dressing [81]. It is unlikely that these findings alone will change operative practices by most burn surgeons; however, the study does provide an important new treatment option in an area of clinical care that has seen little progress during the past few decades.
9. Recombinant tissue factor
As an initiator of the coagulation cascade, tissue factor is both an intriguing and a promising candidate for use as a topical hemostatic agent. Based on compelling preclinical and clinical data [82, 83, 84], a phase II randomized parallel double-blinded study was published in 2017 comparing an investigational topical hemostatic agent “TT-173” that is based on recombinant tissue factor (rTF) to a placebo, for establishing hemostasis at the donor site in burn surgery. The investigational agent “TT-173” reportedly decreased bleeding time from 7 minutes to 3 minutes without causing adverse events, systemic absorption, immunogenic reaction, or perturbance of donor site healing [85]. Further research into rTF as a potential new adjunct in operative hemostasis in burn surgery is clearly warranted based on the above reports.
10. Hydrogen peroxide
Hydrogen peroxide used as a 3% soak applied to the tangential excision site has been reported as a potentially effective and safe means of achieving hemostasis in a burn patient with platelet dysfunction. In one published experience, the investigators reported no apparent morbidity related to corrosive damage or lipid peroxidation, which is a known complication associated with higher concentrations of hydrogen peroxide. With the hydrogen peroxide sufficiently irrigated from the wound bed prior to application of the STSG, the investigators saw excellent graft take [86]. Other reported uses of hydrogen peroxide as a topical hemostat, either alone or in combination with another agent, have been described in maxillofacial and otolaryngology applications [87, 88]. Benefits of the above approach included less blood loss, shorter procedure times, and fewer surgical ties used [87, 88].
11. Oxidized regenerated cellulose
There is some evidence to suggest that the application of oxidized regenerated cellulose (ORC) products to skin graft donor sites may significantly shorten wound healing and recovery time [89]. The difference between ORC-treated donor sites and fine mesh gauze treated with nitrofurazone (FMN) was substantial, with semiclosed ORC dressing group achieving healing endpoint in 6.5 days (compared to 9.9 days for FMN) and closed ORC dressing group achieving healing in 5.4 days (compared to 8.4 days for FMN) [89]. With limited literature on the use of ORC-based products in burn surgery, further research is warranted to determine safety and efficacy of this topical hemostatic approach.
12. Granular zeolite: a topical hemostatic material capable of causing burns
Although this chapter focuses on topical hemostats in burn surgery, one well-known and highly effective topical hemostat warrants a special mention as a risk-factor for thermal injury [90]. Granular zeolite (GZ, also known as QuikClot®) is a material derived from lava rocks and introduced for field use in the early 2000’s [91]. The material is effective via a complex mechanism that involves an exothermic reaction coupled with absorption of water and the ability to concentrate coagulation factors [91, 92, 93]. There are multiple reports of GZ causing both cutaneous and internal burns due to excessive heat generation [90, 94, 95]. In fact, the original formulation was deemed sufficiently dangerous – able to reach temperatures up to 65°C (149°F) and cause burns to the operating surgeon – that it was discontinued in 2008 and replaced with a modified QuikClot® ACS and kaolin-containing QuikClot Combat Gauze formulation [91]. Based on the above observations, GZ should not be utilized in burn surgery, at least in its currently available formulation(s).
13. Conclusions
Although their use is certainly not novel in burn surgery, the awareness of biosurgical hemostats appears to be far from adequate. Given the above, the goal of this chapter was to both review published applications of biosurgicals in burn surgery and to increase awareness of these potentially valuable adjuncts. Especially important in this context is the emergence of new research involving novel topical hemostatic agents, such as the Hemafiber Technology™ and recombinant tissue factor. Similar to other surgical specialties, the management of thermal injuries focuses increasingly on optimizing care protocols, maximizing outcomes, and minimizing the need for potentially harmful and costly interventions such as blood and blood product transfusions. The authors believe that the current chapter provides a solid foundation of relevant clinical knowledge in the emerging area of biosurgical hemostasis in burn surgery.
\n',keywords:"biosurgical hemostats, fibrin, hemorrhage control, surgical bleeding, thrombin",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73924.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73924.xml",downloadPdfUrl:"/chapter/pdf-download/73924",previewPdfUrl:"/chapter/pdf-preview/73924",totalDownloads:119,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 16th 2020",dateReviewed:"October 12th 2020",datePrePublished:"November 4th 2020",datePublished:null,dateFinished:"November 4th 2020",readingETA:"0",abstract:"Management of coagulopathy is a crucial aspect of care for hospitalized burn patients, especially intraoperatively during burn surgery. It is estimated that approximately one-third of blood products utilized during an average burn injury hospitalization are administered intraoperatively during excision of the primary wound and donor sites. Moreover, transfusion of blood products alone during burn surgery does not constitute an adequate method to achieve hemostasis. Biosurgical hemostats should be utilized as adjunctive therapeutic agents to minimize blood loss. Potential options include topical or tumescent epinephrine, fibrin sealants, calcium alginate, platelet rich plasma, topical or intravenous tranexamic acid, NuStat®, recombinant tissue factor, hydrogen peroxide, and oxidized regenerated cellulose. The most abundant clinical evidence is available for the use of topical and tumescent epinephrine and fibrin sealants to achieve hemostasis during burn surgery. The epinephrine technique has been shown to be generally safe, without clinically significant cardiovascular effects from systemic absorption. For fibrin sealants (FS), it is important that surgeons recognize that not all FS are the same, and that different formulations or products may behave in a slightly different fashion. For the other available hemostatic available hemostatic options, further research is needed to fully elucidate their potential roles and utility in minimizing blood loss during burn surgery.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73924",risUrl:"/chapter/ris/73924",signatures:"John Sojka, Shanthi Narla, Carla V. Errickson and Stanislaw P. Stawicki",book:{id:"8206",type:"book",title:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",subtitle:null,fullTitle:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",slug:null,publishedDate:null,bookSignature:"Dr. Michael S. Firstenberg and Dr. Stanislaw P. Stawicki",coverURL:"https://cdn.intechopen.com/books/images_new/8206.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-78984-441-2",printIsbn:"978-1-78984-440-5",pdfIsbn:null,isAvailableForWebshopOrdering:!0,editors:[{id:"64343",title:"Dr.",name:"Michael S.",middleName:null,surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Overview of biosurgical hemostats in burn surgery",level:"1"},{id:"sec_3",title:"3. Epinephrine",level:"1"},{id:"sec_4",title:"4. Fibrin sealants",level:"1"},{id:"sec_5",title:"5. Calcium alginate",level:"1"},{id:"sec_6",title:"6. Platelet rich plasma",level:"1"},{id:"sec_7",title:"7. Tranexamic acid",level:"1"},{id:"sec_8",title:"8. NuStat topical hemostat: clinical equivalency with lower cost",level:"1"},{id:"sec_9",title:"9. Recombinant tissue factor",level:"1"},{id:"sec_10",title:"10. Hydrogen peroxide",level:"1"},{id:"sec_11",title:"11. Oxidized regenerated cellulose",level:"1"},{id:"sec_12",title:"12. Granular zeolite: a topical hemostatic material capable of causing burns",level:"1"},{id:"sec_13",title:"13. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Glas GJ, Levi M, Schultz MJ. Coagulopathy and its management in patients with severe burns. J Thromb Haemost. 2016;14(5):865-874'},{id:"B2",body:'Palmieri, T.L., et al., Restrictive Transfusion Strategy Is More Effective in Massive Burns: Results of the TRIBE Multicenter Prospective Randomized Trial. Mil Med, 2019. 184(Suppl 1): p. 11-15.'},{id:"B3",body:'Kowal-Vern, A., et al., The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state. J Trauma, 1992. 33(1): p. 50-6; discussion 56-7.'},{id:"B4",body:'Lippi, G., L. Ippolito, and G. 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European Journal of Drug Metabolism and Pharmacokinetics, 2017. 42(4): p. 583-592.'},{id:"B83",body:'Centeno, A., et al., Experimental evaluation of a new tissue factor-based topical hemostat (TT-173) for treatment of hepatic bleeding. Journal of Investigative Surgery, 2018.'},{id:"B84",body:'López-López, J., et al., TETIS study: evaluation of new topical hemostatic agent TT-173 in tooth extraction. Clinical oral investigations, 2016. 20(5): p. 1055-1063.'},{id:"B85",body:'Rojas, S., et al., EHTIC study: Evaluation of a new hemostatic agent based on tissue factor in skin grafting procedures. Burns, 2017. 43(4): p. 780-788.'},{id:"B86",body:'Potyondy, L., et al., The use of hydrogen peroxide for achieving dermal hemostasis after burn excision in a patient with platelet dysfunction. J Burn Care Res, 2006. 27(1): p. 99-101.'},{id:"B87",body:'Arakeri, G. and P.A. Brennan, Povidone-iodine and hydrogen peroxide mixture soaked gauze pack: a novel hemostatic technique. Journal of Oral and Maxillofacial Surgery, 2013. 71(11): p. 1833. e1-1833. e3.'},{id:"B88",body:'Al-Abbasi, A.M. and Z.K. Saeed, Hydrogen Peroxide 3%: Is it Beneficial in Tonsillectomy? Sultan Qaboos University Medical Journal, 2008. 8(2): p. 201.'},{id:"B89",body:'Uysal, A.C., et al., An alternative dressing material for the split-thickness skin graft donor site: oxidized regenerated cellulose. Annals of plastic surgery, 2006. 57(1): p. 60-64.'},{id:"B90",body:'Rhee, P., et al., QuikClot use in trauma for hemorrhage control: case series of 103 documented uses. Journal of Trauma and Acute Care Surgery, 2008. 64(4): p. 1093-1099.'},{id:"B91",body:'Schreiber, M.A. and D.J. Neveleff, Achieving hemostasis with topical hemostats: making clinically and economically appropriate decisions in the surgical and trauma settings. AORN journal, 2011. 94(5): p. S1-S20.'},{id:"B92",body:'Arnaud, F., et al., Exothermic reaction in zeolite hemostatic dressings: QuikClot ACS and ACS+®. Annals of biomedical engineering, 2008. 36(10): p. 1708.'},{id:"B93",body:'Arnaud, F., et al., Comparative efficacy of granular and bagged formulations of the hemostatic agent QuikClot. Journal of Trauma and Acute Care Surgery, 2007. 63(4): p. 775-782.'},{id:"B94",body:'Khan, M., et al., An iatrogenic burn from the use of a topical haemostatic agent. Emergency Medicine Journal, 2010. 27(12): p. 950-951.'},{id:"B95",body:'Wright, J.K., et al., Thermal injury resulting from application of a granular mineral hemostatic agent. Journal of Trauma and Acute Care Surgery, 2004. 57(2): p. 224-230.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"John Sojka",address:"john.h.sojka@gmail.com",affiliation:'
Department of Surgery, St. Luke’s University Health Network, USA
Department of Dermatology, St. Luke’s University Health Network, USA
'},{corresp:null,contributorFullName:"Carla V. Errickson",address:null,affiliation:'
Department of Dermatology, St. Luke’s University Health Network, USA
'},{corresp:null,contributorFullName:"Stanislaw P. Stawicki",address:null,affiliation:'
Department of Research and Innovation, St. Luke’s University Health Network, USA
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"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\n
Carlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"
Open Access background
\\n\\n
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\n
IntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\n
At IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n
“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\n
Open Access Standards followed by IntechOpen
\\n\\n
OAI-PMH
\\n\\n
As a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\n
License
\\n\\n
Book chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\n
Peer Review Policies
\\n\\n
All scientific works are Peer Reviewed prior to publishing. Read more
\\n\\n
OA Publishing Fees
\\n\\n
The Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\n
Digital Archiving Policy
\\n\\n
IntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\n
Open Science
\\n\\n
Open Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\n
Open Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\n
Open Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\n
\\n\\t
Promoting open and publicly accessible education tools
\\n\\t
Transparency in experimental methodology, observation, and collection of data
\\n\\t
Reproducible research data and re-analysis
\\n\\t
Public availability and re-usability of scientific data
\\n\\t
Public accessibility and transparency of scientific communication
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Transparent peer-review and publishing practices
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Using web-based tools to facilitate scientific collaboration
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Supporting exchange of knowledge and research materials between disciplines
\\n\\t
Supporting exchange of knowledge and research materials between scientific communities and industry.
\\n
\\n\\n
We aim at improving the quality and availability of scholarly communication by promoting and practicing:
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\n
IntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\n
At IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n
“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\n
Open Access Standards followed by IntechOpen
\n\n
OAI-PMH
\n\n
As a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\n
License
\n\n
Book chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\n
Peer Review Policies
\n\n
All scientific works are Peer Reviewed prior to publishing. Read more
\n\n
OA Publishing Fees
\n\n
The Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\n
Digital Archiving Policy
\n\n
IntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\n
Open Science
\n\n
Open Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\n
Open Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\n
Open Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\n
\n\t
Promoting open and publicly accessible education tools
\n\t
Transparency in experimental methodology, observation, and collection of data
\n\t
Reproducible research data and re-analysis
\n\t
Public availability and re-usability of scientific data
\n\t
Public accessibility and transparency of scientific communication
\n\t
Transparent peer-review and publishing practices
\n\t
Using web-based tools to facilitate scientific collaboration
\n\t
Supporting exchange of knowledge and research materials between disciplines
\n\t
Supporting exchange of knowledge and research materials between scientific communities and industry.
\n
\n\n
We aim at improving the quality and availability of scholarly communication by promoting and practicing:
\n\n
\n\t
Open Access
\n\t
Open Data
\n\t
Open Metrics and Impact
\n\t
Open Source
\n
\n\n
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Among different technologies for hydrogen production, oxygenic natural and artificial photosynthesis using direct photochemistry in synthetic complexes have a great potential to produce hydrogen as both use clean and cheap sources - water and solar energy. Photosynthetic organisms capture sunlight very efficiently and convert it into organic molecules. Artificial photosynthesis is one way to produce hydrogen from water using sunlight by employing biomimetic complexes. However, splitting of water into protons and oxygen is energetically demanding and chemically difficult. In oxygenic photosynthetic microorganisms water is splitted into electrons and protons during primary photosynthetic processes. The electrons and protons are redirected through the photosynthetic electron transport chain to the hydrogen-producing enzymes-hydrogenase or nitrogenase. By these enzymes, e- and H+ recombine and form gaseous hydrogen. Biohydrogen activity of hydrogenase can be very high but it is extremely sensitive to photosynthetic O2. At the moment, the efficiency of biohydrogen production is low. However, theoretical expectations suggest that the rates of photon conversion efficiency for H2 bioproduction can be high enough (> 10%). Our review examines the main pathways of H2 photoproduction using photosynthetic organisms and biomimetic photosynthetic systems and focuses on developing new technologies based on the effective principles of photosynthesis.",book:{id:"3587",slug:"biomimetics-learning-from-nature",title:"Biomimetics",fullTitle:"Biomimetics Learning from Nature"},signatures:"Suleyman I. Allakhverdiev, Vladimir D. Kreslavski, Velmurugan Thavasi, Sergei K. Zharmukhamedov, Vyacheslav V. 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It performs very complex tasks while occupying about 2 liters of volume and consuming very little energy. The computation tasks are performed by special cells in the brain called neurons. They compute using electrical pulses and exchange information between them through chemicals called neurotransmitters. With this as inspiration, there are several compute models which exist today trying to exploit the inherent efficiencies demonstrated by nature. The compute models representing spiking neural networks (SNNs) are biologically plausible, hence are used to study and understand the workings of brain and nervous system. More importantly, they are used to solve a wide variety of problems in the field of artificial intelligence (AI). They are uniquely suited to model temporal and spatio-temporal data paradigms. This chapter explores the fundamental concepts of SNNs, few of the popular neuron models, how the information is represented, learning methodologies, and state of the art platforms for implementing and evaluating SNNs along with a discussion on their applications and broader role in the field of AI and data networks.",book:{id:"10372",slug:"biomimetics",title:"Biomimetics",fullTitle:"Biomimetics"},signatures:"Khadeer Ahmed",authors:[{id:"320026",title:"Dr.",name:"Khadeer",middleName:null,surname:"Ahmed",slug:"khadeer-ahmed",fullName:"Khadeer Ahmed"}]},{id:"65418",title:"Opening the “Black Box” of Silicon Chip Design in Neuromorphic Computing",slug:"opening-the-black-box-of-silicon-chip-design-in-neuromorphic-computing",totalDownloads:1591,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Neuromorphic computing, a bio-inspired computing architecture that transfers neuroscience to silicon chip, has potential to achieve the same level of computation and energy efficiency as mammalian brains. Meanwhile, three-dimensional (3D) integrated circuit (IC) design with non-volatile memory crossbar array uniquely unveils its intrinsic vector-matrix computation with parallel computing capability in neuromorphic computing designs. In this chapter, the state-of-the-art research trend on electronic circuit designs of neuromorphic computing will be introduced. Furthermore, a practical bio-inspired spiking neural network with delay-feedback topology will be discussed. In the endeavor to imitate how human beings process information, our fabricated spiking neural network chip has capability to process analog signal directly, resulting in high energy efficiency with small hardware implementation cost. Mimicking the neurological structure of mammalian brains, the potential of 3D-IC implementation technique with memristive synapses is investigated. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN), Kuala Lumpur from 2002 until 2005. He then completed his Fellowship in Cardiothoracic Surgery at Monash Health, Melbourne, Australia in 2008. He has served in the Malaysian army as a Medical Officer with the rank of Captain upon completing his Internship before joining USM as a trainee lecturer. He is now serving as an academic and researcher at Monash University Malaysia. He is a life-member of the Malaysian Association of Thoracic & Cardiovascular Surgery (MATCVS) and a committee member of the MATCVS Database. He is also a life-member of the College of Surgeons, Academy of Medicine of Malaysia; a life-member of Malaysian Medical Association (MMA), and a life-member of Islamic Medical Association of Malaysia (IMAM). Recently he was appointed as an Interim Chairperson of Examination & Assessment Subcommittee of the UiTM-IJN Cardiothoracic Surgery Postgraduate Program. As an academic, he has published numerous research papers and book chapters. He has also been appointed to review many scientific manuscripts by established journals such as the British Medical Journal (BMJ). He has presented his research works at numerous local and international conferences such as the European Association for Cardiothoracic Surgery (EACTS) and the European Society of Cardiovascular Surgery (ESCVS), to name a few. He has also won many awards for his research presentations at meetings and conferences like the prestigious International Invention, Innovation & Technology Exhibition (ITEX); Design, Research and Innovation Exhibition, the National Conference on Medical Sciences and the Annual Scientific Meetings of the Malaysian Association for Thoracic and Cardiovascular Surgery. He was awarded the Darjah Setia Pangkuan Negeri (DSPN) by the Governor of Penang in July, 2015.",institutionString:null,institution:{name:"Monash University Malaysia",country:{name:"Malaysia"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}}]}},subseries:{item:{id:"38",type:"subseries",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,series:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713"},editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",slug:"meng-chuan-ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",slug:"olga-anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},onlineFirstChapters:{paginationCount:4,paginationItems:[{id:"82367",title:"Spatial Variation and Factors Associated with Unsuppressed HIV Viral Load among Women in an HIV Hyperendemic Area of KwaZulu-Natal, South Africa",doi:"10.5772/intechopen.105547",signatures:"Adenike O. 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\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation"},{id:"39",title:"Environmental Resilience and Management",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",fullName:"Reda R. Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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