\r\n\tunidentifiable by traditional imaging techniques. It has a wide range of applications including remote sensing, industry sorting, food analysis, bio-medical imaging, etc. However, in contrast to RGB images from which information can be intuitively extracted, hyperspectral data is only useful with proper processing and analysis. This emphasizes the importance of using advanced signal processing, image processing and machine learning techniques for such a purpose. Classical hyperspectral image analysis tasks include target detection, classification, and spectral unmixing. This book firstly intends to provide a comprehensive overview of recent state-of-the-art of these three tasks. Thereafter, considering the prosperous study in deep-learning based image and data analysis, this book also aims to collect the very recent results of hyperspectral data analysis that benefit from deep neural networks. Finally, practical applications will be included to show how these analytics are useful in promoting real industry, medical, biological development.
",isbn:"978-1-78985-110-6",printIsbn:"978-1-78985-109-0",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"02b920d9c266e28152227280ff18ebbe",bookSignature:"Dr. Jie Chen, Dr. Yingying Song and Dr. Hengchao Li",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8223.jpg",keywords:"Hyperspectral Unmxing, Endmember Extraction, Abundance Estimation, Hyperspectral Classification, Spatial-spectral Classification, Hyperspectral Detection, Target Detection, Spectral Signature, Spatial Information, Deep Learning, Deep Neural Networks, Hyperspectral analysis, Hyperspectral Applications",numberOfDownloads:311,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 14th 2019",dateEndSecondStepPublish:"March 7th 2019",dateEndThirdStepPublish:"May 6th 2019",dateEndFourthStepPublish:"July 25th 2019",dateEndFifthStepPublish:"September 23rd 2019",remainingDaysToSecondStep:"9 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,editors:[{id:"218017",title:"Dr.",name:"Jie",middleName:null,surname:"Chen",slug:"jie-chen",fullName:"Jie Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/218017/images/system/218017.png",biography:"He is currently a Professor at the Northwestern Polytechnical University (NPU),\r\nConcurrently, he is also the Vice Director of the Center of Intelligent Acoustics and\r\nImmersive Communications in NPU. His research interests include adaptive signal\r\nprocessing and distributed optimization with applications to hyperspectral image analysis, acoustic signal processing, and bioinformatics. Dr. Chen has been recognized\r\nwith the 'Thousand Talents Plan (Youth Program)” Award in China. He serves as\r\nDistinguished Lecture of Asia-Pacific Signal and Information Processing Association\r\n(APSIPA), and he was the Technical Co-Chair of IWAENC’16 .",institutionString:"Northwestern Polytechnical University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Northwestern Polytechnical University",institutionURL:null,country:{name:"China"}}}],coeditorOne:{id:"299173",title:"Dr.",name:"Yingying",middleName:null,surname:"Song",slug:"yingying-song",fullName:"Yingying Song",profilePictureURL:"https://mts.intechopen.com/storage/users/299173/images/system/299173.jpeg",biography:"Dr. Yingying Song received the Dipl.-Ing. degree in the system, network and telecommunication engineering from the University of Technology of Troyes, France, in 2015, and the Ph.D. degree with the Université de Lorraine, France in 2018. She currently works at Centre de Recherche en Automatique de Nancy, University of Lorraine, France. Her current research interests include hyperspectral image deconvolution, adaptive image processing, and hyperspectral image unmixing.",institutionString:"University of Lorraine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Lorraine",institutionURL:null,country:{name:"France"}}},coeditorTwo:{id:"299175",title:"Dr.",name:"Hengchao",middleName:null,surname:"Li",slug:"hengchao-li",fullName:"Hengchao Li",profilePictureURL:"https://mts.intechopen.com/storage/users/299175/images/system/299175.jpeg",biography:"Heng-Chao Li received his B.Sc. and M.Sc. degrees from the Southwest Jiaotong University, Chengdu, China, in 2001 and 2004, respectively, and his Ph.D. degree from the Graduate University of Chinese Academy of Sciences, Beijing, China, in 2008, all in information and communication engineering. He is currently a Professor with the Sichuan Provincial Key Laboratory of Information Coding and Transmission, Southwest Jiaotong University, Chengdu, China. From November 2013 to October 2014, he was a Visiting Scholar working with Prof. W. J. Emery at the University of Colorado at Boulder, Boulder, CO, USA. His research interests include statistical analysis of synthetic aperture radar images, remote sensing image processing, and signal processing in communications. Prof. Li received several scholarships or awards, especially including the Special Grade of the Financial Support from China Postdoctoral Science Foundation in 2009 and the New Century Excellent Talents in University from the Ministry of Education of China in 2011. In addition, he has also been a Reviewer for several international journals and conferences. He is currently serving as an Associate Editor of the IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing.",institutionString:"Southwest Jiaotong University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Southwest Jiaotong University",institutionURL:null,country:{name:"China"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"639",title:"Data Acquisition",slug:"data-acquisition"}],chapters:[{id:"68884",title:"Hyperspectral Endmember Extraction Techniques",slug:"hyperspectral-endmember-extraction-techniques",totalDownloads:18,totalCrossrefCites:0,authors:[null]},{id:"69170",title:"Hyperspectral Image Super-Resolution Using Optimization and DCNN-Based Methods",slug:"hyperspectral-image-super-resolution-using-optimization-and-dcnn-based-methods",totalDownloads:41,totalCrossrefCites:0,authors:[null]},{id:"68910",title:"Fast Chaotic Encryption for Hyperspectral Images",slug:"fast-chaotic-encryption-for-hyperspectral-images",totalDownloads:44,totalCrossrefCites:0,authors:[null]},{id:"69219",title:"Use of Hyperspectral Remote Sensing to Estimate Water Quality",slug:"use-of-hyperspectral-remote-sensing-to-estimate-water-quality",totalDownloads:98,totalCrossrefCites:0,authors:[null]},{id:"66838",title:"NIR Hyperspectral Imaging for Mapping of Moisture Content Distribution in Tea Buds During Dehydration",slug:"nir-hyperspectral-imaging-for-mapping-of-moisture-content-distribution-in-tea-buds-during-dehydratio",totalDownloads:111,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"19096",title:"New Molecular Targets for the Systemic Therapy of Melanoma",doi:"10.5772/20367",slug:"new-molecular-targets-for-the-systemic-therapy-of-melanoma",body:'\n\t\t
\n\t\t\t
1. Introduction
\n\t\t\t
Melanoma is one of the most deadly forms of skin cancer. The incidence of melanoma has been steadily increasing over the last several decades. It is estimated that in 2010 68,130 adults were diagnosed with melanoma, and 8,700 patients died of this disease (Jemal et al.). Melanoma is highly curable when it is diagnosed at early stages. However, patients with distant metastases have a median overall survival of only 6-8 months (Balch et al. 2009). Chemotherapy regimens have not improved survival in patients with metastatic melanoma, and immunotherapies have generally benefited only a small percentage of patients (Koon and Atkins 2006). Thus, there is a critical need to develop more effective therapeutic approaches for this disease. Recently, dramatic results have been reported with agents that specifically target proteins or pathways that are aberrant in this disease, such as BRAF and c-KIT (Flaherty et al. ; Hodi et al. 2008\n\t\t\t\t). These results support the rationale for continued investigation into the molecular events that characterize and contribute to melanoma. This review will describe existing knowledge about several of the molecules and pathways that have been implicated in melanoma, and review the results of clinical studies focused on these targets.
\n\t\t
\n\t\t
\n\t\t\t
2. Melanoma molecular targets
\n\t\t\t
Melanoma has traditionally been classified based on the clinical and pathological features of the tumor. The most commonly observed type of melanoma is cutaneous melanoma (CM), arising from skin with either intermittent or chronic sun exposure. While ultraviolet radiation likely has a significant causative role in these tumors, its role in certain other subtypes is less clear. Cutaneous melanomas can arise in areas with limited sun/UV radiation exposure such as palms, soles and the area under nails (acral lentiginous melanoma). Other melanomas arise from mucosal surfaces of the body, including the upper aerodigestive, gastrointestinal, and genitourinary tracts, and are termed mucosal melanomas. Melanomas also originate from melanocytes in the uveal tract of the eye (uveal/ocular melanoma). In addition to anatomic differences, recent research has demonstrated that the different melanoma subtypes are characterized by distinct regions of DNA copy number gain and loss (Curtin et al. 2005). This finding suggested that each of these tumor types could be characterized by distinct molecular mechanisms, a hypothesis that is also supported by the marked variance of recently described oncogenic mutations across the different melanoma subtypes.
\n\t\t\t
\n\t\t\t\t
2.1. RAS/RAF/MAPK pathway
\n\t\t\t\t
The RAS/RAF/MAPK cascade is a critical growth and survival signaling pathway in cells. The pathway is generally triggered by activation of cell surface receptor(s) [i.e., receptor tyrosine kinases (RTK), G-protein coupled receptors (GPCR), etc] following ligand binding or cell-to-cell contact. The receptors induce activation of RAS through guanine exchange factors (GEFs), which promote the exchange of RAS-GDP to RAS-GTP. GTP-bound RAS recruits and activates the RAF (A-, B- and C-RAF) family of serine-threonine kinases, which then phosphorylate and activate Mitogen Activated Kinase Kinase [MAPKK or MAP/ERK kinase (MEK)]. Phosphorylated MEK, which is also a kinase, activates the downstream Extracellular Regulatory Kinase (ERK1/2 or P44/42 MAPK) through phosphorylation. Once activated, ERK translocates to the nucleus where it regulates the expression of several genes involved in differentiation, survival and proliferation by phosphorylating transcription factors such as ETS, MYC etc. The MAPK pathway also regulates the apoptotic machinery in cells through post-translational regulation of BAD, BIM, MCL-1 and BCL-2 proteins (George, Thomas, and Hannan).
\n\t\t\t\t
In addition to RAF, the RAS proteins activate several other effectors that contribute to the pro-survival and proliferative phenotype, including phospholipase C (PLC), phosphatidyl inositol-3-Kinase (PI3K), Ral, Rac and Rho-GTPases. Mutations in the RAS family genes (HRAS, NRAS and KRAS) have been detected in approximately one-third of all cancers, including pancreatic, colon, leukemia and thyroid cancers (Bos et al. 1987; Bos et al. 1985; Almoguera et al. 1988; Forrester et al. 1987; Padua, Barrass, and Currie 1985). Activating mutations of RAS have been reported in 15-20% of melanomas, and almost exclusively involve the NRAS isoform (Tsao et al. 2000). NRAS mutations are highly conserved in melanoma, as over 90% of the detected mutations occur in codons 12, 13 and 61 (Hocker and Tsao 2007). NRAS mutations occur in 26% of cutaneous and 14% of mucosal melanomas, but only in 4% of acral and less than 1% of uveal melanomas (Hocker and Tsao 2007). Mutant RAS proteins have very little GTPase activity, and thus remain constitutively active. This results in aberrant regulation of its downstream signaling pathways and subsequent uncontrolled cell proliferation and survival. RAS also promotes suppression of p16INK4a and p53 in melanoma models, and knockdown of mutated H-RAS (H-Ras\n\t\t\t\t\t\n\t\t\t\t\t\tV12G\n\t\t\t\t\t\n\t\t\t\t\t) using siRNAs in an doxycycline inducible melanoma mouse model resulted in tumor regression (Chin et al. 1997; Chin et al. 1999).
\n\t\t\t\t
Activating mutations in the serine/threonine kinase BRAF were first reported by Davies and colleagues in 2002, who demonstrated in a small cohort of tumors and cancer cell lines that 66% of melanomas harbored somatic mutations in BRAF, which were also detected in smaller fractions of gliomas, colon and ovarian cancer samples. A recent meta-analysis reported BRAF mutations in 43% of melanoma clinical specimens and 65% of human melanoma cell lines (Hocker and Tsao 2007). BRAF mutations were detected most frequently in cutaneous melanomas (42.5%), but were markedly less common in acral (18.1%), mucosal (5.6%), and uveal (<1%) melanomas. Some studies have also reported significantly lower rates of BRAF mutations in cutaneous melanomas with chronic sun damage (Curtin et al. 2005), but this has not been recapitulated in other studies (\n\t\t\t\t\t\tHandolias, Salemi et al. 2010\n\t\t\t\t\t). Approximately 40 different BRAF mutations have been identified in melanoma. The most frequent mutation (approximately 90% of mutations in clinical samples) arises due to a T→A transversion in position 1799 of the BRAF gene (T1799A) resulting in the substitution of glutamic acid for valine at position 600 (BRAFV600E) of the BRAF protein acid, which has markedly increased catalytic activity compared to the wild-type BRAF protein (Davies et al. 2002; Wan et al. 2004; Hocker and Tsao 2007). Interestingly, some of the BRAF mutations that have been detected in cancer do not increase the catalytic activity of the BRAF protein, but still result in hyperactivation of MEK and ERK through efficient dimerization with other RAF isoforms (Garnett et al. 2005; Heidorn et al. 2010).
\n\t\t\t\t
In melanoma, activating BRAF and NRAS mutations are almost always mutually exclusive, but overlap can occur with non-activating BRAF mutations (Heidorn et al. 2010; \n\t\t\t\t\t\tTsao et al. 2004\n\t\t\t\t\t). While BRAF mutations are extremely common in melanoma, there is significant evidence that they must be complemented by additional genetic events in melanomagenesis. Pollock et al (2002) reported that the BRAFV600E mutation is detectable in 82% of benign nevi, which have virtually no malignant potential. In addition, expression of the BRAFV600E mutation alone in melanocytes failed to induce transformation in several preclinical models, including zebrafish and mice (Patton et al. 2005). Invasive lesions were only seen when other molecules were inactivated concurrently, such as p16/Ink4a, p53, and PTEN or p53 (Dankort et al. 2009; Chudnovsky et al. 2005).
\n\t\t\t\t
The dual specificity kinases MEK1/2 that lie downstream of BRAF are activated in majority of the cancers with deregulated RAS/RAF/MAPK signaling. The MEK kinases phosphorylate ERK1/2 downstream and mediate cell survival signaling through MAPK signaling cascade. Emery et al. (2009), using random mutagenesis and massive parallel sequencing approaches identified mutations in the drug binding and regulatory domains of MEK1 kinase that led to increased phosphorylation of ERK and a MEK inhibitor-resistance phenotype. Subsequently, MEK1 point mutations P124L and C121S have been detected in melanoma patients who progressed after initial clinical responses to MEK or BRAF inhibitors (Wagle et al. ; Emery et al. 2009). To date no MEK1 or MEK2 mutations have been reported de novo in melanoma.
\n\t\t\t\t
Figure 1.
Molecular targets in melanoma. The diagram illustrates pathways that are affected by prevalent genetic alterations in melanoma.
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.2. PI3K/AKT/mTOR pathway
\n\t\t\t\t
The PI3K/AKT/mTOR pathway is one of the most important intracellular signaling pathways. The pathway regulates many important cellular processes, including proliferation, differentiation, motility, metabolism, survival, invasion and intracellular transport (Engelman, Luo, and Cantley 2006). The Phosphatidyl Inositol-3 Kinases (PI3K) are a family of lipid kinases that are composed of an adaptor/regulatory subunit (i.e. p85) and a catalytic unit (i.e. p110). Similar to RAS/RAF/ERK, the PI3K/AKT/mTOR pathway is activated by a variety of signals, including receptor tyrosine kinases and RAS proteins. Activation of PI3K results in phosphorylation of phosphatidylinositols in the cell membrane at the 3’-hydroxyl group. This reaction generates the lipid species PI (3,4)P2 and PI(3,4,5)P3. PI (3,4)P2 and PI(3,4,5)P3 act as second messengers, recruiting proteins that contain a pleckstrin homology (PH) domain to the cell membrane, such as the serine/threonine kinases AKT and PDK1. Upon recruitment to the cell membrane, AKT is phosphorylated at two critical residues, serine 473 and threonine 308. Once phosphorylated, the activated AKT translocates to the cytosol where it promotes cell proliferation and survival by phosphorylating numerous substrate proteins including mTOR, GSK3, FOXO, and BAD, among others.
\n\t\t\t\t
The activity of the PI3K/AKT/mTOR pathway is normally controlled by the lipid phosphatase PTEN (Phosphatase and Tensin Homolog), which dephosphorylates phosphatidyl inositols (PI) at the 3’ position, thereby inhibiting PI3K-mediated signaling (Maehama and Dixon 1998). PTEN, which is a tumor suppressor, is inactivated in a variety of tumor types, through both genetic and epigenetic mechanisms (Li et al. 1997; Myers et al. 1998; Mirmohammadsadegh et al. 2006). Tumors with loss of PTEN are characterized by markedly increased basal activation of AKT (Davies et al. 1999; Davies et al. 1998; Davies et al. 2009).
\n\t\t\t\t
In melanoma, PTEN loss is observed in up to 20% of tumors and 30% of melanoma cell lines (Tsao et al. 1998; Tsao, Mihm, and Sheehan 2003; Tsao et al. 2000). This prevalence is primarily defined for cutaneous melanomas; the prevalence in other subtypes is poorly described. Similar to BRAF, loss of PTEN appears to be mutually exclusive with the presence of an NRAS mutation in melanoma tumors and cell lines. While this pattern suggests functional redundancy, quantitative analysis of AKT activation demonstrated that PTEN loss correlated with significantly higher levels of phosphorylated AKT than NRAS mutations in both clinical specimens and cell lines (Davies et al. 2009). In contrast to NRAS, PTEN loss frequently occurs in melanomas with a concurrent activating BRAF mutation (Tsao et al. 2000; Goel et al. 2006; \n\t\t\t\t\t\tTsao et al. 2004\n\t\t\t\t\t). The functional nature of this pattern is supported by mouse studies, which demonstrated that crossing mice with the BRAFV600E mutation in melanocytes with mice that harbour PTEN loss resulted in frankly invasive and metastatic melanomas, which did not occur with either lesion alone (Dankort et al. 2009).
\n\t\t\t\t
In addition to loss of PTEN, the PI3K/AKT/mTOR pathway may also be activated by gene amplifications and gain of function mutations in other pathway components. Rare activating mutations in PI3KCA have been detected in 2-3% of melanomas (Omholt et al. 2006). Studies by Stahl et al\n\t\t\t\t\t, identified activation of AKT3 in 43 to 60% of sporadic melanomas, which was associated with an increase in copy number of the AKT3 gene along with a simultaneous decreased activity of PTEN, either due to loss or haploinsufficiency of the PTEN gene. Knockdown of AKT3 by siRNA induced apoptosis and reduced melanoma tumor development (Stahl et al. 2004). Davies et al\n\t\t\t\t\t recently also reported rare gain of function point mutations in the regulatory pleckstrin homology domains of AKT1 and AKT3 (AKT1 E17K, AKT3 E17K) in ~2% melanoma cell lines and tumor specimens (Davies et al. 2008). Every melanoma with an AKT1 or AKT3 mutation also had a concurrent BRAF mutation.
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\n\t\t\t
\n\t\t\t\t
2.3. Receptor tyrosine kinases
\n\t\t\t\t
Activating mutations or amplifications of receptor tyrosine kinases are implicated in multiple tumor types, including gastrointestinal stromal tumors (GIST) (c-KIT), breast (HER2/neu), and lung (EGFR) cancers. However, until recently there has been little evidence of significant aberrations in melanoma. The relatively low rate of BRAF and NRAS mutations in non-cutaneous melanomas led to focused searches for other oncogenic drivers in these tumor types. Comparative genome hybridization (CGH) analysis identified selective amplification of the 4q12 chromosomal region in acral and mucosal melanomas (Curtin et al. 2005). Detailed analysis of the genes in this region identified focal amplifications of the c-KIT gene (Curtin et al. 2006). C-KIT is a receptor tyrosine kinase which is affected by activating mutations in ~80% of GISTs (Hirota et al. 1998). Subsequent to the discovery of gene amplifications, sequencing demonstrated that the c-KIT gene is also frequently mutated in the same melanoma subtypes in which amplifications had been detected(Curtin et al. 2006). Overall,\n\t\t\t\t\tc-KIT gene amplification or mutation was identified in 39% of mucosal and 36% of acral melanomas. Among cutaneous melanomas, c-KIT gene alterations were also detected in 28% of cutaneous melanomas with chronic sun damage (CSD), but no c-KIT gene aberrations were reported in cutaneous melanomas without CSD (Curtin et al. 2006). However, other studies have reported lower rates of c-KIT alterations in cutaneous melanomas with CSD (\n\t\t\t\t\t\tHandolias, Salemi et al. 2010\n\t\t\t\t\t). The mutations in c-KIT gene generally affect the same exons that are mutated in GIST, although the distribution in melanoma shows a higher prevalence of mutations in exons associated with resistance to many c-KIT inhibitors. Interestingly, while most c-KIT mutations in GIST are short insertions or deletions, the overwhelming majority of changes in melanoma are point mutations, with the most common event being the L576P substitution at exon 11 of the juxtamembrane region (Beadling et al. 2008). The finding of activating c-KIT mutations was surprising, as previous reports had demonstrated that although c-KIT is essential for the development of normal melanocytes, c-KIT activation suppressed the growth of melanoma cells, and melanoma progression was associated with loss of c-KIT expression (Huang et al. 1996; Lassam and Bickford 1992). However, the lack of mutations in c-KIT in cutaneous melanomas suggests that other lineage-specific genetic or environmental factors in the non-cutaneous melanocytes may critically interact with the c-KIT mutations.
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More recently, high-throughput sequencing analysis of all protein kinases identified novel somatic mutations in 19 different genes (Prickett et al. 2009). The most frequently mutated gene was ERBB4 (24 missense mutations in 15 patients; 19% prevalence in the cohort), which encodes a receptor tyrosine kinase that is a member of the epidermal growth factor receptor family (EGFR, HER2, HER3). ERBB4 mutations have previously been reported in lung, colon, stomach and breast cancers (Soung et al. 2006; Ding et al. 2008). Interestingly, the mutations in the melanomas were distributed throughout the entire ERBB4 gene. Despite this unusual pattern for an activating event, Prickett et al., found that every tumor-derived mutation ERBB4 tested had higher levels of receptor tyrosine kinase activity, promoted anchorage independent growth, and induced cellular transformation (Prickett et al. 2009). In contrast to the distinct patterns seen with other mutations, ERBB4 mutations were not mutually exclusive with BRAF or NRAS mutations. Further investigation is needed to gain a better understanding of the role of ERBB4 in melanoma, and to understand the therapeutic potential of inhibitors against this target.
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2.4. G proteins
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Heterotrimeric guanine nucleotide-binding proteins (G proteins) are a diverse family of proteins that regulate and propagate signals from G-Protein Coupled Receptors (GPCRs) that are expressed at the cell membrane. The complex of G-proteins and GPCRs activate several key signaling pathways involved in cell survival, proliferation, and transformation. There is growing evidence that this family of genes may play a significant role in certain subtypes of melanoma.
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A role for G proteins in melanoma was first suggested by a preclinical study that was designed to identify genes that promote melanin synthesis and pigmentation in mice. Two different G protein alpha subunits, GNAQ and GNA11, were identified in this screen (Van Raamsdonk et al. 2004). In order to determine the clinical relevance of these genes in patients, panels of melanomas and nevi were then screened for alterations in these genes. Remarkably, point mutations in GNAQ were identified in ~50% of primary uveal melanomas (Onken et al. 2008; Van Raamsdonk, Bezrookove, Green, Bauer, Gaugler, O/\'Brien et al. 2009). GNAQ mutations were also identified in 50-80% of blue nevi, and in 6% of rare lesions called nevi of Ota, which are associated with an increased risk of uveal melanoma (Van Raamsdonk, Bezrookove, Green, Bauer, Gaugler, O/\'Brien et al. 2009). In contrast, no GNAQ mutations were identified in cutaneous melanomas without chronic sun damage, acral melanomas, or mucosal melanomas; 1 of 27 cutaneous melanomas with chronic sun damage tested had a mutation. Further sequencing identified point mutations of GNA11 in 32% of primary uveal melanomas, all of which were mutually exclusive with GNAQ mutations (Van Raamsdonk et al. 2010). Interestingly, analysis of a cohort of uveal melanoma metastases identified a higher prevalence of GNA11 (56%) than GNAQ (22%) mutations. Overall, somatic mutations in GNAQ and GNA11 were detected in over 80% of all uveal melanomas analyzed (Van Raamsdonk, Bezrookove, Green, Bauer, Gaugler, O\'Brien et al. 2009).
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Over 90% of the reported mutations in GNAQ and GNA11 affect the Q209 residue. This occurs in a RAS-like domain of these proteins, and is specifically analogous to the Q61 residue that is the most common site of point mutations in the RAS gene. Functional studies of the Q209L mutation in both GNAQ and GNA11 demonstrated that this mutation promotes anchorage independent growth, tumorigenicity, and activation of the RAS/RAF/MAPK pathway (Van Raamsdonk, Bezrookove, Green, Bauer, Gaugler, O/\'Brien et al. 2009; Van Raamsdonk et al. 2010). These findings suggest that these mutations may obviate the requirement for BRAF or NRAS mutations, which are virtually non-existant in uveal melanomas (Cohen et al. 2003; Rimoldi et al. 2003). Studies to determine the various functions of GNAQ and GNA11 mutations in uveal melanoma, and determine the therapeutic potential of inhibiting these genes or their effectors, are currently ongoing.
\n\t\t\t\t
In addition to these mutations in uveal melanoma, high-throughput sequencing for mutations in G protein family members in cutaneous melanomas identified 18 non-synonymous somatic mutations in G protein subunits spanning seven genes (Cardenas-Navia et al.). Mutations were identified in GNA12, GNG10, GNAZ, GNG14, GNA15, GNA11, and GNB3 (Cardenas-Navia et al.). Further work needs to be done to understand the pathways and processes affected by these mutations.
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2.5. Other affected genes
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Alterations in several regulators of cell cycle progression have also been implicated in melanoma. Allelic alterations in CDK4 and CCND1 have been reported in melanoma (Curtin et al. 2005; Smalley et al. 2008). Inactivation of the tumor suppressor p53, which is associated with DNA damage and metabolic stress, has also been reported. (Yang, Rajadurai, and Tsao 2005; Jonsson et al. 2007). P53 may also be functionally inactivated by loss of function of p16\n\t\t\t\t\t\n\t\t\t\t\t\tINK4a\n\t\t\t\t\t\n\t\t\t\t\t/p14\n\t\t\t\t\t\n\t\t\t\t\t\tARF\n\t\t\t\t\t genes (Pomerantz et al. 1998; Stott et al. 1998; Zhang, Xiong, and Yarbrough 1998). Loss of function of p16INK4a/p14ARF is present in most familial melanomas (Cannon-Albright et al. 1992; Goldstein et al. 2007). Loss of both p16 and p14 is seen in both melanoma cell lines and primary tumors and is a selection factor for the survival of melanoma cells in vitro (Daniotti et al. 2004; Rakosy et al. 2008). However, currently there are no therapies in place to restore the expression of these tumor suppressors.
\n\t\t\t\t
A comparative genetic analysis of melanomas with other tumor types identified selective amplifications of the gene encoding the microphthalmia-associated transcription factor (MITF) in melanoma (Garraway et al. 2005\n\t\t\t\t\t). MITF is a transcription factor that regulates many genes associated with melanin production and melanocyte development (Levy, Khaled, and Fisher 2006). Initial studies demonstrated the MITF could function as an oncogene, and was able to cooperate with the mutant BRAF gene to induce transformation of normal melanocytes (Garraway et al. 2005). Amplification of the MITF locus occurs in 10-20% melanomas, and subsequent studies have also detected rare somatic mutations in the gene in melanomas (Cronin et al. 2009).
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3. Clinical targeting of activated pathways in melanoma
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The treatment of many cancers has changed dramatically due to an improved understanding of the genes and pathways that contribute to the aggressive nature of many of these diseases. The discovery of activating events in kinase signaling pathways in melanoma rapidly led to clinical testing of a number of targeted therapies for this disease. The early results illustrate both the promise and challenge of this strategy.
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3.1. The RAS/RAF/MAPK pathway
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The high prevalence of mutations in components of the RAS/RAF/MAPK pathway in melanoma, particularly in the most common subtype (cutaneous), strongly supports the rationale to test the clinical efficacy of drugs against it. After the discovery of activating BRAF mutations (Davies et al. 2002), the first drug against the pathway to be tested clinically was sorafenib. Sorafenib is a small molecule that inhibits a number of kinases, including BRAF, CRAF, vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-Kit (Strumberg 2005). Preclinical studies demonstrated that sorafenib slowed the growth of melanoma xenografts with activating BRAF mutations, but did not result in tumor eradication (Karasarides et al. 2004). Subsequently, in a single-agent phase II trial, treatment with sorafenib resulted in only 1 clinical response among 34 evaluable patients (Eisen et al. 2006). More promising results were observed in a phase I trial that tested the safety of combined treatment with sorafenib, carboplatin, and paclitaxel. Ten clinical responses were observed, all of which occurred in patients with metastatic melanoma [n=24; 40% overall response rate (ORR)] (Flaherty et al. 2008). Of note, the clinical benefit among the melanoma patients did not correlate with the presence of activating BRAF mutations. Despite these promising results, a subsequent randomized phase III trial of treatment with carboplatin and paclitaxel with or without sorafenib definitively showed that sorafenib did not improve the ORR or progression-free survival (PFS) that was achieved with the chemotherapy agents alone (Hauschild et al. 2009). Combined with preclinical studies that showed the high prevalence of BRAF mutations in benign nevi, and induction of cellular senescence only following expression of mutant BRAF in normal melanocytes, these results raised doubts about the value of BRAF as a therapeutic target.
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The identification of mutant BRAF as a therapeutic target in melanoma has now been confirmed by clinical trials with potent, selective second-generation BRAF inhibitors. PLX4032 (vemurafenib) is a small molecule that has an in vitro IC50 for the BRAFV600E protein of ~ 10 nM. This is one log lower than the IC50 for the wild-type BRAF protein, and 2-3 logs lower than the IC50 for other related kinases (Tsai et al. 2008). Experiments in xenografts models demonstrated that PLX4720, a closely related compound used for preclinical studies, eradicated melanomas with a BRAFV600E mutation (Yang et al. 2010). More importantly, the phase I trial of PLX4032 in patients with advanced melanoma reported an unconfirmed ORR of 81% among patients with the BRAFV600E mutation (Flaherty et al. 2010). The selectivity of the agent in vivo is supported by the relatively mild toxicity of the drug, which was well-tolerated by patients. In addition, no clinical responses were observed in the 5 patients included in the trial who had a wild-type BRAF gene. In fact, 4 of those patients demonstrated clinical progression of disease at their initial restaging. This clinical finding is consistent with work in preclinical models that demonstrated that treatment of human melanoma cell lines with a wild-type BRAF gene with PLX4720 and other selective BRAF inhibitors resulted in hyperactivation of MEK and MAPK, and increased growth of cancer cells in vitro and in vivo (Halaban et al. 2010; Hatzivassiliou et al. 2010; Heidorn et al. 2010; Poulikakos et al. 2010). A second selective inhibitor of the BRAFV600E protein, GSK2118436, has demonstrated similar activity, with a 62% ORR in phase I testing in advanced melanoma patients with a BRAF mutation (Kefford et al. 2010).
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While the high response rate with minimal toxicity with PLX4032 and GSK2118436 is unprecedented, it is now becoming clear that resistance will be a major problem with these agents. In the phase I trial of PLX4032, virtually all patients who responded clinically went on to develop disease progression, with a median duration of response of approximately 7 months (Flaherty et al. 2010). While the experience with resistance to targeted therapies in other diseases made it reasonable to hypothesize that secondary BRAF mutations could cause this, to date the analysis of tumors and cell lines with secondary resistance to selective BRAF inhibitors have failed to identify any such mutations (Nazarian et al. 2010; Villanueva et al. 2010). Instead, cells lines and tumors have developed changes that either maintain activation of the RAS/RAF/MAPK pathway in the presence of the BRAF inhibitors, or changes that allow cells to survive even when that pathway is inhibited. Mechanisms that result in continued activation of the RAS/RAF/MAPK pathway include (1) concurrent NRAS or MEK1 mutation (Nazarian et al. 2010; Wagle et al.), (2) induction of the serine-threonine kinase COT1 (Johannessen et al. 2010), or (2) utilization of all 3 RAF isoforms to activate MEK (Villanueva et al. 2010). Mechanisms that result in resistance to cell killing despite continued inhibition of MEK and MAPK generally implicate activation of the PI3K-AKT pathway, either through the increased expression of receptor tyrosine kinases or through the loss of PTEN (Nazarian et al. 2010; Villanueva et al. 2010). Activation of the PI3K-AKT pathway by loss of PTEN also results in de novo resistance to cell killing by BRAF inhibitors, but the relationship between PTEN loss and clinical responsiveness in patients has yet to be determined (Paraiso et al. 2011).
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In addition to BRAF inhibitors, MEK inhibitors have shown promise in the treatment of metastatic melanoma. The initial presentation of the preliminary results of the phase I trial of GSK1120212, an orally available MEK inhibitor with a very long half life, reported a 40% ORR response among patients with metastatic melanoma (Infante et al. 2010). This response rate is higher than previous reports with other MEK inhibitors, such as AZD6244 (Dummer et al. 2008). Preclinical studies demonstrated that, similar to the results with BRAF inhibitors, loss of PTEN correlates with increased resistance to cell killing by MEK inhibitors (Gopal et al. 2010). Interestingly, several cells with normal PTEN expression but similar resistance developed activation of the PI3K-AKT pathway following treatment with MEK inhibitors. This compensatory mechanism, which was mediated by the insulin-like growth factor-1 receptor, gives further support to the rationale for testing the effects of targeted therapy combinations to improve clinical results with both BRAF and MEK inhibitors.
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3.2. c-KIT
\n\t\t\t\t
Imatinib, a small molecule inhibitor of a number of kinases, is approved by the FDA for the first-line treatment of metastatic GISTs, which are characterized by a high (~80%) prevalence of activating mutations in the c-KIT gene. This clinical experience gave cause for optimism for the use of imatinib in melanoma, a mesenchymal tumor like GIST with very poor responsiveness to cytotoxic chemotherapies. Prior to the identification of c-KIT mutations in acral and mucosal melanomas, three different phase II trials with imatinib were conducted in advanced melanoma patients (Kim et al. 2008; Ugurel et al. 2005; Wyman et al. 2006). The cumulative ORR was only 1.5% for these trials. However, the patients overwhelmingly consisted of patients with cutaneous primary melanomas, and thus were unlikely to harbor activating c-Kit mutations.
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There are now several case reports describing impressive clinical responses to c-KIT inhibitors in melanoma patients with mutations in the c-KIT gene (\n\t\t\t\t\t\tHandolias, Hamilton et al. 2010\n\t\t\t\t\t; Hodi et al. 2008). In addition, relatively large clinical trials are ongoing testing the efficacy of c-KIT inhibitors in this patient population. An initial report from one of the imatinib trials reported an ORR of approximately 50% among patients with c-KIT mutations, but 0 of 10 patients with only gene amplification of the wild-type gene responded (Fisher et al. 2010). In addition, while c-KIT inhibitors have induced some durable responses, other dramatic responses have lasted for only a few months (Woodman et al. 2009). Thus, the further development of therapies for melanoma patients with c-KIT mutations will likely require an improved understanding of mechanisms of resistance to these agents, and combinatorial approaches.
The testing and treatment of melanoma patients is evolving rapidly due to an improved understanding of the genes and pathways that are genetically altered in this disease. The dramatic responses of melanoma patients with BRAF and c-KIT mutations to inhibitors against these targets demonstrate the power and benefit of research to uncover the underpinnings of cancer. However, the early experience with these targets has also illuminated the challenges of this approach.
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There is a clear need to improve our understanding of the factors that are present at baseline that allow resistance to occur to BRAF and c-KIT inhibitors, as well as changes that evolve over time to manifest the resistance. An improved understanding of pre-treatment factors that facilitate the eventual emergence of resistance may suggest rational combinatorial approaches that can prevent resistance from developing. Such factors may also serve as markers that clinically distinguish patients who need combinatorial treatments, which are likely to incur additional toxicities, from those who may achieve significant benefit from single-agent therapy. Similarly, determining the changes that evolve over time and correlate with functional resistance will also suggest rational combinatorial approaches that can be used after single-agent therapies fail. While it is reasonable to hypothesize that many of the critical mechanisms that underlie resistance will involve changes in signaling pathways in the tumors, the possibility of other factors should not be dismissed. For example, recent research has demonstrated that targeted therapies against the RAS/RAF/MAPK pathway can influence both the ability of immune cells to recognize melanomas, and their proliferation and survival (Boni et al. 2010). As immunotherapies have been associated with relatively low response rates but durable benefit when they occur, it is possible that strategies that combine such approaches with targeted therapies may have synergistic clinical benefit.
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While there are now clearly defined challenges for patients with BRAF and c-KIT mutations, the picture remains much less clear for other patients. To date, effective treatment strategies for tumors with mutations in RAS family members have not been validated clinically. Research clearly needs to be undertaken to develop such approaches for patients with NRAS mutations, and perhaps the analogous mutations in GNAQ and GNA11 in uveal melanomas. Furthermore, a significant number of patients (i.e. ~30% of cutaneous melanomas) do not have a detectable mutation in BRAF, NRAS, or c-KIT. As has been described here, the number of other mutations that have been identified in melanoma is now rapidly increasing, but the functions and therapeutic implications of many of these events remain poorly characterized. It is highly likely that many more events will be identified in the future, as the first whole-genome sequencing effort revealed almost 200 non-synonymous coding region substitutions in a single patient-derived melanoma (Pleasance et al. 2010). Unraveling the functional interactions and significance of the multiple mutations that are present in each tumor will require extensive testing and innovation. In addition, additional pathways, such as metabolism, oxidative stress, and angiogenesis likely play key functional roles, and may be important therapeutic targets without being directly involved by genetic alterations.
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Overall, recent discoveries have provided new hope and therapeutic options for patients with melanoma. These advances highlight the potential of translational research, and provide the impetus for continued research of this highly aggressive disease.
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Acknowledgments
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M.A.D. reports receiving research funding from AstraZeneca, GlaxoSmithKline, and Merck. M.A.D. is supported by a Career Development Award from the American Society of Clinical Oncology, a Young Investigator Award from the Melanoma Research Alliance, and is the Goodfellow Scholar of the MD Anderson Cancer Center Physician Scientist Program.
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/19096.pdf",chapterXML:"https://mts.intechopen.com/source/xml/19096.xml",downloadPdfUrl:"/chapter/pdf-download/19096",previewPdfUrl:"/chapter/pdf-preview/19096",totalDownloads:1944,totalViews:154,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,dateSubmitted:"November 8th 2010",dateReviewed:"April 10th 2011",datePrePublished:null,datePublished:"September 12th 2011",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/19096",risUrl:"/chapter/ris/19096",book:{slug:"research-on-melanoma-a-glimpse-into-current-directions-and-future-trends"},signatures:"Kausar Begam Riaz Ahmed and Michael A. Davies",authors:[{id:"38597",title:"Dr.",name:"Michael",middleName:null,surname:"Davies",fullName:"Michael Davies",slug:"michael-davies",email:"mdavies@mdanderson.org",position:null,institution:null},{id:"38611",title:"Ms",name:"Kausar Begam",middleName:null,surname:"Riaz Ahmed",fullName:"Kausar Begam Riaz Ahmed",slug:"kausar-begam-riaz-ahmed",email:"kausarbegam@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Melanoma molecular targets",level:"1"},{id:"sec_2_2",title:"2.1. RAS/RAF/MAPK pathway",level:"2"},{id:"sec_3_2",title:"2.2. PI3K/AKT/mTOR pathway",level:"2"},{id:"sec_4_2",title:"2.3. Receptor tyrosine kinases",level:"2"},{id:"sec_5_2",title:"2.4. G proteins",level:"2"},{id:"sec_6_2",title:"2.5. Other affected genes ",level:"2"},{id:"sec_8",title:"3. Clinical targeting of activated pathways in melanoma",level:"1"},{id:"sec_8_2",title:"3.1. The RAS/RAF/MAPK pathway",level:"2"},{id:"sec_9_2",title:"3.2. c-KIT",level:"2"},{id:"sec_11",title:"4. Summary",level:"1"},{id:"sec_12",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\tAlmoguera\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\tShibata\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\tForrester\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\tMartin\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\tArnheim\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\tPerucho\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1988\n\t\t\t\t\tMost human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.\n\t\t\t\t\tCell\n\t\t\t\t\t53\n\t\t\t\t\t4\n\t\t\t\t\t549\n\t\t\t\t\t54\n\t\t\t\t\n\t\t\t'},{id:"B2",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\tBalch\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\tLe Warrick\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\tPatterson\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\tTown\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\tHarlow\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\tCruz\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\t3rd Azar\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\tRubin\n\t\t\t\t\t\t\tB. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuller\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\tWest\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\tHeinrich\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\tCorless\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tKIT gene mutations and copy number in melanoma subtypes\n\t\t\t\t\tClin Cancer Res\n\t\t\t\t\t14\n\t\t\t\t\t21\n\t\t\t\t\t6821\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B4",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\tBoni\n\t\t\t\t\t\t\tAndrea.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlexandria\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\tCogdill\n\t\t\t\t\t\t\tPing.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDang\n\t\t\t\t\t\t\tDurga.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUdayakumar-Ni\n\t\t\t\t\t\t\tChing.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJenny\n\t\t\t\t\t\t\tNjauw.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCallum\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\tSloss\n\t\t\t\t\t\t\tCristina. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerrone\n\t\t\t\t\t\t\tKeith. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFlaherty\n\t\t\t\t\t\t\tDonald. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLawrence\n\t\t\t\t\t\t\tDavid. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFisher\n\t\t\t\t\t\t\tHensin.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsao\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\tJennifer\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\tWargo\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\t2010\n\t\t\t\t\tSelective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function.\n\t\t\t\t\tCancer Research\n\t\t\t\t\n\t\t\t'},{id:"B5",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\tBos\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\tFearon\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHamilton\n\t\t\t\t\t\t\tS. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerlaan-de\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\tVries\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\tvan Boom\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan der Eb\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\tVogelstein\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1987\n\t\t\t\t\tPrevalence of ras gene mutations in human colorectal cancers.\n\t\t\t\t\tNature\n\t\t\t\t\t327\n\t\t\t\t\t6120\n\t\t\t\t\t293\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B6",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\tBos\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\tToksoz\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\tMarshall\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\tVerlaan-de\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\tVries\n\t\t\t\t\t\t\tG. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVeeneman\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan der Eb\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\tvan Boom\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJanssen\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\tSteenvoorden\n\t\t\t\t\t\t\tA. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985\n\t\t\t\t\tAmino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia.\n\t\t\t\t\tNature\n\t\t\t\t\t315\n\t\t\t\t\t6022\n\t\t\t\t\t726\n\t\t\t\t\t30\n\t\t\t\t\n\t\t\t'},{id:"B7",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\tCannon-Albright\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\tGoldgar\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeyer\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\tLewis\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\tAnderson\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFountain\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHegi\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\tWiseman\n\t\t\t\t\t\t\tR. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPetty\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\tBale\n\t\t\t\t\t\t\tA. E.\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\tAssignment of a locus for familial melanoma, MLM, to chromosome 913\n\t\t\t\t\t\tp22 .\n\t\t\t\t\tScience 258 (5085):1148-52.\n\t\t\t'},{id:"B8",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\tCardenas-Navia\n\t\t\t\t\t\t\tL. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCruz\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\tLin\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\tRosenberg\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSamuels\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\tNovel somatic mutations in heterotrimeric G proteins in melanoma\n\t\t\t\t\tCancer Biol Ther\n\t\t\t\t\t10\n\t\t\t\t\t1\n\t\t\t\t\t33\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B9",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\tChin\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\tPomerantz\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\tPolsky\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\tJacobson\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\tCohen\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\tCordon-Cardo\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\tHorner\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t2nd\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\tDe Pinho\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997\n\t\t\t\t\tCooperative effects of INK4a and ras in melanoma susceptibility in vivo\n\t\t\t\t\tGenes Dev\n\t\t\t\t\t11\n\t\t\t\t\t21\n\t\t\t\t\t2822\n\t\t\t\t\t34\n\t\t\t\t\n\t\t\t'},{id:"B10",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\tChin\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\tTam\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\tPomerantz\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\tWong\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\tHolash\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\tBardeesy\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\tShen\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\tO’Hagan\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\tPantginis\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\tZhou\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\tHorner\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t2nd\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\tCordon-Cardo\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYancopoulos\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\tDe Pinho\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tEssential role for oncogenic Ras in tumour maintenance.\n\t\t\t\t\tNature\n\t\t\t\t\t400\n\t\t\t\t\t6743\n\t\t\t\t\t468\n\t\t\t\t\t72\n\t\t\t\t\n\t\t\t'},{id:"B11",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\tChudnovsky\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\tAdams\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobbins\n\t\t\t\t\t\t\tP. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\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\tKhavari\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tUse of human tissue to assess the oncogenic activity of melanoma-associated mutations.\n\t\t\t\t\tNat Genet\n\t\t\t\t\t37\n\t\t\t\t\t7\n\t\t\t\t\t745\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B12",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\tCohen\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\tGoldenberg-Cohen\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\tParrella\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\tChowers\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\tMerbs\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\tPe’er\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\tSidransky\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tLack of BRAF mutation in primary uveal melanoma.\n\t\t\t\t\tInvest Ophthalmol Vis Sci\n\t\t\t\t\t44\n\t\t\t\t\t7\n\t\t\t\t\t2876\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B13",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\tCronin\n\t\t\t\t\t\t\tJulia. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohn\n\t\t\t\t\t\t\tWunderlich.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStacie\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\tLoftus\n\t\t\t\t\t\t\tTodd. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrickett\n\t\t\t\t\t\t\tXiaomu.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWei\n\t\t\t\t\t\t\tKatie.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRidd\n\t\t\t\t\t\t\tSwapna.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVemula\n\t\t\t\t\t\t\tAllison. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurrell\n\t\t\t\t\t\t\tNeena. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAgrawal\n\t\t\t\t\t\t\tJimmy. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tCarolyn. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBanister\n\t\t\t\t\t\t\tPhillip.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuckhaults\n\t\t\t\t\t\t\tSteven. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosenberg\n\t\t\t\t\t\t\tBoris. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBastian\n\t\t\t\t\t\t\tWilliam. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPavan\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\tYardena\n\t\t\t\t\t\t\tSamuels.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tFrequent mutations in the MITF pathway in melanoma\n\t\t\t\t\tPigment Cell Melanoma Res\n\t\t\t\t\t22\n\t\t\t\t\t4\n\t\t\t\t\t435\n\t\t\t\t\t444\n\t\t\t\t\n\t\t\t'},{id:"B14",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\tCurtin\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBusam\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\tPinkel\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\tBastian\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tSomatic activation of KIT in distinct subtypes of melanoma.\n\t\t\t\t\tJ Clin Oncol\n\t\t\t\t\t24\n\t\t\t\t\t26\n\t\t\t\t\t4340\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B15",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\tCurtin\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFridlyand\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\tKageshita\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\tPatel\n\t\t\t\t\t\t\tH. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBusam\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKutzner\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\tCho\n\t\t\t\t\t\t\tK. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAiba\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\tBrocker\n\t\t\t\t\t\t\tE. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLe Boit\n\t\t\t\t\t\t\tP. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPinkel\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\tBastian\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tDistinct sets of genetic alterations in melanoma.\n\t\t\t\t\tN Engl J Med\n\t\t\t\t\t353\n\t\t\t\t\t20\n\t\t\t\t\t2135\n\t\t\t\t\t47\n\t\t\t\t\n\t\t\t'},{id:"B16",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\tDaniotti\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\tOggionni\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\tRanzani\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\tVallacchi\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\tCampi\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\tDi Stasi\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\tTorre\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPerrone\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\tLuoni\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\tSuardi\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\tFrattini\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\tPilotti\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\tAnichini\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\tTragni\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\tParmiani\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\tPierotti\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRodolfo\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tBRAF alterations are associated with complex mutational profiles in malignant melanoma.\n\t\t\t\t\tOncogene\n\t\t\t\t\t23\n\t\t\t\t\t35\n\t\t\t\t\t5968\n\t\t\t\t\t77\n\t\t\t\t\n\t\t\t'},{id:"B17",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\tDankort\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\tCurley\n\t\t\t\t\t\t\tD. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCartlidge\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\tNelson\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\tKarnezis\n\t\t\t\t\t\t\tA. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDamsky\n\t\t\t\t\t\t\tW. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJr \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\tYou\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\tDe Pinho\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\tMc Mahon\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\tBosenberg\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Braf(600Ecooperates with Pten loss to induce metastatic melanoma. Nat Genet 41 (5):544-52.\n\t\t\t'},{id:"B18",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\tDavies\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\tBignell\n\t\t\t\t\t\t\tG. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\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\tStephens\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\tEdkins\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\tClegg\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\tTeague\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\tWoffendin\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\tGarnett\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\tBottomley\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\tDavis\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\tDicks\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\tEwing\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\tFloyd\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\tGray\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\tHall\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\tHawes\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\tHughes\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\tKosmidou\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\tMenzies\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\tMould\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\tParker\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\tStevens\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\tWatt\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\tHooper\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\tWilson\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\tJayatilake\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\tGusterson\n\t\t\t\t\t\t\tB. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCooper\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\tShipley\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\tHargrave\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\tPritchard-Jones\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\tMaitland\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\tChenevix-Trench\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\tRiggins\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBigner\n\t\t\t\t\t\t\tD. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPalmieri\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\tCossu\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\tFlanagan\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\tNicholson\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\tHo\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeung\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuen\n\t\t\t\t\t\t\tS. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeber\n\t\t\t\t\t\t\tB. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeigler\n\t\t\t\t\t\t\tH. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDarrow\n\t\t\t\t\t\t\tT. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaterson\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\tMarais\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\tMarshall\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\tWooster\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\tStratton\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\tFutreal\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002Mutations of the BRAF gene in human cancer. Nature\n\t\t\t\t\t417\n\t\t\t\t\t6892\n\t\t\t\t\t949\n\t\t\t\t\t54\n\t\t\t\t\n\t\t\t'},{id:"B19",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\tDavies\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoul\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\tDhesi\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\tBerman\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\tMc Donnell\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Conkey\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\tYung\n\t\t\t\t\t\t\tW. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteck\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res\n\t\t\t\t\t59\n\t\t\t\t\t11\n\t\t\t\t\t2551\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B20",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\tDavies\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLu\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\tSano\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\tFang\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\tTang\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\tLa Pushin\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\tKoul\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\tBookstein\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\tStokoe\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\tYung\n\t\t\t\t\t\t\tW. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMills\n\t\t\t\t\t\t\tG. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteck\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res\n\t\t\t\t\t58\n\t\t\t\t\t23\n\t\t\t\t\t5285\n\t\t\t\t\t90\n\t\t\t\t\n\t\t\t'},{id:"B21",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\tDavies\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStemke-Hale\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\tLin\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\tTellez\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\tDeng\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\tGopal\n\t\t\t\t\t\t\tY. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWoodman\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCalderone\n\t\t\t\t\t\t\tT. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJu\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\tLazar\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrieto\n\t\t\t\t\t\t\tV. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAldape\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\tMills\n\t\t\t\t\t\t\tG. B.\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\n\t\t\t\t\t2009Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma. Clin Cancer Res\n\t\t\t\t\t15\n\t\t\t\t\t24\n\t\t\t\t\t7538\n\t\t\t\t\t7546\n\t\t\t\t\n\t\t\t'},{id:"B22",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\tDavies\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStemke-Hale\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\tTellez\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\tCalderone\n\t\t\t\t\t\t\tT. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeng\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\tPrieto\n\t\t\t\t\t\t\tV. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLazar\n\t\t\t\t\t\t\tA. J.\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\tMills\n\t\t\t\t\t\t\tG. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer\n\t\t\t\t\t99\n\t\t\t\t\t8\n\t\t\t\t\t1265\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B23",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\tDing\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\tGetz\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\tWheeler\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMardis\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Lellan\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCibulskis\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\tSougnez\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\tGreulich\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\tMuzny\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorgan\n\t\t\t\t\t\t\tM. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFulton\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\tFulton\n\t\t\t\t\t\t\tR. S.\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\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWendl\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\tLawrence\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\tLarson\n\t\t\t\t\t\t\tD. 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\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDooling\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\tSabo\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\tHawes\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\tShen\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\tJhangiani\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLewis\n\t\t\t\t\t\t\tL. R.\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\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\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\tMathew\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\tRen\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\tYao\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\tScherer\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClerc\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\tMetcalf\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNg\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\tMilosavljevic\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\tGonzalez-Garay\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOsborne\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeyer\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\tShi\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\t\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\t2008Somatic mutations affect key pathways in lung adenocarcinoma. Nature\n\t\t\t\t\t455\n\t\t\t\t\t7216\n\t\t\t\t\t1069\n\t\t\t\t\t75\n\t\t\t\t\n\t\t\t'},{id:"B24",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\tDummer\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\tRobert\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\tChapman\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\tSosman\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\tMiddleton\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\tBastholt\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\tKemsley\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\tCantarini\n\t\t\t\t\t\t\tM. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorris\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\tKirkwood\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008AZD6244 (ARR-142886) vs temozolomide (TMZ) in patients with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol 26 (May 20 supplement):9033.\n\t\t\t'},{id:"B25",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\tEisen\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\tAhmad\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\tFlaherty\n\t\t\t\t\t\t\tK. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGore\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\tKaye\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\tMarais\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\tGibbens\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\tHackett\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\tJames\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\tSchuchter\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\tNathanson\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\tXia\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\tSimantov\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\tSchwartz\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\tPoulin-Costello\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\tO’Dwyer\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRatain\n\t\t\t\t\t\t\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer\n\t\t\t\t\t95\n\t\t\t\t\t5\n\t\t\t\t\t581\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B26",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\tEmery\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\tVijayendran\n\t\t\t\t\t\t\tK. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZipser\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\tSawyer\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\tNiu\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\tKim\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHatton\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\tChopra\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\tOberholzer\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarpova\n\t\t\t\t\t\t\tM. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMac\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\tConaill\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\tZhang\n\t\t\t\t\t\t\tN. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGray\n\t\t\t\t\t\t\tW. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSellers\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\tDummer\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\tGarraway\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A\n\t\t\t\t\t106\n\t\t\t\t\t48\n\t\t\t\t\t20411\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B27",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\tEngelman\n\t\t\t\t\t\t\tJ. A.\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\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCantley\n\t\t\t\t\t\t\tL. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet\n\t\t\t\t\t7\n\t\t\t\t\t8\n\t\t\t\t\t606\n\t\t\t\t\t19\n\t\t\t\t\n\t\t\t'},{id:"B28",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\tFisher\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarnhill\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\tHodi\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\tHerlyn\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\tMerlino\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\tMedrano\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\tBastian\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\tLandi\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\tSosman\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Melanoma from bench to bedside: meeting report from the 6th international melanoma congress. Pigment Cell Melanoma Res\n\t\t\t\t\t23\n\t\t\t\t\t1\n\t\t\t\t\t14\n\t\t\t\t\t26\n\t\t\t\t\n\t\t\t'},{id:"B29",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\tFlaherty\n\t\t\t\t\t\t\tK. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPuzanov\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\tKim\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\tRibas\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\tMc Arthur\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSosman\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Dwyer\n\t\t\t\t\t\t\tP. J.\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\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrippo\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\tNolop\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\tChapman\n\t\t\t\t\t\t\tP. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInhibition\n\t\t\t\t\t\t\tof.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tmutated\n\t\t\t\t\t\t\tactivated. B. R. A. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tin\n\t\t\t\t\t\t\tmetastatic.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tmelanoma\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\tEngl\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\tMed\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\n\t\t\t\t\t363\n\t\t\t\t\t9\n\t\t\t\t\t809\n\t\t\t\t\t19\n\t\t\t\t\n\t\t\t'},{id:"B30",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\tFlaherty\n\t\t\t\t\t\t\tKeith. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIgor\n\t\t\t\t\t\t\tPuzanov.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKevin\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\tKim\n\t\t\t\t\t\t\tAntoni.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRibas\n\t\t\t\t\t\t\tGrant. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Arthur\n\t\t\t\t\t\t\tJeffrey. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSosman\n\t\t\t\t\t\t\tPeter. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Dwyer\n\t\t\t\t\t\t\tRichard. J.\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\tJoseph. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrippo\n\t\t\t\t\t\t\tKeith.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNolop\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\tPaul\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\tChapman\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\t2010Inhibition of Mutated, Activated BRAF in Metastatic Melanoma. New England Journal of Medicine\n\t\t\t\t\t363\n\t\t\t\t\t9\n\t\t\t\t\t809\n\t\t\t\t\t819\n\t\t\t\t\n\t\t\t'},{id:"B31",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\tFlaherty\n\t\t\t\t\t\t\tKeith. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJoan\n\t\t\t\t\t\t\tSchiller.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLynn\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\tSchuchter\n\t\t\t\t\t\t\tGlenn.\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\tDavid. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTuveson\n\t\t\t\t\t\t\tMaryann.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRedlinger\n\t\t\t\t\t\t\tChetan.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLathia\n\t\t\t\t\t\t\tChenghua.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXia\n\t\t\t\t\t\t\tOana.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPetrenciuc\n\t\t\t\t\t\t\tSunil. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHingorani\n\t\t\t\t\t\t\tMichael. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJacobetz\n\t\t\t\t\t\t\tPatricia. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan Belle\n\t\t\t\t\t\t\tDavid.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tElder\n\t\t\t\t\t\t\tMarcia. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrose\n\t\t\t\t\t\t\tBarbara. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeber\n\t\t\t\t\t\t\tMark. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlbertini\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\tPeter\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\tO’Dwyer\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\t2008A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel. 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N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeng\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\tWoodman\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKomurov\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\tRam\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\tSmith\n\t\t\t\t\t\t\tP. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavies\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res\n\t\t\t\t\t70\n\t\t\t\t\t21\n\t\t\t\t\t8736\n\t\t\t\t\t47\n\t\t\t\t\n\t\t\t'},{id:"B39",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\tHalaban\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\tZhang\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\tBacchiocchi\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\tCheng\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\tParisi\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\tAriyan\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\tKrauthammer\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\tMc Cusker\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\tKluger\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\tSznol\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010PLX4032, a selective BRAF(600Ekinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res 23 (2):190-200.\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\tHandolias\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\tHamilton\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalemi\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\tTan\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\tMoodie\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\tKerr\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\tDobrovic\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\tMc Arthur\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br J Cancer\n\t\t\t\t\t102\n\t\t\t\t\t8\n\t\t\t\t\t1219\n\t\t\t\t\t1223\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\tHandolias\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\tSalemi\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\tMurray\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\tTan\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\tLiu\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\tViros\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\tDobrovic\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\tKelly\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\tMc Arthur\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Mutations in KIT occur at low frequency in melanomas arising from anatomical sites associated with chronic and intermittent sun exposure. Pigment Cell Melanoma Res\n\t\t\t\t\t23\n\t\t\t\t\t210\n\t\t\t\t\t215\n\t\t\t\t\n\t\t\t'},{id:"B42",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\tHatzivassiliou\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\tSong\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\tYen\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\tBrandhuber\n\t\t\t\t\t\t\tB. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAnderson\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\tAlvarado\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\tLudlam\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\tStokoe\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\tGloor\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\tVigers\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\tMorales\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\tAliagas\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\tLiu\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\tSideris\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\tHoeflich\n\t\t\t\t\t\t\tK. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJaiswal\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\tSeshagiri\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\tKoeppen\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\tBelvin\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\tFriedman\n\t\t\t\t\t\t\tL. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMalek\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature.\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\tHauschild\n\t\t\t\t\t\t\tAxel.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSanjiv\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\tAgarwala\n\t\t\t\t\t\t\tUwe.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrefzer\n\t\t\t\t\t\t\tDavid.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHogg\n\t\t\t\t\t\t\tCaroline.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobert\n\t\t\t\t\t\t\tPeter.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHersey\n\t\t\t\t\t\t\tAlexander.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEggermont\n\t\t\t\t\t\t\tStephan.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrabbe\n\t\t\t\t\t\t\tRene.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGonzalez\n\t\t\t\t\t\t\tJens.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGille\n\t\t\t\t\t\t\tChristian.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeschel\n\t\t\t\t\t\t\tDirk.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchadendorf\n\t\t\t\t\t\t\tClaus.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarbe\n\t\t\t\t\t\t\tSteven.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tO’Day\n\t\t\t\t\t\t\tAdil.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDaud\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\tMichael\n\t\t\t\t\t\t\tWhite.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChenghua\n\t\t\t\t\t\t\tXia.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKiran\n\t\t\t\t\t\t\tPatel.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohn\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\tKirkwood\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\tUlrich\n\t\t\t\t\t\t\tKeilholz.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma. J Clin Oncol\n\t\t\t\t\t27\n\t\t\t\t\t17\n\t\t\t\t\t2823\n\t\t\t\t\t2830\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\tHeidorn\n\t\t\t\t\t\t\tSonja. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarla\n\t\t\t\t\t\t\tMilagre.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteven\n\t\t\t\t\t\t\tWhittaker.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArnaud\n\t\t\t\t\t\t\tNourry.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIon-Duvas\n\t\t\t\t\t\t\tNiculescu.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNathalie\n\t\t\t\t\t\t\tDhomen.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJahan\n\t\t\t\t\t\t\tHussain.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJorge\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\tReis-Filho\n\t\t\t\t\t\t\tCaroline. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpringer\n\t\t\t\t\t\t\tCatrin.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPritchard\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\tRichard\n\t\t\t\t\t\t\tMarais.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF. Cell\n\t\t\t\t\t140\n\t\t\t\t\t2\n\t\t\t\t\t209\n\t\t\t\t\t221\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\tHirota\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\tIsozaki\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\tMoriyama\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\tHashimoto\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\tNishida\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\tIshiguro\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\tKawano\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\tHanada\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\tKurata\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\tTakeda\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\tMuhammad\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\tTunio\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\tMatsuzawa\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\tKanakura\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\tShinomura\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\tKitamura\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\t1998Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science\n\t\t\t\t\t279\n\t\t\t\t\t5350\n\t\t\t\t\t577\n\t\t\t\t\t80\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\tHocker\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\tTsao\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat\n\t\t\t\t\t28\n\t\t\t\t\t6\n\t\t\t\t\t578\n\t\t\t\t\t88\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\tHodi\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\tFriedlander\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\tCorless\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeinrich\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\tMac\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\tRae\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\tKruse\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\tJagannathan\n\t\t\t\t\t\t\tA. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan den\n\t\t\t\t\t\t\tAbbeele. E. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVelazquez\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDemetri\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\tFisher\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol\n\t\t\t\t\t26\n\t\t\t\t\t12\n\t\t\t\t\t2046\n\t\t\t\t\t51\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\tHuang\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\tLuca\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\tGutman\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\tMc Conkey\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\tLangley\n\t\t\t\t\t\t\tK. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLyman\n\t\t\t\t\t\t\tS. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBar-Eli\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996Enforced c-KIT expression renders highly metastatic human melanoma cells susceptible to stem cell factor-induced apoptosis and inhibits their tumorigenic and metastatic potential. Oncogene\n\t\t\t\t\t13\n\t\t\t\t\t11\n\t\t\t\t\t2339\n\t\t\t\t\t47\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\tInfante\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFecher\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\tNallapareddy\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\tGordon\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\tFlaherty\n\t\t\t\t\t\t\tK. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tD. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Marini\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\tMorris\n\t\t\t\t\t\t\tS. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBurris\n\t\t\t\t\t\t\tH. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMessersmith\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Safety and efficacy results from the first time in humans study of the oral MEK1/2 inhibitor GSK1120212. J Clin Oncol.\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\tJemal\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\tSiegel\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\tXu\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\tWard\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\tCancer\n\t\t\t\t\t\t\tstatistics.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tCA Cancer J Clin\n\t\t\t\t\t60\n\t\t\t\t\t5\n\t\t\t\t\t277\n\t\t\t\t\t300\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\tJohannessen\n\t\t\t\t\t\t\tCory. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJesse\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\tBoehm\n\t\t\t\t\t\t\tSo.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoung\n\t\t\t\t\t\t\tKim.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSapana\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\tThomas\n\t\t\t\t\t\t\tLeslie.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWardwell\n\t\t\t\t\t\t\tLaura. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tCaroline. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEmery\n\t\t\t\t\t\t\tNicolas.\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\tAlexandria. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCogdill\n\t\t\t\t\t\t\tJordi.\n\t\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\tGiordano.\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\tHaley.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHieronymus\n\t\t\t\t\t\t\tRyan. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurray\n\t\t\t\t\t\t\tKourosh.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalehi-Ashtiani\n\t\t\t\t\t\t\tDavid. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHill\n\t\t\t\t\t\t\tMarc.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVidal\n\t\t\t\t\t\t\tJean. J.\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\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature\n\t\t\t\t\t468\n\t\t\t\t\t7326\n\t\t\t\t\t968\n\t\t\t\t\t972\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\tJonsson\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\tDahl\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\tStaaf\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\tSandberg\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\tBendahl\n\t\t\t\t\t\t\tP. O.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRingner\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\tGuldberg\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\tBorg\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007Genomic profiling of malignant melanoma using tiling-resolution arrayCGH. Oncogene\n\t\t\t\t\t26\n\t\t\t\t\t32\n\t\t\t\t\t4738\n\t\t\t\t\t48\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\tKarasarides\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\tChiloeches\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\tHayward\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\tNiculescu-Duvaz\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\tScanlon\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\tFriedlos\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\tOgilvie\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\tHedley\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\tMartin\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\tMarshall\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\tSpringer\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\tMarais\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004B-RAF is a therapeutic target in melanoma. Oncogene\n\t\t\t\t\t23\n\t\t\t\t\t37\n\t\t\t\t\t6292\n\t\t\t\t\t8\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\tKefford\n\t\t\t\t\t\t\tRichard. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArkenau\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\tBrown\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\tMilward\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\tInfante\n\t\t\t\t\t\t\tJ. R.\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\tG. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOuellet\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\tCurtis\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\tLebowitz\n\t\t\t\t\t\t\tP. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFalchook\n\t\t\t\t\t\t\tG. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol 28 (15s):8503.\n\t\t\t'},{id:"B55",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\tKim\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\tEton\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\tDavis\n\t\t\t\t\t\t\tD. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrazier\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Conkey\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\tDiwan\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\tPapadopoulos\n\t\t\t\t\t\t\tN. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBedikian\n\t\t\t\t\t\t\tA. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCamacho\n\t\t\t\t\t\t\tL. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoss\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\tCormier\n\t\t\t\t\t\t\tJ. N.\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\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\tMansfield\n\t\t\t\t\t\t\tP. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBillings\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\tNg\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\tCharnsangavej\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\tBar-Eli\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\tJohnson\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\tMurgo\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrieto\n\t\t\t\t\t\t\tV. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer\n\t\t\t\t\t99\n\t\t\t\t\t5\n\t\t\t\t\t734\n\t\t\t\t\t40\n\t\t\t\t\n\t\t\t'},{id:"B56",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\tKoon\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\tAtkins\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Autoimmunity and immunotherapy for cancer. N Engl J Med\n\t\t\t\t\t354\n\t\t\t\t\t7\n\t\t\t\t\t758\n\t\t\t\t\t60\n\t\t\t\t\n\t\t\t'},{id:"B57",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\tLassam\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\tBickford\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992Loss of c-kit expression in cultured melanoma cells. Oncogene\n\t\t\t\t\t7\n\t\t\t\t\t1\n\t\t\t\t\t51\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B58",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\tLevy\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\tKhaled\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\tFisher\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med\n\t\t\t\t\t12\n\t\t\t\t\t9\n\t\t\t\t\t406\n\t\t\t\t\t14\n\t\t\t\t\n\t\t\t'},{id:"B59",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\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYen\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\tLiaw\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\tPodsypanina\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\tBose\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\tWang\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\tPuc\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\tMiliaresis\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\tRodgers\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\tMc Combie\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\tBigner\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGiovanella\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIttmann\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\tTycko\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\tHibshoosh\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\tWigler\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParsons\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science\n\t\t\t\t\t275\n\t\t\t\t\t5308\n\t\t\t\t\t1943\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B60",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\tMaehama\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\tDixon\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem\n\t\t\t\t\t273\n\t\t\t\t\t22\n\t\t\t\t\t13375\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B61",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\tMirmohammadsadegh\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\tMarini\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\tNambiar\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\tHassan\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\tTannapfel\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\tRuzicka\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\tHengge\n\t\t\t\t\t\t\tU. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Epigenetic silencing of the PTEN gene in melanoma. Cancer Res\n\t\t\t\t\t66\n\t\t\t\t\t13\n\t\t\t\t\t6546\n\t\t\t\t\t52\n\t\t\t\t\n\t\t\t'},{id:"B62",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\tMyers\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\tPass\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\tBatty\n\t\t\t\t\t\t\tI. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVan der Kaay\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\tStolarov\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\tHemmings\n\t\t\t\t\t\t\tB. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWigler\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDownes\n\t\t\t\t\t\t\tC. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTonks\n\t\t\t\t\t\t\tN. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A\n\t\t\t\t\t95\n\t\t\t\t\t23\n\t\t\t\t\t13513\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B63",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\tNazarian\n\t\t\t\t\t\t\tRamin.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHubing\n\t\t\t\t\t\t\tShi.\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\tWang.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiangju\n\t\t\t\t\t\t\tKong.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRichard\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\tKoya\n\t\t\t\t\t\t\tHane.\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\tZugen.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen-Kyung\n\t\t\t\t\t\t\tMi.\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\tNarsis.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAttar\n\t\t\t\t\t\t\tHooman.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSazegar\n\t\t\t\t\t\t\tThinle.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChodon\n\t\t\t\t\t\t\tStanley. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNelson\n\t\t\t\t\t\t\tGrant.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Arthur\n\t\t\t\t\t\t\tJeffrey. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSosman\n\t\t\t\t\t\t\tAntoni.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRibas\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\tRoger\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\tLo\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\t2010Melanomas acquire resistance to B-RAF(600Einhibition by RTK or N-RAS upregulation. Nature 468 (7326):973-977.\n\t\t\t'},{id:"B64",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\tOmholt\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\tKrockel\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\tRingborg\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\tHansson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Mutations of PIK3CA are rare in cutaneous melanoma. Melanoma Res\n\t\t\t\t\t16\n\t\t\t\t\t2\n\t\t\t\t\t197\n\t\t\t\t\t200\n\t\t\t\t\n\t\t\t'},{id:"B65",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\tOnken\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWorley\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\tLong\n\t\t\t\t\t\t\tM. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDuan\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\tCouncil\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBowcock\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\tHarbour\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci\n\t\t\t\t\t49\n\t\t\t\t\t12\n\t\t\t\t\t5230\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B66",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\tPadua\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\tBarrass\n\t\t\t\t\t\t\tN. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCurrie\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985Activation of N-ras in a human melanoma cell line. Mol Cell Biol\n\t\t\t\t\t5\n\t\t\t\t\t3\n\t\t\t\t\t582\n\t\t\t\t\t5\n\t\t\t\t\n\t\t\t'},{id:"B67",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\tParaiso\n\t\t\t\t\t\t\tK. H.\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.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRebecca\n\t\t\t\t\t\t\tV. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbel\n\t\t\t\t\t\t\tE. V.\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\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMunko\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\tWood\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\tFedorenko\n\t\t\t\t\t\t\tI. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSondak\n\t\t\t\t\t\t\tV. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAnderson\n\t\t\t\t\t\t\tA. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRibas\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\tDalla\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\tPalma\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\tNathanson\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoomen\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\tMessina\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\tSmalley\n\t\t\t\t\t\t\tK. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res:In press.\n\t\t\t'},{id:"B68",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\tPatton\n\t\t\t\t\t\t\tE. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWidlund\n\t\t\t\t\t\t\tH. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKutok\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\tKopani\n\t\t\t\t\t\t\tK. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmatruda\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\tMurphey\n\t\t\t\t\t\t\tR. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerghmans\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\tMayhall\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\tTraver\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\tFletcher\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\tAster\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\tGranter\n\t\t\t\t\t\t\tS. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLook\n\t\t\t\t\t\t\tA. T.\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\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFisher\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZon\n\t\t\t\t\t\t\tL. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005BRAF mutations are sufficient to promote nevi formation and cooperate with 53in the genesis of melanoma. Curr Biol 15 (3):249-54.\n\t\t\t'},{id:"B69",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\tPleasance\n\t\t\t\t\t\t\tErin. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKeira\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\tCheetham\n\t\t\t\t\t\t\tPhilip. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStephens\n\t\t\t\t\t\t\tDavid. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Bride\n\t\t\t\t\t\t\tSean. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHumphray\n\t\t\t\t\t\t\tChris. D.\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\tIgnacio.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVarela-Lay\n\t\t\t\t\t\t\tMeng.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tGonzalo. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOrdonez\n\t\t\t\t\t\t\tGraham. R.\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\tKai.\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\tJulie.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlipaz\n\t\t\t\t\t\t\tMarkus. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBauer\n\t\t\t\t\t\t\tDavid.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeare\n\t\t\t\t\t\t\tAdam.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tButler\n\t\t\t\t\t\t\tRichard. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarter\n\t\t\t\t\t\t\tLina.\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\tAnthony. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCox\n\t\t\t\t\t\t\tSarah.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdkins\n\t\t\t\t\t\t\tPaula. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKokko-Gonzales\n\t\t\t\t\t\t\tNiall. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGormley\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\t2010A comprehensive catalogue of somatic mutations from a human cancer genome. Nature\n\t\t\t\t\t463\n\t\t\t\t\t7278\n\t\t\t\t\t191\n\t\t\t\t\t196\n\t\t\t\t\n\t\t\t'},{id:"B70",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\tPomerantz\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\tSchreiber-Agus\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\tLiegeois\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\tSilverman\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\tAlland\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\tChin\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\tPotes\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\tChen\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\tOrlow\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\tLee\n\t\t\t\t\t\t\tH. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCordon-Cardo\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\tDe Pinho\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998The Ink4a tumor suppressor gene product, 19Arfinteracts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 92 (6):713-23.\n\t\t\t'},{id:"B71",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\tPoulikakos\n\t\t\t\t\t\t\tPoulikos. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChao\n\t\t\t\t\t\t\tZhang.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGideon\n\t\t\t\t\t\t\tBollag.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKevan\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\tShokat\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\tNeal\n\t\t\t\t\t\t\tRosen.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature\n\t\t\t\t\t464\n\t\t\t\t\t7287\n\t\t\t\t\t427\n\t\t\t\t\t430\n\t\t\t\t\n\t\t\t'},{id:"B72",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\tPrickett\n\t\t\t\t\t\t\tT. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAgrawal\n\t\t\t\t\t\t\tN. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWei\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\tYates\n\t\t\t\t\t\t\tK. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\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\tWunderlich\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCronin\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\tCruz\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\tRosenberg\n\t\t\t\t\t\t\tS. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSamuels\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\t2009Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet\n\t\t\t\t\t41\n\t\t\t\t\t10\n\t\t\t\t\t1127\n\t\t\t\t\t32\n\t\t\t\t\n\t\t\t'},{id:"B73",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\tRakosy\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\tVizkeleti\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\tEcsedi\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\tBegany\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\tEmri\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\tAdany\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\tBalazs\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Characterization of 921copy number alterations in human melanoma by fluorescence in situ hybridization. Cancer Genet Cytogenet 182 (2):116-21.\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\tRimoldi\n\t\t\t\t\t\t\tDonata.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuzanne\n\t\t\t\t\t\t\tSalvi.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDanielle\n\t\t\t\t\t\t\tLienard.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerdy\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\tLejeune\n\t\t\t\t\t\t\tDaniel.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpeiser\n\t\t\t\t\t\t\tLeonidas.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZografos\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\tJean-Charles\n\t\t\t\t\t\t\tCerottini.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003Lack of BRAF Mutations in Uveal Melanoma. Cancer Res\n\t\t\t\t\t63\n\t\t\t\t\t18\n\t\t\t\t\t5712\n\t\t\t\t\t5715\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\tSmalley\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\tContractor\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\tNguyen\n\t\t\t\t\t\t\tT. K.\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\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdwards\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\tMuthusamy\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\tKing\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFlaherty\n\t\t\t\t\t\t\tK. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBosenberg\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\tHerlyn\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\tNathanson\n\t\t\t\t\t\t\tK. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. Cancer Res\n\t\t\t\t\t68\n\t\t\t\t\t14\n\t\t\t\t\t5743\n\t\t\t\t\t52\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\tSoung\n\t\t\t\t\t\t\tY. H.\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. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tS. Y.\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. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJo\n\t\t\t\t\t\t\tK. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoon\n\t\t\t\t\t\t\tS. W.\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\tW. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNam\n\t\t\t\t\t\t\tS. W.\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. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoo\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\tLee\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Somatic mutations of the ERBB4 kinase domain in human cancers. Int J Cancer\n\t\t\t\t\t118\n\t\t\t\t\t6\n\t\t\t\t\t1426\n\t\t\t\t\t9\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\tStahl\n\t\t\t\t\t\t\tJ. M.\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\t\n\t\t\t\t\t\t\tCheung\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\tZimmerman\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\tCheng\n\t\t\t\t\t\t\tJ. Q.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBosenberg\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\tKester\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\tSandirasegarane\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\tRobertson\n\t\t\t\t\t\t\tG. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res\n\t\t\t\t\t64\n\t\t\t\t\t19\n\t\t\t\t\t7002\n\t\t\t\t\t10\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\tStott\n\t\t\t\t\t\t\tF. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBates\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\tJames\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\tMc Connell\n\t\t\t\t\t\t\tB. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStarborg\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\tBrookes\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\tPalmero\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\tRyan\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\tHara\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\tVousden\n\t\t\t\t\t\t\tK. H.\n\t\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\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998The alternative product from the human CDKN2A locus, 14ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17 (17):5001-14.\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\tStrumberg\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc)\n\t\t\t\t\t41\n\t\t\t\t\t12\n\t\t\t\t\t773\n\t\t\t\t\t84\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\tTsai\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\tLee\n\t\t\t\t\t\t\tJ. T.\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\tW.\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\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCho\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\tMamo\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\tBremer\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\tGillette\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\tKong\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\tHaass\n\t\t\t\t\t\t\tN. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSproesser\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\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\tSmalley\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\tFong\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\tZhu\n\t\t\t\t\t\t\tY. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarimuthu\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\tNguyen\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\tLam\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\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\tCheung\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\tRice\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\tSuzuki\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\tLuu\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\tSettachatgul\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\tShellooe\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\tCantwell\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\tKim\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchlessinger\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\tZhang\n\t\t\t\t\t\t\tK. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWest\n\t\t\t\t\t\t\tB. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPowell\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\tHabets\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\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\tIbrahim\n\t\t\t\t\t\t\tP. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHirth\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\tArtis\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHerlyn\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\tBollag\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\t2008Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A\n\t\t\t\t\t105\n\t\t\t\t\t8\n\t\t\t\t\t3041\n\t\t\t\t\t6\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\tTsao\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\tGoel\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\tWu\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\tYang\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\tHaluska\n\t\t\t\t\t\t\tF. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol\n\t\t\t\t\t122\n\t\t\t\t\t2\n\t\t\t\t\t337\n\t\t\t\t\t41\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\tTsao\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\tMihm\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\tJr \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\tSheehan\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. J Am Acad Dermatol\n\t\t\t\t\t49\n\t\t\t\t\t5\n\t\t\t\t\t865\n\t\t\t\t\t72\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\tTsao\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\tZhang\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\tBenoit\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\tHaluska\n\t\t\t\t\t\t\tF. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene\n\t\t\t\t\t16\n\t\t\t\t\t26\n\t\t\t\t\t3397\n\t\t\t\t\t402\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\tTsao\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\tZhang\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\tFowlkes\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\tHaluska\n\t\t\t\t\t\t\tF. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res\n\t\t\t\t\t60\n\t\t\t\t\t7\n\t\t\t\t\t1800\n\t\t\t\t\t4\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\tTsao\n\t\t\t\t\t\t\tHensin.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVikas\n\t\t\t\t\t\t\tGoel.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeng\n\t\t\t\t\t\t\tWu.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuang\n\t\t\t\t\t\t\tYang.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrank\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\tHaluska\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\t2004Genetic Interaction Between NRAS and BRAF Mutations and PTEN//MMAC1 Inactivation in Melanoma. J Investig Dermatol\n\t\t\t\t\t122\n\t\t\t\t\t2\n\t\t\t\t\t337\n\t\t\t\t\t341\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\tUgurel\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\tHildenbrand\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\tZimpfer\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\tLa Rosee\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\tPaschka\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\tSucker\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\tKeikavoussi\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\tBecker\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\tRittgen\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\tHochhaus\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\tSchadendorf\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer\n\t\t\t\t\t92\n\t\t\t\t\t8\n\t\t\t\t\t1398\n\t\t\t\t\t405\n\t\t\t\t\n\t\t\t'},{id:"B87",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 Raamsdonk\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\tBezrookove\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\tGreen\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\tBauer\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\tGaugler\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\tO’Brien\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSimpson\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\tBarsh\n\t\t\t\t\t\t\tG. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBastian\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature\n\t\t\t\t\t457\n\t\t\t\t\t7229\n\t\t\t\t\t599\n\t\t\t\t\t602\n\t\t\t\t\n\t\t\t'},{id:"B88",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 Raamsdonk\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\tFitch\n\t\t\t\t\t\t\tK. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFuchs\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\tde Angelis\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarsh\n\t\t\t\t\t\t\tG. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004Effects of G-protein mutations on skin color. Nat Genet\n\t\t\t\t\t36\n\t\t\t\t\t9\n\t\t\t\t\t961\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B89",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 Raamsdonk\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\tGriewank\n\t\t\t\t\t\t\tK. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCrosby\n\t\t\t\t\t\t\tM. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarrido\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\tVemula\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\tWiesner\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\tObenauf\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\tWackernagel\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\tGreen\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\tBouvier\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\tSozen\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\tBaimukanova\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\tRoy\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\tHeguy\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\tDolgalev\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\tKhanin\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\tBusam\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\tSpeicher\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\tO’Brien\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\tBastian\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Mutations in GNA11 in uveal melanoma. N Engl J Med\n\t\t\t\t\t363\n\t\t\t\t\t23\n\t\t\t\t\t2191\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B90",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 Raamsdonk\n\t\t\t\t\t\t\tCatherine. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVladimir\n\t\t\t\t\t\t\tBezrookove.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGary\n\t\t\t\t\t\t\tGreen.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJurgen\n\t\t\t\t\t\t\tBauer.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLona\n\t\t\t\t\t\t\tGaugler.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJoan\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\tO/’Brien\n\t\t\t\t\t\t\tElizabeth. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSimpson\n\t\t\t\t\t\t\tGregory. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarsh\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\tBoris\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\tBastian\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\t2009Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature\n\t\t\t\t\t457\n\t\t\t\t\t7229\n\t\t\t\t\t599\n\t\t\t\t\t602\n\t\t\t\t\n\t\t\t'},{id:"B91",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\tVillanueva\n\t\t\t\t\t\t\tJessie.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdina\n\t\t\t\t\t\t\tVultur.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohn\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\tLee\n\t\t\t\t\t\t\tRajasekharan.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSomasundaram\n\t\t\t\t\t\t\tMizuho.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukunaga-Kalabis\n\t\t\t\t\t\t\tAngela. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCipolla\n\t\t\t\t\t\t\tBradley.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWubbenhorst\n\t\t\t\t\t\t\tXiaowei.\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\tPhyllis. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGimotty\n\t\t\t\t\t\t\tDamien.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKee\n\t\t\t\t\t\t\tAdemi. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSantiago-Walker\n\t\t\t\t\t\t\tRichard.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLetrero\n\t\t\t\t\t\t\tKurt.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tD’Andrea\n\t\t\t\t\t\t\tAnitha.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPushparajan\n\t\t\t\t\t\t\tJames. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHayden\n\t\t\t\t\t\t\tKimberly.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDahlman\n\t\t\t\t\t\t\tBrown.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSylvie\n\t\t\t\t\t\t\tLaquerre.\n\t\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\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Arthur\n\t\t\t\t\t\t\tJeffrey. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSosman\n\t\t\t\t\t\t\tKatherine. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNathanson\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\tMeenhard\n\t\t\t\t\t\t\tHerlyn.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K. Cancer Cell\n\t\t\t\t\t18\n\t\t\t\t\t6\n\t\t\t\t\t683\n\t\t\t\t\t695\n\t\t\t\t\n\t\t\t'},{id:"B92",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\tWagle\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\tEmery\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\tBerger\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavis\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\tSawyer\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\tPochanard\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\tKehoe\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\tJohannessen\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\tMacconaill\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\tHahn\n\t\t\t\t\t\t\tW. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeyerson\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\tGarraway\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\tDissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling. J Clin Oncol.\n\t\t\t'},{id:"B93",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\tWan\n\t\t\t\t\t\t\tP. T.\n\t\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\tM. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoe\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\tLee\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\tNiculescu-Duvaz\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\tGood\n\t\t\t\t\t\t\tV. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJones\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\tMarshall\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\tSpringer\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\tBarford\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\tMarais\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell\n\t\t\t\t\t116\n\t\t\t\t\t6\n\t\t\t\t\t855\n\t\t\t\t\t67\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\tWoodman\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrent\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\tStemke-Hale\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\tLazar\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPricl\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\tPavan\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFermeglia\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\tGopal\n\t\t\t\t\t\t\tY. N.\n\t\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\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPodoloff\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvan\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\tKim\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\tPapadopoulos\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\tHwu\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\tMills\n\t\t\t\t\t\t\tG. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavies\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther\n\t\t\t\t\t8\n\t\t\t\t\t8\n\t\t\t\t\t2079\n\t\t\t\t\t85\n\t\t\t\t\n\t\t\t'},{id:"B95",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\tWyman\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\tAtkins\n\t\t\t\t\t\t\tM. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPrieto\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\tEton\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\tMc Dermott\n\t\t\t\t\t\t\tD. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHubbard\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\tByrnes\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\tSanders\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\tSosman\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer\n\t\t\t\t\t106\n\t\t\t\t\t9\n\t\t\t\t\t2005\n\t\t\t\t\t11\n\t\t\t\t\n\t\t\t'},{id:"B96",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\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRajadurai\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\tTsao\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005Recurrent patterns of dual RB and 53pathway inactivation in melanoma. J Invest Dermatol 125 (6):1242-51.\n\t\t\t'},{id:"B97",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\tHong.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrian\n\t\t\t\t\t\t\tHiggins.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKenneth\n\t\t\t\t\t\t\tKolinsky.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKathryn\n\t\t\t\t\t\t\tPackman.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZenaida\n\t\t\t\t\t\t\tGo.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRaman\n\t\t\t\t\t\t\tIyer.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStanley\n\t\t\t\t\t\t\tKolis.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSylvia\n\t\t\t\t\t\t\tZhao.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRichard\n\t\t\t\t\t\t\tLee.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJoseph\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\tGrippo\n\t\t\t\t\t\t\tKathleen.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchostack\n\t\t\t\t\t\t\tMary.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEllen\n\t\t\t\t\t\t\tSimcox.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavid\n\t\t\t\t\t\t\tHeimbrook.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGideon\n\t\t\t\t\t\t\tBollag.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFei\n\t\t\t\t\t\t\tSu.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010RG7204 (PLX4032), a Selective BRAFV600E Inhibitor, Displays Potent Antitumor Activity in Preclinical Melanoma Models. Cancer Research\n\t\t\t\t\t70\n\t\t\t\t\t13\n\t\t\t\t\t5518\n\t\t\t\t\t5527\n\t\t\t\t\n\t\t\t'},{id:"B98",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\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiong\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\tYarbrough\n\t\t\t\t\t\t\tW. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998ARF promotes MDM2 degradation and stabilizes 53ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92 (6):725-34.\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ahmed Kausar Begam Riaz",address:"",affiliation:'
The University of Texas MD Anderson Cancer Center, USA
'},{corresp:null,contributorFullName:"Michael A. Davies",address:null,affiliation:'
The University of Texas MD Anderson Cancer Center, USA
'}],corrections:null},book:{id:"273",title:"Research on Melanoma",subtitle:"A Glimpse into Current Directions and Future Trends",fullTitle:"Research on Melanoma - A Glimpse into Current Directions and Future Trends",slug:"research-on-melanoma-a-glimpse-into-current-directions-and-future-trends",publishedDate:"September 12th 2011",bookSignature:"Mandi Murph",coverURL:"https://cdn.intechopen.com/books/images_new/273.jpg",licenceType:"CC BY-NC-SA 3.0",editedByType:"Edited by",editors:[{id:"32293",title:"Prof.",name:"Mandi",middleName:null,surname:"Murph",slug:"mandi-murph",fullName:"Mandi Murph"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"19089",title:"Predictive Capacity and Functional Significance of MicroRNA in Human Melanoma",slug:"predictive-capacity-and-functional-significance-of-microrna-in-human-melanoma",totalDownloads:1401,totalCrossrefCites:1,signatures:"Xiaobo Li and Yaguang Xi",authors:[{id:"32242",title:"Dr.",name:"Yaguang",middleName:null,surname:"Xi",fullName:"Yaguang Xi",slug:"yaguang-xi"},{id:"51393",title:"Dr.",name:"Xiaobo",middleName:null,surname:"Li",fullName:"Xiaobo Li",slug:"xiaobo-li"}]},{id:"19090",title:"Epigenetic Changes in Melanoma and the Development of Epigenetic Therapy for Melanoma",slug:"epigenetic-changes-in-melanoma-and-the-development-of-epigenetic-therapy-for-melanoma",totalDownloads:1139,totalCrossrefCites:0,signatures:"Duc P. Do and Syed A.A. Rizvi",authors:[{id:"33548",title:"Dr.",name:"Duc",middleName:"P.",surname:"Do",fullName:"Duc Do",slug:"duc-do"},{id:"60880",title:"Dr.",name:"Syed",middleName:"A",surname:"Rizvi",fullName:"Syed Rizvi",slug:"syed-rizvi"}]},{id:"19091",title:"Genetic, Epigenetic and Molecular Changes in Melanoma: A New Paradigm for Biological Classification",slug:"genetic-epigenetic-and-molecular-changes-in-melanoma-a-new-paradigm-for-biological-classification",totalDownloads:1910,totalCrossrefCites:0,signatures:"Stefania Staibano, Massimo Mascolo, Maria Siano, Gennaro Ilardi and Gaetano De Rosa",authors:[{id:"36959",title:"Prof.",name:"Stefania",middleName:null,surname:"Staibano",fullName:"Stefania Staibano",slug:"stefania-staibano"},{id:"36990",title:"Prof.",name:"Gaetano",middleName:null,surname:"De Rosa",fullName:"Gaetano De Rosa",slug:"gaetano-de-rosa"},{id:"48394",title:"Dr.",name:"Massimo",middleName:null,surname:"Mascolo",fullName:"Massimo Mascolo",slug:"massimo-mascolo"},{id:"48395",title:"Dr.",name:"Maria",middleName:null,surname:"Siano",fullName:"Maria Siano",slug:"maria-siano"},{id:"93383",title:"Dr.",name:"Gennaro",middleName:null,surname:"Ilardi",fullName:"Gennaro Ilardi",slug:"gennaro-ilardi"}]},{id:"19958",title:"A Bromophosphonate Analogue of Lysophosphatidic Acid Surpasses Dacarbazine in Reducing Cell Proliferation and Viability of MeWo Melanoma Cells",slug:"a-bromophosphonate-analogue-of-lysophosphatidic-acid-surpasses-dacarbazine-in-reducing-cell-prolifer",totalDownloads:1198,totalCrossrefCites:0,signatures:"Duy Nguyen, Oanh Nguyen, Honglu Zhang, Glenn D. 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Viguier",authors:[{id:"39832",title:"Dr.",name:"Manuelle",middleName:null,surname:"Viguier",fullName:"Manuelle Viguier",slug:"manuelle-viguier"},{id:"49842",title:"Dr.",name:"Cécile",middleName:null,surname:"Pagès",fullName:"Cécile Pagès",slug:"cecile-pages"}]},{id:"17910",title:"Malignant Melanoma in Genito-Urinary Tract",slug:"malignant-melanoma-in-genito-urinary-tract",signatures:"Abdulkadir Tepeler, Mehmet Remzi Erdem, Sinasi Yavuz Onol, Abdullah Armagan and Alpaslan Akbas",authors:[{id:"37474",title:"Dr.",name:"Alpaslan",middleName:null,surname:"Akbas",fullName:"Alpaslan Akbas",slug:"alpaslan-akbas"},{id:"51219",title:"Mr.",name:"Sinasi Yavuz",middleName:null,surname:"Onol",fullName:"Sinasi Yavuz Onol",slug:"sinasi-yavuz-onol"},{id:"51220",title:"Mr.",name:"Abdulkadir",middleName:null,surname:"Tepeler",fullName:"Abdulkadir Tepeler",slug:"abdulkadir-tepeler"},{id:"51221",title:"Dr",name:"Mehmet Remzi",middleName:null,surname:"Erdem",fullName:"Mehmet Remzi Erdem",slug:"mehmet-remzi-erdem"},{id:"52275",title:"Mr",name:"Abdullah",middleName:null,surname:"Armagan",fullName:"Abdullah Armagan",slug:"abdullah-armagan"}]},{id:"17911",title:"The Stage of Melanogenesis in Amelanotic Melanoma",slug:"the-stage-of-melanogenesis-in-amelanotic-melanoma",signatures:"Naoki Oiso and Akira Kawada",authors:[{id:"32053",title:"Dr.",name:"Naoki",middleName:null,surname:"Oiso",fullName:"Naoki Oiso",slug:"naoki-oiso"},{id:"94422",title:"Prof.",name:"Akira",middleName:null,surname:"Kawada",fullName:"Akira Kawada",slug:"akira-kawada"}]},{id:"17912",title:"The Interaction Between Melanoma and Psychiatric Disorder",slug:"the-interaction-between-melanoma-and-psychiatric-disorder",signatures:"Steve Kisely, David Lawrence, Gill Kelly, Joanne Pais and Elizabeth Crowe",authors:[{id:"33322",title:"Prof.",name:"Steve",middleName:null,surname:"Kisely",fullName:"Steve Kisely",slug:"steve-kisely"},{id:"46901",title:"Dr.",name:"David",middleName:null,surname:"Lawrence",fullName:"David Lawrence",slug:"david-lawrence"},{id:"46902",title:"Ms.",name:"Gill",middleName:null,surname:"Kelly",fullName:"Gill Kelly",slug:"gill-kelly"},{id:"46903",title:"Ms",name:"Joanne",middleName:null,surname:"Pais",fullName:"Joanne Pais",slug:"joanne-pais"},{id:"46904",title:"Dr.",name:"Elizabeth",middleName:null,surname:"Crowe",fullName:"Elizabeth Crowe",slug:"elizabeth-crowe"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"65533",title:"Green Synthesis of Zinc Oxide Nanostructures",doi:"10.5772/intechopen.83338",slug:"green-synthesis-of-zinc-oxide-nanostructures",body:'\n
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1. Introduction
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There are many conventional zinc oxide (ZnO) nanostructure synthesis routes employing the chemical and physical methods, which require particular set-up, high cost, high temperature-pressure conditions, and nonecological chemicals [1]. However, high-energy consumption of these routes and released toxic chemicals after the process can be hazardous to the environment and human health. In recent years, the green synthesis approach has been gaining attention, which eliminates the use of toxic chemicals and applies environmentally friendly routes. These strategies handle the use of plant-extracts, microorganisms, biomolecules, and ionic liquids by applying hydrothermal, microwave-assisted, sonochemical, and low-temperature processes (Figure 1).
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Figure 1.
Green synthesis strategies of ZnO nanostructures with various morphologies.
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The aim of these developments is to allow the use of toxic chemicals and reduce energy consumption by using simple, rapid, and safe routes. Green synthesis strategies for the ZnO nanostructures could be summarized as biosynthesis (natural extract-based, microorganism-based, and biomolecule-based) and nontoxic chemical synthesis (water-based, calcination, solvent-free, and ionic liquid).
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2. Biosynthesis of ZnO nanostructures
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2.1 Natural extract-based ZnO nanostructures
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Natural extracts (mainly phytochemicals) obtained from plants, leaves, fruit peels, flowers, and seeds have been utilized for the green synthesis of metal oxide nanoparticles for years. After the plants are collected from different sources, they are washed with water and basic extraction procedures are applied to obtain plant extracts in which leaves are ground and immersed in water by stirring at room temperature for a while. Then, the solutions are filtered and the eluted extract solution is separated for further use in ZnO synthesis (Figure 2). The eluent solution could be used directly for ZnO synthesis or could be dried for the concentration of solid extracts. Afterward, zinc precursors and plant extracts are reacted under various pH and temperature conditions [2]. If the extract is used as an aqueous solution, the zinc precursors are added into the solution. Otherwise, the zinc precursor and powder form of leaf extract are mixed in distilled water. The key mechanism is the oxidation and reduction of metal ion ‘zinc’ by phytochemicals, which are found in natural extracts. The leaf extracts behave as reducing and capping agents. Under favor of plant extracts, the synthesis procedure can be accomplished without using any chemical stabilizers. Finally, the obtained powders are washed with methanol or ethanol and annealed at high temperatures to attain purity [3].
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Figure 2.
Synthesis route of ZnO nanostructures from leaf extracts.
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The green synthesized ZnO nanoparticles have been used in various fields such as biomedical application due to their significant antibacterial activities, photocatalysis, and metal ion adsorption purposes [4]. Moreover, nanoparticles synthesized by the green route exhibit better antibacterial performances due to the functional groups on their surfaces that come from phytochemicals. Here, we will describe the main applications of natural extract-based green synthesized ZnO nanoparticles.
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2.2 Biomedical applications
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The advantage of using natural extracts for the synthesis of ZnO nanoparticles is that coating of nanoparticles with various pharmacologically active biomolecules on the metal oxide surface allows the conjugation of nanoparticles with receptors of the bacterial membrane. These molecules might be flavones, aldehydes, amides, polysaccharides, etc. and the green synthesized nanoparticles exhibit better biomedical activity than the chemically synthesized ones [1]. Inorganic metal oxides have widely emerged as antibacterial, antioxidant, antifungal, and anticancer agents in the last decades. Moreover, because of their specific targeting and nominal toxicity, the metal oxide nanoparticles could be used in personalized medicine applications. In the area of nanoscaled metal oxides, ZnO has shown promising activity in the biomedical field due to its unique electronic, optical, and medicinal properties. The ZnO nanoparticles show antibacterial activity against a broad spectrum of pathogenic bacteria, and these nanoparticles adopt various mechanisms such as reactive oxygen species (ROS) generation, cell membrane integrity disruption, biofilm formation, or enzyme inhibition [5]. Under UV irradiation, ROS such as superoxide ions, hydroxyl ions, singlet oxygen species, and peroxide molecules are formed. The formed peroxide ions could easily penetrate through the cell membrane and result in cell death. Figure 3 shows the possible ROS generation mechanism and its effect on the bacterial cell wall.
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Figure 3.
ROS mechanism of ZnO nanoparticles [6].
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Cell membrane integrity disruption is another significant mechanism for the antibacterial effect of ZnO nanoparticles. Penetration of ZnO nanoparticles results in cell death by the loss of phospholipid bilayer integrity and leakage of intracellular components of the cell. While the Gram-positive bacteria have a thick layer of peptidoglycan, teichoic acid, and lipoteichoic acid in their cell membrane, Gram-negative bacteria have a triple layer of peptidoglycan. The different structure of cell membranes of these two types of bacteria results in a different mechanism of nanoparticle penetration through the cell membranes. In this part, we focused on the biomedical activity of ZnO nanoparticles, and in Table 1, the used plant extracts, zinc precursors, biomedical applications and related biomolecules are summarized.
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Plant type
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Zinc precursor type
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Size of ZnO (nm)
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Treated biomolecule
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Biomedical field
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Ref.
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Momordica charantia
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Nitrate
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21
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R. microplus, P. humanus capitis, An. stephensi, and Cx. Quinquefasciatus
Biomedical activities of plant extract-based synthesized ZnO nanoparticles.
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Sathishkumar et al. synthesized ZnO nanoflakes using Couroupita guianensis Aubl leaf extract and demonstrated the bactericidal activity against various types of bacteria. They reported that the main constituent of the extract, phenol, reduced the zinc acetate precursor into ZnO nanostructures. In history, Aloe (Aloe barbadensis Miller) extract has been used in therapeutic applications due to its antifungal, antidiabetic, anticancer, and antibacterial properties. Ali et al. also synthesized small-sized ZnO nanoparticles using Aloe vera extract and showed their antibacterial activity and cell damage of Escherichia coli and MRSA cells before and after ZnO nanoparticle treatment [7]. On the other hand, Gunalan et al. synthesized ZnO nanoparticles with Aloe vera extract and compared their results with the chemically synthesized ZnO nanoparticles. The results proved the enhanced antibacterial activity against various pathogens, and variation in the particle size is responsible for the significant bactericidal activity [8]. The effect of Aloe vera extract on the synthesis of ZnO nanoparticles and their antibacterial activity was investigated. Moreover, the antioxidant activity of the particles was evaluated by using five different free radical scavenging assays and the anticancer activity was tested against three cancerous cell lines [9].
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In a very recent work, Zare et al. presented the effect of Cuminum cyminum leaf extract on the synthesis of ZnO nanoparticles by using zinc nitrate precursors. The resulting nanoparticle diameter is around 7 nm, and the nanoparticles show high sensitivity to Gram-negative bacteria [10]. The nanoparticle formation of zinc nitrate precursors has been investigated by using several types of plant extracts such as Limonia acidissima [11, 12], Cochlospermum religiosum [13], Tabernaemontana divaricata [14], Conyza Canadensis, Citrus maxima [15], Aristolochia indica [16], Echinacea [17], Mentha [18, 19], Salvadora oleoides [20], Boswellia ovalifoliolata [21], and Costus pictus [22]. The synthesized ZnO nanostructures have shown an enhanced antibacterial effect for a broad spectrum of bacterial cultures (see Table 1). Zinc acetate precursor is another choice for the plant-based ZnO nanoparticle synthesis, and Santoshkumar et al. synthesized ZnO nanoparticles using Passiflora caerulea extract against urinary tract infection pathogens. The ZnO nanostructures have a particle size of around 37 nm and show good zone of inhibition to various pathogens [23]. Hibiscus sabdariffa [24] and Acalypha indica leaves [25] were used in ZnO nanoparticle synthesis, and the nanoparticles showed an enhanced antibacterial activity against E. coli and S. aureus.
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ZnO nanoparticles are currently under investigation due to their utilization in cancer treatment and diagnostic applications [26]. Since the treatment of cancer by chemotherapy is limited because of the adverse effect of tumor drugs and drug resistance by cancer cells, natural plant-based drug researches have focused on overcoming these limitations. Vijayakumar et al. investigated the anticancer activity of ZnO nanoparticles, which were synthesized by Laurus nobilis extract-mediated synthesis. The nanoparticles showed anti-lung cancer activity against human A549 lung cancer cells [27]. Toxicity is an important parameter for the in-vivo and in-vitro activity of nanoparticles because some nanoparticles can generate free radicals even under dark conditions. Anacardium occidentale extract was used in the synthesis of ZnO nanoparticles, and the resulting nanostructures exhibited concentration-dependent cytotoxicity against pancreatic cancer cells [28]. Yuvakkumar et al. utilized the Rambutan peels (Nephelium lappaceum) for the synthesis of ZnO nanoparticles and explored the effect of these particles on HepG2 liver cancer cells [29].
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On the other hand, zinc acts as an actuator for several enzymes, and blood sugar regulation is significantly affected in the presence of zinc element. Thus, the enzymatic and anti-diabetic activity of ZnO nanoparticles must be mentioned in their biomedical applications. Bayrami et al. synthesized ZnO nanoparticles by using Vaccinium arctostaphylos extract via a microwave-assisted method. The biosynthesized ZnO nanoparticles showed an enhanced efficiency for the treatment of diabetic problems and reduced the fasting blood glucose level effectively [55]. Rehana et al. demonstrated the antidiabetic activity of ZnO nanoparticles by using several types of plant extracts. The results showed that Tamarindus indica extract-based ZnO nanoparticles exhibited enhanced activity for α-amylase and α-glucosidase due to the presence of amino acids in the plant extract [76]. As an environmentally benign material, coffee powder extract was utilized in the biosynthesis of ZnO nanoparticles. Koupaei et al. studied the reduced effect of ZnO nanoparticles on proteinase K activity [56].
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2.3 Photocatalytic application
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Photocatalytic degradation of organic pollutants is a promising approach for the removal of dyes in wastewaters. ZnO nanoparticles have been involved in photocatalytic applications due to their optical and electronic properties (Table 2). When the ZnO nanoparticles are irradiated with UV light, valence band electrons are excited to the conduction band, which leaves holes behind. Then the generated holes create hydroxyl radicals by oxidizing \n\n\nH\n2\n\nO\n\n\n and \n\nO\n\nH\n−\n\n\n and the excited electrons are captured by oxygen in the air. The resulting anionic radicals are highly reactive and degrade the organic dyes in to carbon dioxide and water (Figure 4).
Photocatalytic activities of plant-extract based synthesized ZnO nanoparticles (MB = methylene blue, MO = methyl orange, MR = methyl red, RhB = Rhodamine B, and PR = phenol red).
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Figure 4.
Schematic diagram of dye degradation by ZnO nanostructures.
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Nava et al. addressed the effect of different amounts of Camellia sinensis extract on the synthesis of ZnO nanoparticles. The synthesized nanoparticles were studied in photocatalytic degradation of methylene blue (MB) dye where the nanoparticles presented MB degradation over 84% in 120 min [81]. In another study, Parkia roxburghii extracts have been used for the synthesis of ZnO nanoparticles, and they were found to be efficient in degradation with nearly 98% efficiency in 8 min for both MB and Rhodamine B (RhB) dyes [82]. The degradation of Congo Red dye has also been studied for the ZnO photocatalysis applications. Prasad et al. and Vidya et al. studied the degradation of Congo Red in aqueous solutions by ZnO nanoparticles. The dye was degraded with 90% efficiency in 35 and 60 min by using lemon juice [83] and Artocarpus heterophyllus [84] extracts in the nanoparticle synthesis, respectively. The aqueous leaf extract of Coriandrum sativum was used for the nanoparticle synthesis and the resulting materials have been used for the photocatalytic degradation of anthracene with 96% efficiency in 240 min [85].
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2.4 Adsorption/sensing application
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Heavy metal ion pollutants in wastewaters create a problem worldwide because of their serious effects on both human health and environment. ZnO nanostructures have also been used as an adsorbent material due to their low toxicity and became more effective than the other adsorbent materials [100]. The plant-based synthesis of ZnO nanostructures enhances metal ion adsorption capacity due to the chemical interactions between ions and functional groups of plant extracts. Fazlzadeh et al. synthesized ZnO nanoparticle-loaded activated carbon by using Peganum harmala for the removal of chromium from aqueous systems. Peganum harmala acted as a stabilizing agent and enhanced the chromium uptake up to 68.48 mg g−1 [101]. The lead ion removal was studied by Azizi et al. using Zerumbone extract-mediated ZnO nanoparticles. They reported that the lead ion adsorption capacity reached up to 19.65 mg g−1 [100]. Sensing application of ZnO nanostructures is another field where the glucose sensing mechanism of ZnO nanostructures was studied by Muthuchamy et al. They fabricated a glucose sensor using ZnO nanoparticles and peach juice as a carbon source. The fabricated ZnO sensor showed high sensitivity (231.7 μA mM−1 cm−2) and low detection limit (6.3 μM) [102]. Sharma et al. also studied silymarin detection capability of ZnO nanostructures by using Carica papaya extract. The results showed that ZnO-modified sensors have 2-fold greater electrochemical signals than the neat ones [103].
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2.5 Microorganism-based ZnO nanostructures
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Synthesis of ZnO nanostructures by using microorganisms has gained considerable interest, and numerous microorganisms can be utilized for their synthesis. Bacteria, fungus, and algae are the possible microorganisms in a green synthesis of ZnO nanostructures. Because of their easy genetic manipulation and easy handling, bacteria are preferred microorganisms [104]. Jayaseelan et al. used Aeromonas hydrophila bacteria as green capping agent, and the synthesized ZnO nanoparticles showed antibacterial activity against Pseudomonas aeruginosa and Aspergillus flavus [104]. In another study, Pseudomonas aeruginosa was used as a capping agent in ZnO nanoparticle synthesis, and the resulting particles demonstrated antioxidant activity [105]. Kundu et al. used Rhodococcus pyridinivorans as metabolically versatile Actinobacteria in the fabrication of self-cleaning, UV-blocking, and antibacterial textile fabrics with ZnO nanoparticles. Besides, the ZnO nanoparticles showed photocatalytic activity against malachite green and anticancer activity against HT-29 cancerous cells [106]. Tripathi et al. synthesized ZnO nanoflowers by using Bacillus licheniformis and assessed their photocatalytic activity against methylene blue [107]. However, bacterial utilization in ZnO green synthesis could be somewhat problematic because of the uncontrolled growth of bacteria and unavoidable contaminations [108].
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Fungus-based green synthesis of ZnO nanoparticles is generally preferred over the bacteria based synthesis because of their large-scale production and better tolerance property [109]. Raliya et al. synthesized ZnO nanoparticles via an environmental method by using Aspergillus fumigatus as a stabilizing agent and investigated the effect of ZnO nanoparticles on phosphorus mobilizing enzymes in rhizosphere and gum contents in clusterbean grains [110]. In another study, ureolytic bacterium (Serratia ureilytica)-mediated green synthesis of ZnO nanoparticles was reported. The cotton fabrics were coated with the synthesized nanoparticles and their killing efficiency against S. aureus and E. coli bacteria was revealed [111].
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Algae are the members of a diverse group of aquatic photosynthetic organisms and they have been utilized sometimes in the synthesis of ZnO nanostructures. Sargassum muticum extract, which is a brown marine macroalga, was used in the biosynthesis of ZnO nanoparticles [112]. Nagajaran et al. used the seaweed extracts of green Caulerpa peltata, red Hypnea Valencia and brown Sargassum myriocystum in the synthesis of ZnO nanoparticles. The results revealed that among three seaweeds, only S. myriocystum could stabilize and reduce ZnO nanoparticles of size 36 nm. Also, the nanoparticles showed antimicrobial activity against a wide spectrum of bacterial cultures [109].
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2.6 Biomolecule-based ZnO nanostructures
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Synthesis of ZnO nanoparticles with controlled morphologies and using environmentally friendly chemicals could be possible in biomolecule-based synthesis routes, and utilization of amino acids, polysaccharides, gums, and enzymes is highly preferable. Gharagozlou et al. synthesized ZnO nanoparticles by using alanine amino acid, and a Schiff base complex was obtained at the end of the study [113]. Bovine skin gelatin has also been used in the synthesis of ZnO nanostructures, and Alnarabiji et al. demonstrated the environmentally friendly synthesis route for ZnO nanoparticles [114]. Arabic gum and gum tragacanth-based green synthesis of ZnO nanoparticles have been demonstrated by Fardood et al. [115] and Daraoudi et al. [116], respectively. Thus, they demonstrated an alternative method for the synthesis of ZnO nanoparticles instead of conventional ZnO reduction methods by using hazardous polymers or surfactants [115, 116]. Casein is another biomolecule that can be used as a capping and reducing agent in the ZnO nanoparticle synthesis. Somu et al. synthesized ZnO nanoparticles, which show heavy metal ion adsorption, dye adsorption, and antibacterial activity in wastewater treatment at the same time [117]. The resulting nanoparticles effectively remove Cd(III), Pd(II), and Co(II) ions, methylene blue, and Congo red dye from the wastewaters. Also, they demonstrated high antibacterial activity against E. coli cultures. Subramanian et al. synthesized ZnO nanoflowers, which comprise nanorods and ellipsoids as subunits, by using l-lysine as a capping and precipitating agent [118].
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3. Synthesis of ZnO nanostructures using nontoxic chemicals
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Combating the major drawbacks of common ZnO nanostructure synthesis methods, mainly identified as the generation of pollutants, toxic materials, and side products during reactions, green chemical techniques using only nontoxic and biologically compatible materials were developed. Gharagozlou et al. [113] reported a novel method to synthesize ZnO nanoparticles without any pollutant or combustible side product in the process. Water was used as a solvent with a biologically compatible nitrogen source, amino acid instead of toxic amines, alanine and sodium salicylaldehyde-5-sulfonate, and zinc acetate to prepare the zinc Schiff-base complex and then subsequently heated to obtain ZnO nanoparticles. This work showed that the solid-state decomposition process applied at moderate temperatures has yielded nanoparticles ranging from 5 to 110 nm with fewer defects yet interestingly high crystallinity.
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Biomimetic and bioinspired synthesis has also been regarded among the most attractive strategies in fabricating novel functional materials, and biological materials like eggshell membrane, oyster shells, nacre, diatoms, cuttlefish bone, DNA chains, and sea urchin spines have been actually employed as templates or bioreactive substrates. Silk fibroin fibers (SFFs) extracted from silkworm Bombyx mori cocoons were used for their capping and directing functions to control the morphology of ZnO crystals. Acting at the same time, zinc ions are anchored on the SFF and in-situ react with \n\nO\n\nH\n−\n\n\n generating ZnO nanoparticles. It was observed that several petals composed of ZnO nanoparticles form ZnO flowers and bestrewed the SFF substrates due to the electron-donating groups (amino and carboxyl groups) contained in SFF [119]. Another ZnO nanoparticle synthesis method through biological roots such as the use of natural biopolymers was to be presented as more cost-effective compared to both physical and chemical methods available [120]. A recent work has focused on integrating ZnO nanoparticles with biopolymers that are excellent vehicles for cross-linking molecules. Thereby, collagen was used for zinc acetate in basic solution, to give a precipitate that was processed and thermally heated at 350°C giving birth to ZnO nanoparticles, yielding an interesting antibiofilm, anti-cancer, and ecotoxicity material [121].
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Extrusion dripping is another novel technique using environmentally friendly, cost-effective, degradable, and renewable biomass materials. Generally, the process yields monodispersed spherical particles by controlled dripping of working solution into a biopolymer solution after extruding it through a narrow tube, thanks to the effect of viscous-surface tension forces and impact-drag forces that help to preserve the spherical shape of the drop [122]. Goes et al. have reported that spherical uniform sized ZnO nanoparticles were obtained by dropwise addition of alginate solution to zinc nitrate solution under a long slow magnetic stirring to ensure the ion-exchange to happen and stabilize ZnO nanoparticles; the heated ZnO outcome was used to fabricate a polymeric nanocrystalline microfilm, exhibiting interesting photodegradation results, as ZnO on the surface is likely to accept photons and generate holes promoting the oxidative decomposition of the dye [123].
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Chemical bath deposition and soft-template sol-gel methods are two wet organic solvent-free routes studied by a group led by Leone et al [124]. to obtain a nanostructured ZnO employed as a reservoir of clotrimazole for pharmaceutical purposes. Identifying the synthesis of carriers and active pharmaceutical ingredient loading as the main steps in which the waste of organic solvents occur, ZnO nanostructures have been introduced as green alternative carriers for their intrinsic biological properties, low toxicity, and high biocompatibility [125]. For the chemical bath deposition approach, a nanosheet-like zinc carbonate hydroxide hydrate was transformed into ZnO using solutions containing urea and different zinc salts [126]. As for the sol-gel method, pluronic F127 was used as a soft template forming an opalescent solution with zinc acetate in water, and then dried and calcined at 500°C to sacrifice the template and obtain the ZnO nanostructure [124].
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In our previous work, we successfully enhanced the antibacterial activity of ZnO nanowires by modifying the cooling route. Zinc acetate was calcined in a muffle oven, followed by a rapid cooling; the three resulting samples were compared to a free cooled batch synthesized under the same conditions, revealing noticeable effects on ZnO nanowire morphology in addition to the improvement of surface area due to the limiting time for crystallite growth [127].
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3.1 Ionic liquid as solvents for ZnO nanostructures
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Ionic liquids (ILs) are an area of chemistry, which has received important attention in both academia and industry, because of the cost effectiveness coupled with being environmentally friendly [128]. ILs usually act as solvents and reactants as well as templates for inorganic nanomaterial synthesis and scavenging agents [129]. As a subdivision, room temperature ionic liquids (RTILs) are particularly doted of special considerations as nontoxic solvents with a wide liquid temperature range, remarkable chemical stability, negligible vapor pressures, and high fire resistance [130]. ILs have been great templates for the synthesis of nanomaterials as it was shown that only by modifying the structure of their cations or anions, it is possible to alter their properties in order to control the size, morphology, and thus the properties of nanomaterials [131]. Sabbaghan et al. have synthesized different morphologies of ZnO nanostructures using zinc acetate as the metal source in a basic media to react with different symmetrical imidazolium-based ILs, yielding nanoparticles, nanoparticle-like, spherical-like, nanosheet in different sizes ranging from 16 to 30 nm and different band gaps between 2.98 and 3.17 eV, demonstrating through this work the relation morphology-IL [128].
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ZnO nanostructures with nanosheet morphology have been successfully fabricated in another work by refluxing the mixture of zinc acetate and the ionic liquid in water according to Menshutkin reaction [132]. A comparative study has shown that when zinc is used with ILs as a template, ZnO nanoparticles with smaller crystallite size were formed compared to the yield without ILs. This work revealed as well that the template and the pH control the direction of growth of ZnO crystals and the shape of nanomaterials obtained. The final band gap values of ZnO with different morphology ranged around 2.88–3.16 eV [133]. Alammar et al. have studied the effect of five different ILs on ZnO morphologies, and claimed that the habitus and morphology come as the system naturally tends to reduce the total surface energy during formation; it is to note that the anion of the IL is proposed to be interacting with the ZnO surface during the growth [134]. Yet, the best performance was for ZnO nanoparticles that are obtained by use of IL with a long alkyl chain, reaching 95% in 9 h for methyl orange decomposition, proposing that along with high surface area, oxygen vacancies and polar plans that act like electron traps are the main factors for such interesting photocatalytic activity [135, 136]. It was also reported by Amde et al. [137] that common techniques for the determination of fungicide concentration in water are usually non-environmentally friendly, organic solvent, and time consuming; the group has prepared ZnO nanofluids by a green two-step method, dispersing the as-synthesized sol-gel ZnO nanoparticles in 1-hexyl-3-methylimidazolium hexafluorophosphate, hand shaking it to attain a homogeneous distribution, then sonicating it to break NPs clusters. The as-prepared ZnO nanofluids are applied in a modified, simple, versatile, and inexpensive liquid-liquid microextraction technique; this technique, called single drop microextraction not only reduces the amount of extraction solvent radically but also offers other functionalities such as high enrichment factor, different extraction modes, and full automation of the process [138]. It is proclaimed that the preferences of ZnO-based nanofluids for the investigation were driven from the fact that ZnO dotes on surface charges that enable to form stable suspensions, unlike many metallic nanofluids, and without the need of any additional stabilizer intervention.
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4. Processes of synthesis of ZnO nanostructures
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ZnO nanostructures can be synthesized by following different approaches, and each has its own distinctive advantages and downsides. In this section, we report some interesting methods and findings having the common main aim to avoid drawbacks like the use of toxic reagents, promoter, and stabilizer organic additives, lowering the reaction time, as well as high temperature and pressure. These methods have plenty of scopes to provide both qualitative and quantitative support for nanosized ZnO synthesis along with being simple, fast, efficient, and convenient.
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4.1 Hydrothermal synthesis of ZnO nanostructures
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Hydrothermal method has gained particular interest as an efficient method for high quality and mass production of ZnO nanostructures [139]; it is indeed environmentally friendly as there is no need to control pH and subsequently no release of unwanted by-products. A work led by Guo et al. [140] reported a controllable hydrothermal synthesis of ZnO nanorods reacting with zinc carbonate hydroxide hydrate powder and H2O2 at various temperatures for different periods of time. The group claims that the formation mechanism of ZnO starts by the formation of ZnO2 when subjecting it to hydrothermal treatment at 170°C for more time (3–6 h), and then the thermally unstable ZnO2 would decompose into ZnO and O2. ZnO nanorods exhibited an optical band gap of 3.3 eV [140].
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It has also been reported that flower shaped ZnO nanoparticles were synthesized by hydrothermal method, where zinc nitrate and hexamethylenetetramine solutions were prepared separately in double distilled water, while NaOH solution was added dropwise to adjust the pH to 10. The obtained milky solution was refluxed at 80°C for 7 h, washed, and dried. XRD asserted the formation of hexagonal crystal structure ZnO that had a flower-shape, formed by agglomeration during the hydrothermal process. Dynamic light scattering (DLS) data have affirmed the average diameter of ZnO between 600 and 800 nm. The effect of different pH values from 2 to 10 on the removal performance of ZnO has been studied and the results showed a maximum increase of 80% removal efficiency when pH reached 6; increasing the temperature of the process also improved the removal efficiency from 68 to 97%. The contact time had a sharp rise at the value of 15 min of initiation of the experiment, and higher stirring had an enhancing effect as well. Jamal Al-Sabahi and his group have treated for the first time the degradation of HPAM polymer in oil produced water with supported ZnO nanorods synthesized via a microwave-assisted hydrothermal method in an aqueous solution [141, 142, 143]. Placing a prepared microscope glass substrate (25 mm × 75 mm) on a hotplate (350°C), 10 mM zinc acetate dihydrate solution is sprayed, and then the plate is immersed in an equimolar solution of zinc nitrate hexahydrate and hexamethylenetetramine, then heated in a domestic microwave oven for 45 min, and then cooled down for 15 min; the produced ZnO nanorod-covered substrate was afterward annealed in air at 350°C for 1 h. The morphology was of a typical ZnO array and the average length was about 4 μm while the average diameter reached around 95 nm [144].
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Singh et al. have adopted a cost-effective and environmentally friendly method to fabricate a 3D self-assembled wool ball like spherical ZnO with high porosity by combining a urea-glycerol assisted hydrothermal approach with calcination under air atmosphere [145], where hydrated zinc carbonate was synthesized hydrothermally in a Teflon-lined stainless steel autoclave reacting zinc nitrate with urea in a triplet (glycerol, ethyl alcohol, and water (7:7:10)) solvent system. After drying the outcome, the white powder intermediate product was calcined at 450°C for 3 h to get hierarchical 3D porous ZnO. The group carried out a series of experiments to investigate the effect of synthesis parameters over the morphology, while 7 h and 140°C were about the optimum duration of synthesis and temperature to get the best ZnO with W-ball like spherical morphology. This ZnO photocatalyst has shown 98% of highly toxic Rhodamine B degradation in 60 min of UV photolysis catalysts at a pH of 4.
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A green hydrothermal method was used recently to fabricate ZnO nanorods without any organic solvent or surfactant, by starting with ZnO powder and H2O2 aqueous solution in the sealed autoclave. Then the precipitates were washed and dried. In this work, Lam et al. reported as well that the hydrothermal treatment of ZnO at 100°C promotes the slow conversion of ZnO2 to ZnO and O2 without using any toxic reactant, nor releasing any pollutant by-product. XRD indicated the high purity of the ZnO wurtzite phase [146]. This environmentally friendly method has generated highly performing ZnO nanorods that completely degrade the resorcinol in aqueous solution after 120 min. The same group has used a similar hydrothermal method to fabricate ZnO nanotubes (NTs) with a diameter of around 10 nm, a wall thickness of 3.5 nm, and average lengths of up to 200 nm by scrolling of the ZnO2 layer nanosheet, which transforms to ZnO NTs with a symmetrical layer in both shell-tube structures. XRD asserted the hexagonal phase and then confirmed the purity of ZnO NTs that showed a ferromagnetic behavior because of the grain boundaries and developed free surfaces [147]; the band gap energy was measured to be around 3.21 eV, and the degradation of methylparaben over the surface of ZnO NTs had an efficiency of 87.6% in 105 min [148].
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4.2 Microwave-assisted synthesis of ZnO nanostructures
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Microwave-assisted sol-gel synthesis is based on subjecting samples to frequencies ranging from 300 MHz to 300 GHz [149]; besides its high selectivity of specific morphologies, dramatic reduction of reaction time (minutes), and remarkable increase of product yield, it generates localized superheating at the reaction sites promoting metal ion reduction in the solution [150]. It presents a promising green method for metal oxide nanostructures production. Azizi et al. [151] have worked on a green microwave-assisted combustion approach to synthesize ZnO-nanoparticles, presenting combustion as a fast, low cost, homogenous and highly pure outcome, as well a distinguished surface area at low temperature. Using fruit, seed, and pulp extracts of Citrullus colocynthis (L.) as biofuels with zinc nitrate as the zinc source, an in vitro cytotoxicity study has been made showing that smaller nanoparticles were more efficient penetrating in the cells membranes, while the optical band gap increased with the rear of the particle size from 3.25 to 3.40 eV. An interesting nontoxic and eco-friendly single-step, and green synthesis method of ZnO nanoparticles with excellent reproducibility was reported using coffee powder extract as a reducing material under microwave heating at 540 W for 5 min and the precipitate was dried in a hot air oven. SEM asserted a size of 80–120 nm for the nanoparticles. Afterward, a thin nanocomposite film was prepared using the as-prepared ZnO nanoparticles with natural graphite powder. The nanocomposite film showed a remarkable photovoltaic efficiency of 3.12% [152]. ZnO sub-micrometer particles and nanowires were synthesized by microwave assisted sol-gel reaction. Zinc acetate and N,N-dimethylacetamide were stirred into a beaker, and then, the solution was cooled rapidly to 15°C. After only a couple of minutes of the microwave, a white suspension was obtained. The average diameter of the particles prepared given by DLS analyses was around 275–352 nm [153]. Salari et al. reported a microwave-assisted synthesis of biogenic nanoparticles using Lavandula vera leaf extract as a reducing agent in the presence of zinc sulfate; the method led to simple and fast formation of microstructures that exhibited high antioxidant cytotoxic activity [154]. In a separate work, vertically aligned ZnO nanorods were grown at 90°C on a Si substrate by microwave synthesis and compared with nanorods made by the traditional heated waterbath method changing the pH from 10.07 to 10.9. The microwave synthesis was performed at a power of 100 W [155]. The same group observed that the increase of ammonia led in both methods to sparser and longer nanorods with the larger diameter, as well as an increase of oxygen percentages in the samples. The microwave synthesized samples exhibit a uniform distribution of nanorods as well as a better crystalline structure with fewer defects than the heated water bath-grown samples, which can be beneficial for band-edge transition optoelectronic devices.
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4.3 Sonochemical synthesis of ZnO nanostructures
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Microwave synthesis and ultrasound sonication have proven numerous advantages and actually become amid the most frequently sought nanosized material synthesis methods [156, 157]. Zak et al. have used ultrasonication to synthesize ZnO nanostructures at room temperature without any specific conditions or organic solvents, starting from an as-prepared zinc solution where zinc acetate was dissolved in ammonia solution, and sodium hydroxide was dropped in the solution. Deionized water was wisely added till attaining a concentration of 1 M zinc. The ultrasonication performed at different durations was sufficient to stimulate the formation of nanostructures. XRD asserted the presence of hexagonal pure ZnO and the band gap energies estimated by UV-Vis spectra are 3.3, 3.22, and 3.2 eV for ZnO seeds, nanorods, and nanoflowers, respectively [158]. Ultrasound was conducted as well for the synthesis of different ZnO nanostructures without any organic solvents, surfactants, or templating agents; zinc acetate and sodium hydroxide in ionic liquids (ILs) are reported to be a green, fast, and effective, yet highly selective route to 0D, 1D, and 2D nanostructures of ZnO [134]. A facile calcination-free ultrasound assisted approach has been reported by Bhatte et al. involving zinc acetate as a metal source and 1, 3-propane diol as a solvent, base, stabilizer, and template for the growth of nanocrystalline ZnO [159]. The mixture of both materials has been sonicated under 22 kHz frequency for 2 h with a 5 s interval on-off pulse. After sonication, the formed ZnO was collected, washed and dried. XRD confirmed the successful formation of ZnO without any impurities [159].
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4.4 Low temperature synthesis of ZnO nanostructures
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For the large-scale production of pure ZnO nanocrystallites, low thermal processes are one of the most efficient methods minimizing the generated waste yet implementing sustainable processes: simple, cheap, and nonpolluting, addressing the key issues that draw much consideration in a green solid-state synthetic method, by eliminating the use of nontoxic materials and reducing energy consumption. ZnO2 nanocrystallites were employed as the precursor for ZnO production, because of their facile preparation, the absence of unwanted by-products, and low-temperature decomposition reaction [160]. Zinc acetate and hydrogen peroxide were used first to synthesize ZnO2 nanocrystallites hydrothermally at 100°C for 12 h in an alkaline aqueous solution; the product was subjected to 180°C in air for 12 h yielding pure ZnO phase shaped nanocrystallites of 8–10 nm and blue shift at around 350 nm in the UV-Vis spectra [161].
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ZnO nanosized structures were also synthesized starting from zinc acetate and urea in a 1:1 stoichiometry, where the decomposition of urea helped the formation of ZnO. Then two different heating methods were applied: microwave hydrothermal (MH) method and waterbath heating. XRD proved the purity of the wurtzite phase for both methods, while FE-SEM showed a difference in shape regularity in favor of the MH process; thus, the MH method contributes to the production of spherical and uniform particles after a short processing time by enhancing the interface mobility and the diffusivity in the medium [162].
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Raja et al. have reported a laboratory procedure based on sol-gel for the preparation of nano-ZnO particles. Zinc acetate solution was stirred at room temperature while adding sodium hydroxide until reaching a pH of 14 and the solution went through a microemulsion. The suspension obtained was transferred for thermal treatment at 180°C for 3 h, and then the white precipitate was collected, washed, centrifuged, and dried under vacuum to reveal well-shaped uniform ZnO nanoparticles of 35 nm on average [163].
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Another group has proposed a simple, eco-friendly approach to synthesize ZnO nanoparticles by using carboxylic curdlan (cc) as a reducing and stabilizing agent. A solution of zinc acetate was blended with cc aqueous solution and stirred at 70°C for 6 h, and then the outcome was freeze-dried [164]. The carboxyl group is in charge of chelating and reducing zinc ions for the sake of the formation of ZnO nanoparticles, thanks to the numerous negatively charged carboxyl groups it contains. The average diameter of cc-ZnO nanoparticles is around 58 nm exhibiting a band gap energy of 3.3 eV. Furthermore, the interaction between the as-prepared nanoparticles and bovine serum albumin (BSA) at room temperature was investigated, which suggested the formation of a certain complex revealed by a blue shift of the fluorescence peak by about 8 nm with increasing nanoparticle concentration, due to the binding of cc-ZnO nanoparticles and BSA [164].
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Conflict of interest
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The authors declare no conflict of interest.
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\n',keywords:"biosynthesis, hydrothermal, microwave, nontoxic, sonochemical",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65533.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65533.xml",downloadPdfUrl:"/chapter/pdf-download/65533",previewPdfUrl:"/chapter/pdf-preview/65533",totalDownloads:1654,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 17th 2018",dateReviewed:"December 5th 2018",datePrePublished:"February 7th 2019",datePublished:"October 9th 2019",readingETA:"0",abstract:"ZnO-based nanomaterials have been proven to be of great use for several leading applications since the beginning of nanoscience due to the abundance of zinc element and the relatively easy conversion of its oxide to nanostructures. Nowadays, ZnO as nanoparticles, nanowires, nanofibers as well as plenty of other sophisticated nanostructures takes place among the pioneer nanomaterials employed in the photovoltaic systems, fuel cells, and biomedical fields. Nevertheless, optimizing energy consumption and being eco-friendly are the challenging requirements that are still to be overcome for their synthesis. Green chemistry has been strongly presented recently in the scientific arena as an adequate potential alternative; worldwide investigations have been held on subjects involving bacteria, fungus, or algae-based synthesis as efficient options, and some of the intriguing scientific findings on this subject are reported hereafter.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65533",risUrl:"/chapter/ris/65533",signatures:"Tuğba Isık, Mohamed Elhousseini Hilal and Nesrin Horzum",book:{id:"8446",title:"Zinc Oxide Based Nano Materials and Devices",subtitle:null,fullTitle:"Zinc Oxide Based Nano Materials and Devices",slug:"zinc-oxide-based-nano-materials-and-devices",publishedDate:"October 9th 2019",bookSignature:"Ahmed M. Nahhas",coverURL:"https://cdn.intechopen.com/books/images_new/8446.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"140058",title:"Prof.",name:"Prof. Dr. Ahmed",middleName:"M",surname:"Nahhas,",slug:"prof.-dr.-ahmed-nahhas",fullName:"Prof. Dr. Ahmed Nahhas,"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"262515",title:"Dr.",name:"Nesrin",middleName:null,surname:"Horzum",fullName:"Nesrin Horzum",slug:"nesrin-horzum",email:"nesrin.horzum.polat@ikc.edu.tr",position:null,institution:null},{id:"278120",title:"Mr.",name:"Mohamed",middleName:null,surname:"Elhousseini Hilal",fullName:"Mohamed Elhousseini Hilal",slug:"mohamed-elhousseini-hilal",email:"med.el.hilal@gmail.com",position:null,institution:null},{id:"278122",title:"Ms.",name:"Tuğba",middleName:null,surname:"Isık",fullName:"Tuğba Isık",slug:"tugba-isik",email:"tugbaisik@iyte.edu.tr",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"2. Biosynthesis of ZnO nanostructures",level:"2"},{id:"sec_1_3",title:"Table 1.",level:"3"},{id:"sec_1_4",title:"Table 1.",level:"4"},{id:"sec_2_4",title:"Table 2.",level:"4"},{id:"sec_3_4",title:"2.4 Adsorption/sensing application",level:"4"},{id:"sec_5_3",title:"2.5 Microorganism-based ZnO nanostructures",level:"3"},{id:"sec_6_3",title:"2.6 Biomolecule-based ZnO nanostructures",level:"3"},{id:"sec_8_2",title:"3. Synthesis of ZnO nanostructures using nontoxic chemicals",level:"2"},{id:"sec_8_3",title:"3.1 Ionic liquid as solvents for ZnO nanostructures",level:"3"},{id:"sec_10_2",title:"4. Processes of synthesis of ZnO nanostructures",level:"2"},{id:"sec_10_3",title:"4.1 Hydrothermal synthesis of ZnO nanostructures",level:"3"},{id:"sec_11_3",title:"4.2 Microwave-assisted synthesis of ZnO nanostructures",level:"3"},{id:"sec_12_3",title:"4.3 Sonochemical synthesis of ZnO nanostructures",level:"3"},{id:"sec_13_3",title:"4.4 Low temperature synthesis of ZnO nanostructures",level:"3"},{id:"sec_16",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Agarwal H, Menon S, Kumar SV, Rajeshkumar S. Mechanistic study on antibacterial action of zinc oxide nanoparticles synthesized using green route. Chemico-Biological Interactions. 2018;286:60-70'},{id:"B2",body:'Vishnukumar P, Vivekanandhan S, Misra M, Mohanty AK. Recent advances and emerging opportunities in phytochemical synthesis of ZnO nanostructures. Materials Science in Semiconductor Processing. 2018;80:143-161'},{id:"B3",body:'Thema FT, Manikandan E, Dhlamini MS, Maaza M. 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RSC Advances. 2016;6:77752-77759'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Tuğba Isık",address:null,affiliation:'
Materials Science and Engineering Department, İzmir Institute of Technology, Turkey
Department of Engineering Sciences, Izmir Katip Celebi University, Turkey
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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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4,000 GBP Compacts Monograph - Short Form
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
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\n\n
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Indexing and listing across major repositories
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Live Performance Metrics to track readership and the impact of your chapter
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Proven world leader in Open Access book publishing with over 10 years experience
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Personal support during every step of the publication process
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+84,800 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
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