FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2047698726> ?p ?o ?g. }

• W2047698726 endingPage "10" @default.
• W2047698726 startingPage "7" @default.
• W2047698726 abstract "Signaling pathways responsible for embryogenesis play a critical role in the maintenance of stem cells in adult life and cellular responses to injury. Dysfunction of the developmental signaling pathways during adult homeostasis leads to various events resulting in the development of neoplasia. We review the biology of the hedgehog signaling pathway and its potential role in the development of lung cancer. Signaling pathways responsible for embryogenesis play a critical role in the maintenance of stem cells in adult life and cellular responses to injury. Dysfunction of the developmental signaling pathways during adult homeostasis leads to various events resulting in the development of neoplasia. We review the biology of the hedgehog signaling pathway and its potential role in the development of lung cancer. Signaling pathways responsible for embryogenesis appear to play a critical role in the maintenance of stem cells in adult life and cellular responses to injury. Dysregulation of these signaling pathways during adult homeostasis can lead to various events resulting in the development of neoplasia (Figure 1). Hedgehog (Hh) signaling pathway is one such pathway that is crucial in the embryogenesis. Hh pathway also plays a central role in the repair and regeneration of adult tissue. The Hh signaling pathway was first studied in drosophilae. During embryonic development, drosophilae with a mutation in the Hh gene were covered with pointed denticles, resembling a hedgehog, hence the name. Several studies have recently demonstrated that dysregulation of the Hh signaling plays a role in several cancers including the brain, skin, gastrointestinal tract, pancreas, and lung.1Goodrich LV Milenkovic L Higgins KM Scott MP Altered neural cell fates and medulloblastoma in mouse patched mutants.Science. 1997; 277: 1109-1113Crossref PubMed Scopus (1366) Google Scholar, 2Berman DM Karhadkar SS Hallahan AR et al.Medulloblastoma growth inhibition by hedgehog pathway blockade.Science. 2002; 297: 1559-1561Crossref PubMed Scopus (674) Google Scholar, 3Sanchez P Hernandez AM Stecca B et al.Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.Proc Natl Acad Sci U S A. 2004; 101: 12561-12566Crossref PubMed Scopus (435) Google Scholar, 4Thayer SP di Magliano MP Heiser PW et al.Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis.Nature. 2003; 425: 851-856Crossref PubMed Scopus (1248) Google Scholar, 5Bak M Hansen C Tommerup N Larsen LA The Hedgehog signaling pathway—implications for drug targets in cancer and neurodegenerative disorders.Pharmacogenomics. 2003; 4: 411-429Crossref PubMed Scopus (19) Google Scholar, 6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar Mammalian Hh signaling pathway (Figure 2) constitutes (a) Hh ligand with three variants: desert (Dhh), Indian (Ihh), and sonic (Shh); (b) a transmembrane receptor-patched homolog 1 and 2 (Ptch1 and 2); (c) smoothened (Smo), a G protein–coupled receptor; and (d) a cytoplasmic complex that regulates the cubitus interruptus (Ci) or glioma-associated oncogene homolog (Gli) family of transcriptional effectors. All the three ligands bind to the same receptors and elicit similar responses. Shh is the most extensively characterized variant and is widely expressed during embryogenesis. Shh acts as a morphogen and plays an important role in the formation of the neural tube, axial skeleton, primitive gut, and the tracheobronchial tree.7Mahlapuu M Enerback S Carlsson P Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations.Development. 2001; 128: 2397-2406Crossref PubMed Google Scholar, 8Bellusci S Furuta Y Rush MG Henderson R Winnier G Hogan BL Involvement of sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.Development. 1997; 124: 53-63Crossref PubMed Google Scholar Autocatalytic cleavage and coupling of cholesterol are the essential posttranslational processes that maintain the signaling capability of the Hh ligands.9Gallet A Rodriguez R Ruel L Therond PP Cholesterol modification of hedgehog is required for trafficking and movement, revealing an asymmetric cellular response to hedgehog.Dev Cell. 2003; 4: 191-204Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar The secretion of the functional Hh ligand by the Hh-secreting cell is dependent on the availability of dispatched (Disp), a transmembrane protein with homology to patched (Ptch), which is an Hh receptor on the Hh responsive cell.10Burke R Nellen D Bellotto M et al.Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells.Cell. 1999; 99: 803-815Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 11Tian H Jeong J Harfe BD Tabin CJ McMahon AP Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand.Development. 2005; 132: 133-142Crossref PubMed Scopus (74) Google Scholar The Ptch 1 and 2 are membrane receptors for Hh ligands. Ptch 1 is more widely expressed and well characterized. Binding of Hh ligand with the Ptch alters the interactions of Ptch with Smo, resulting in the activation of Smo. This initiates a cascade of events resulting in the Ci and Gli entering the nucleus and acting as transcriptional activators. It is unclear how the activation of Smo communicates with the cytoplasmic Ci/Gli transcription factor complex. Gli bind to the DNA through zinc finger domains directed to particular target genes regulating key cell survival and differentiation functions. Gli1 is a transcription activator, and Gli2 and Gli3 are both activators and repressors of transcription. Gli3 and Ci regulate transcription by binding to the CREB-binding protein, which is a transcription coactivator. Cyclin D and cyclin E are known transcriptional targets of Hh signaling, and these proteins are vital in the G1-to-S transition in the cell cycle.12Pasca di Magliano M Hebrok M Hedgehog signalling in cancer formation and maintenance.Nat Rev Cancer. 2003; 3: 903-911Crossref PubMed Scopus (695) Google Scholar Hh signaling activates the mitosis promoting factor by increasing the intranuclear availability of cyclin B.13Barnes EA Kong M Ollendorff V Donoghue DJ Patched1 interacts with cyclin B1 to regulate cell cycle progression.EMBO J. 2001; 20: 2214-2223Crossref PubMed Scopus (183) Google Scholar Hh signaling also opposes normal stimuli for epithelial cell cycle arrest (by inhibiting P21) and promotes cell growth.14Fan H Khavari PA Sonic hedgehog opposes epithelial cell cycle arrest.J Cell Biol. 1999; 147: 71-76Crossref PubMed Scopus (127) Google Scholar Hh signaling inhibits a well-known regulator of apoptosis, the p53 tumor suppressor gene.15Yoshinori A, Oda-Sato E, Tobiume K, et al. 2006. The negative regulation of p53 by hedgehog signaling. Presented at the AACR Annual Meeting, Washington, DC, 2006. (Abstract# 1135-b).Google Scholar When the Hh ligand is unavailable Ptch1 inhibits the activity of Smo, thus repressing the downstream signaling events. When the Hh signaling is lacking, Gli proteins are bound to microtubules in the cytosol along with a multiprotein complex consisting of Fused (Fu) and suppressor of Fu (SuFu). The Hh operates through a series of inhibitory steps. The availability of the Hh ligand for signaling is regulated by the expression of Hh interacting protein (HIP) on the cell surface of Hh responsive cell. The HIP is a membrane glycoprotein that binds to Hh ligands with an affinity similar to that of the membrane protein Ptch1. HIP lacks signal transduction capacity and acts to internalize and degrade the Hh ligand.16Chuang PT McMahon AP Vertebrate hedgehog signalling modulated by induction of a hedgehog-binding protein.Nature. 1999; 397: 617-621Crossref PubMed Scopus (587) Google Scholar Activation of the Hh pathway causes an increased expression of the HIP via a negative feedback mechanism, thus serving as an inducible antagonist of Shh signaling.16Chuang PT McMahon AP Vertebrate hedgehog signalling modulated by induction of a hedgehog-binding protein.Nature. 1999; 397: 617-621Crossref PubMed Scopus (587) Google Scholar The Hh signaling is regulated at various levels, indicating the importance of tight control of Hh signaling. Several inhibitors of the pathway like Ptch and HIP are transcriptional target genes and Hh activation induces negative feedback, reducing the intensity of Hh signaling. Gli genes are regulated by complex mechanisms at both the posttranslational and transcriptional level. Hh signaling up-regulates Gli1 expression while repressing Gli3 expression.5Bak M Hansen C Tommerup N Larsen LA The Hedgehog signaling pathway—implications for drug targets in cancer and neurodegenerative disorders.Pharmacogenomics. 2003; 4: 411-429Crossref PubMed Scopus (19) Google Scholar Dysregulation of the Hh signaling can occur from ligand-dependent and -independent mechanisms (Table 1).TABLE 1Dysregulation of Hh Pathway in CancerPathway ComponentType of CancerIncreased Hh ligandBasal cell carcinoma,1,31 medulloblastoma, small cell lung cancer,6 digestive tract tumors,32–34 ovarian tumors,35 prostate cancer36Reduced expression of Hh interacting proteinPancreatic cancer,37 liver,23 lung,23 digestive tract tumors,23 prostate cancer36Inactivating mutations in the PtchMedulloblastoma,1 basal cell carcinoma,38 rhabdomyosarcoma39Activating mutations in the transmembrane helices of SmoBasal cell carcinoma,40 ovarian tumors35Overexpression of the Gli proteinsBasal cell carcinoma,41 small cell lung cancer,6 esophageal cancers,33 gastric cancers34Loss of function mutations of SuFuMedulloblastoma,42 rhabdomyosarcoma,39 prostate cancer36Hh, hedgehog; Ptch, transmembrane receptor-patched homolog; Smo, smoothened a G protein–coupled receptor; Gli, glioma-associated oncogene homolog; SuFu, suppressor of fused. Open table in a new tab Hh, hedgehog; Ptch, transmembrane receptor-patched homolog; Smo, smoothened a G protein–coupled receptor; Gli, glioma-associated oncogene homolog; SuFu, suppressor of fused. The lungs develop from an outpouching of the primitive endodermal tube into the surrounding mesenchyme. In the developing lung in mouse models, an elevated Shh expression was detected in the tracheal diverticulum and in the trachea and lung endoderm.17Litingtung Y Lei L Westphal H Chiang C Sonic hedgehog is essential to foregut development.Nat Genet. 1998; 20: 58-61Crossref PubMed Scopus (545) Google Scholar Studies indicate that the Hh signaling pathway is essential for the growth and differentiation of the trachea and lung, and aberrations in the signaling components may be involved in abnormal development of the lung.7Mahlapuu M Enerback S Carlsson P Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations.Development. 2001; 128: 2397-2406Crossref PubMed Google Scholar, 8Bellusci S Furuta Y Rush MG Henderson R Winnier G Hogan BL Involvement of sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.Development. 1997; 124: 53-63Crossref PubMed Google Scholar, 17Litingtung Y Lei L Westphal H Chiang C Sonic hedgehog is essential to foregut development.Nat Genet. 1998; 20: 58-61Crossref PubMed Scopus (545) Google Scholar Natural teratogens like cyclopamine and jervine (extracted from of corn lilies) are inhibitors of Hh signaling. Pregnant animals treated with these inhibitors of Hh signaling at an early gestation period results in multiple developmental anomalies including abnormal lung development.18Cooper MK Porter JA Young KE Beachy PA Teratogen-mediated inhibition of target tissue response to Shh signaling.Science. 1998; 280: 1603-1607Crossref PubMed Scopus (739) Google Scholar The airway epithelial progenitor (stem) cells play an important role in the development of the respiratory epithelium. The differentiation of these progenitor cells to form the neuroendocrine or non-neuroendocrine (ciliated, mucous, clara, or basal cells) component of the respiratory epithelium is tightly regulated by a complex bipotential notch signaling.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar, 19Watkins DN Berman DM Baylin SB Hedgehog signaling: progenitor phenotype in small-cell lung cancer.Cell Cycle. 2003; 2: 196-198Crossref PubMed Scopus (84) Google Scholar Notch and Wnt signaling are evolutionary conserved signaling pathways tightly regulating cell death, cell movement, and cell division and differentiation during embryogenesis. During development and repair of the lung epithelium, Hh signaling maintains this bipotential notch signaling.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar, 19Watkins DN Berman DM Baylin SB Hedgehog signaling: progenitor phenotype in small-cell lung cancer.Cell Cycle. 2003; 2: 196-198Crossref PubMed Scopus (84) Google Scholar Hh and Wnt pathways possibly play an important role in the maintenance and the expansion of the progenitor (stem) cells during development and can mediate lung growth by signaling to adjacent lung mesenchyme.20Taipale J Beachy PA The hedgehog and Wnt signalling pathways in cancer.Nature. 2001; 411: 349-354Crossref PubMed Scopus (1128) Google Scholar Hh signaling is possibly inactive in the human adult lung epithelium except in the epithelial progenitor (stem) cells. This persistence of Hh signaling in the epithelial progenitor (stem) cells could help maintain these cells and play a critical role in the response to airway epithelial injury.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar, 19Watkins DN Berman DM Baylin SB Hedgehog signaling: progenitor phenotype in small-cell lung cancer.Cell Cycle. 2003; 2: 196-198Crossref PubMed Scopus (84) Google Scholar, 21Watkins DN Peacock CD Hedgehog signalling in foregut malignancy.Biochem Pharmacol. 2004; 68: 1055-1060Crossref PubMed Scopus (68) Google Scholar Studies on animal lung airway epithelial injury/regeneration model suggest that persistent injury to the airway is a potent stimulus for the activation of the Hh signaling, and this helps the expansion of airway epithelial progenitor cells.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar, 19Watkins DN Berman DM Baylin SB Hedgehog signaling: progenitor phenotype in small-cell lung cancer.Cell Cycle. 2003; 2: 196-198Crossref PubMed Scopus (84) Google Scholar, 21Watkins DN Peacock CD Hedgehog signalling in foregut malignancy.Biochem Pharmacol. 2004; 68: 1055-1060Crossref PubMed Scopus (68) Google Scholar Shh and Gli1 are expressed in the regenerating lung airway epithelium.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar Studies on cell lines showed that all the seven small cell lung cancer (SCLC) and seven non-small cell lung cancer (NSCLC) cell lines expressed Shh protein. Five of seven SCLC cell lines expressed both Shh and Gli1 in contrast to NSCLC, which expressed only Shh but not Gli1.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar Analysis of clinical samples of human lung cancer tissue demonstrated 50% (five of 10) of SCLC expressed both Shh and Gli1 compared to only 10% (four of 40) of NSCLC.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar Another study investigating the expression of Gli1 in SCLC tissue reported that 85% (34 of 40) of SCLC express Gli1 and more than 60% have a medium to strong expression correlating with increased Hh signaling.22Vestergaard J Pedersen MW Pedersen N et al.Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro.Lung Cancer. 2006; 52: 281-290Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar It thus appears that lung cancer cells retain aspects of the Hh signaling seen in the primitive lung endodermal cells. However, the degree of dependence on this signaling varies ahmong the subtypes of lung cancer. Inhibition of Shh ligand activity using monoclonal antibody and cyclopamine resulted in the significant growth inhibition in SCLC cell lines expressing both Shh and Gli but not NSCLC cell lines (which do not express both Shh and Gli).6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar Similar results were found in in vivo studies on lung cancer xenografts in nude mice.6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar HIP is a natural antagonist of Hh signaling as discussed above. Reduced expression of HIP as been reported in lung cancer A549 cell line xenograft in nude mice and a decrease in the expression of HIP was seen in five of 10 human NSCLC tissues.23Olsen CL Hsu PP Glienke J Rubanyi GM Brooks AR Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors.BMC Cancer. 2004; 4: 43Crossref PubMed Scopus (130) Google Scholar Experimental models studying HIP knockout mice confirmed increased Hh signaling.24Kawahira H Ma NH Tzanakakis ES McMahon AP Chuang PT Hebrok M Combined activities of hedgehog signaling inhibitors regulate pancreas development.Development. 2003; 130: 4871-4879Crossref PubMed Scopus (96) Google Scholar, 25Chuang PT Kawcak T McMahon AP Feedback control of mammalian hedgehog signaling by the hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung.Genes Dev. 2003; 17: 342-347Crossref PubMed Scopus (199) Google Scholar There appears to be down-regulation of HIP in endothelial cells during angiogenesis.23Olsen CL Hsu PP Glienke J Rubanyi GM Brooks AR Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors.BMC Cancer. 2004; 4: 43Crossref PubMed Scopus (130) Google Scholar These findings suggest that reduced expression of HIP could potentially enhance the Hh signaling and possibly facilitate angiogenesis. Hh signaling thus appears to play a role in proliferation of malignant cells and promote angiogenesis. Therapeutic inactivation of the Hh signaling offers a potential treatment for cancer. Inactivation of the Hh signaling can be done at various levels, mainly (1) extracellular blocking of the Shh ligands using Shh antibodies, (2) activation of Smo in the cell membrane, (3) modulating intracytoplasmic regulators of Hh signaling like protein kinase A and SuFu, and (4) altering the intranuclear functioning of Gli. Curis Inc. developed a Shh antagonist that showed promising results in preclinical models.26Hua Tian DM, Ahn C, Modrusan Z, et al. 2006. Characterization of a Hedgehog pathway antagonist in a mouse medulloblastoma allograft model (abstract 5639). Presented at the 97th AACR Annual Meeting, Washington, DC, 2006.Google Scholar, 27Tang TT, Dongwei L, Reich M, et al. Inhibition of the Hedgehog pathway as a therapeutic approach for the treatment of basal cell carcinomas (abstract 3809). Presented at the 97th AACR Annual Meeting, Washington, DC, 2006.Google Scholar Antibodies to Shh are currently being evaluated in phase I clinical trials for basal cell carcinoma. Cyclopamine is another potential molecule of interest for the inhibition of Hh signaling.26Hua Tian DM, Ahn C, Modrusan Z, et al. 2006. Characterization of a Hedgehog pathway antagonist in a mouse medulloblastoma allograft model (abstract 5639). Presented at the 97th AACR Annual Meeting, Washington, DC, 2006.Google Scholar, 27Tang TT, Dongwei L, Reich M, et al. Inhibition of the Hedgehog pathway as a therapeutic approach for the treatment of basal cell carcinomas (abstract 3809). Presented at the 97th AACR Annual Meeting, Washington, DC, 2006.Google Scholar Cyclopamine has demonstrated a good safety profile in mice.2Berman DM Karhadkar SS Hallahan AR et al.Medulloblastoma growth inhibition by hedgehog pathway blockade.Science. 2002; 297: 1559-1561Crossref PubMed Scopus (674) Google Scholar, 4Thayer SP di Magliano MP Heiser PW et al.Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis.Nature. 2003; 425: 851-856Crossref PubMed Scopus (1248) Google Scholar, 6Watkins DN Berman DM Burkholder SG Wang B Beachy PA Baylin SB Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.Nature. 2003; 422: 313-317Crossref PubMed Scopus (904) Google Scholar Several other compounds that bind to Smo and inhibit the downstream events have been identified (KAAD-cyclop, SANT1-4, CUR61414).28Chen JK Taipale J Young KE Maiti T Beachy PA Small molecule modulation of smoothened activity.Proc Natl Acad Sci U S A. 2002; 99: 14071-14076Crossref PubMed Scopus (774) Google Scholar However, patients with downstream alterations in the Hh signaling could be resistant to the treatment with Shh antagonist and Smo targeted therapies. Another potential mechanism for blocking Gli activity is the use of protein kinase A agonists like forskolin, which maintain the Gli in inactive state.29Shindo N Sakai A Arai D Matsuoka O Yamasaki Y Higashinakagawa T The ESC-E(Z) complex participates in the hedgehog signaling pathway.Biochem Biophys Res Commun. 2005; 327: 1179-1187Crossref PubMed Scopus (9) Google Scholar Antisense oligonucleotides targeting Gli RNA also provide a viable option to prevent Gli-mediated activation of target genes.3Sanchez P Hernandez AM Stecca B et al.Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.Proc Natl Acad Sci U S A. 2004; 101: 12561-12566Crossref PubMed Scopus (435) Google Scholar, 30Chang DZ. Synthetic miRNAs targeting the GLI-1 transcription factor inhibit division and induce apoptosis in pancreatic tumor cells (abstract 2718). Presented at the 97th AACR Annual Meeting, 2006, Washington, DC.Google Scholar It is important to clarify the role of activation of Hh pathway in the process of carcinogenesis and progression in lung cancer. Numerous mechanisms have been implicated in the development, proliferation, and progression of lung cancer; it is critical to understand how the Hh pathway interacts with the other pathways implicated in lung cancer. There have been virtually no significant advances in the systemic therapy of SCLC in the past three decades. With the current trend toward developing targeted therapies, the Hh pathway modulators offer a potential new avenue in the treatment of lung cancer." @default.
• W2047698726 created "2016-06-24" @default.
• W2047698726 creator A5066861614 @default.
• W2047698726 creator A5068824818 @default.
• W2047698726 date "2007-01-01" @default.
• W2047698726 modified "2023-09-27" @default.
• W2047698726 title "Hedgehog Signaling Pathway and Lung Cancer" @default.
• W2047698726 cites W1500827124 @default.
• W2047698726 cites W1585922331 @default.
• W2047698726 cites W1594815607 @default.
• W2047698726 cites W1607596367 @default.
• W2047698726 cites W1964470628 @default.
• W2047698726 cites W1973121483 @default.
• W2047698726 cites W1982824007 @default.
• W2047698726 cites W1983341583 @default.
• W2047698726 cites W1986820364 @default.
• W2047698726 cites W1989313612 @default.
• W2047698726 cites W1995338672 @default.
• W2047698726 cites W1997560595 @default.
• W2047698726 cites W2002233575 @default.
• W2047698726 cites W2002249795 @default.
• W2047698726 cites W2002355858 @default.
• W2047698726 cites W2011314859 @default.
• W2047698726 cites W2020691941 @default.
• W2047698726 cites W2021354108 @default.
• W2047698726 cites W2055296003 @default.
• W2047698726 cites W2056914659 @default.
• W2047698726 cites W2059456940 @default.
• W2047698726 cites W2086152184 @default.
• W2047698726 cites W2086751240 @default.
• W2047698726 cites W2090455515 @default.
• W2047698726 cites W2091275560 @default.
• W2047698726 cites W2101902403 @default.
• W2047698726 cites W2113492051 @default.
• W2047698726 cites W2114471035 @default.
• W2047698726 cites W2120665189 @default.
• W2047698726 cites W2127001212 @default.
• W2047698726 cites W2140619393 @default.
• W2047698726 cites W2152301579 @default.
• W2047698726 cites W2153111026 @default.
• W2047698726 cites W2153889566 @default.
• W2047698726 cites W2155068099 @default.
• W2047698726 cites W2164101293 @default.
• W2047698726 cites W4297903474 @default.
• W2047698726 cites W2083978270 @default.
• W2047698726 doi "https://doi.org/10.1097/jto.0b013e31802c0276" @default.
• W2047698726 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17410003" @default.
• W2047698726 hasPublicationYear "2007" @default.
• W2047698726 type Work @default.
• W2047698726 sameAs 2047698726 @default.
• W2047698726 citedByCount "53" @default.
• W2047698726 countsByYear W20476987262012 @default.
• W2047698726 countsByYear W20476987262013 @default.
• W2047698726 countsByYear W20476987262014 @default.
• W2047698726 countsByYear W20476987262015 @default.
• W2047698726 countsByYear W20476987262016 @default.
• W2047698726 countsByYear W20476987262017 @default.
• W2047698726 countsByYear W20476987262018 @default.
• W2047698726 countsByYear W20476987262019 @default.
• W2047698726 countsByYear W20476987262020 @default.
• W2047698726 countsByYear W20476987262021 @default.
• W2047698726 countsByYear W20476987262022 @default.
• W2047698726 countsByYear W20476987262023 @default.
• W2047698726 crossrefType "journal-article" @default.
• W2047698726 hasAuthorship W2047698726A5066861614 @default.
• W2047698726 hasAuthorship W2047698726A5068824818 @default.
• W2047698726 hasBestOaLocation W20476987261 @default.
• W2047698726 hasConcept C126322002 @default.
• W2047698726 hasConcept C143998085 @default.
• W2047698726 hasConcept C2776256026 @default.
• W2047698726 hasConcept C2777714996 @default.
• W2047698726 hasConcept C2778539099 @default.
• W2047698726 hasConcept C502942594 @default.
• W2047698726 hasConcept C62478195 @default.
• W2047698726 hasConcept C71924100 @default.
• W2047698726 hasConcept C86803240 @default.
• W2047698726 hasConcept C88498014 @default.
• W2047698726 hasConcept C95444343 @default.
• W2047698726 hasConceptScore W2047698726C126322002 @default.
• W2047698726 hasConceptScore W2047698726C143998085 @default.
• W2047698726 hasConceptScore W2047698726C2776256026 @default.
• W2047698726 hasConceptScore W2047698726C2777714996 @default.
• W2047698726 hasConceptScore W2047698726C2778539099 @default.
• W2047698726 hasConceptScore W2047698726C502942594 @default.
• W2047698726 hasConceptScore W2047698726C62478195 @default.
• W2047698726 hasConceptScore W2047698726C71924100 @default.
• W2047698726 hasConceptScore W2047698726C86803240 @default.
• W2047698726 hasConceptScore W2047698726C88498014 @default.
• W2047698726 hasConceptScore W2047698726C95444343 @default.
• W2047698726 hasIssue "1" @default.
• W2047698726 hasLocation W20476987261 @default.
• W2047698726 hasLocation W20476987262 @default.
• W2047698726 hasOpenAccess W2047698726 @default.
• W2047698726 hasPrimaryLocation W20476987261 @default.
• W2047698726 hasRelatedWork W1819606683 @default.
• W2047698726 hasRelatedWork W2009892806 @default.
• W2047698726 hasRelatedWork W2038008001 @default.
• W2047698726 hasRelatedWork W2105544413 @default.

• next