Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors

The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and fun...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cellular signalling 2001-12, Vol.13 (12), p.887-894
Hauptverfasser: Juarranz, Marı́a G., Bolaños, Oscar, Gutiérrez-Cañas, Irene, Lerner, Ethan A., Robberecht, Patrick, Carmena, Marı́a J., Prieto, Juan C., Rodrı́guez-Henche, Nieves
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 894
container_issue 12
container_start_page 887
container_title Cellular signalling
container_volume 13
creator Juarranz, Marı́a G.
Bolaños, Oscar
Gutiérrez-Cañas, Irene
Lerner, Ethan A.
Robberecht, Patrick
Carmena, Marı́a J.
Prieto, Juan C.
Rodrı́guez-Henche, Nieves
description The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC 1, VPAC 1, and VPAC 2) with a major role for VPAC 1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.
doi_str_mv 10.1016/S0898-6568(01)00199-1
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_72314730</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0898656801001991</els_id><sourcerecordid>72314730</sourcerecordid><originalsourceid>FETCH-LOGICAL-c361t-bcebd0746ea8e254f60fdfaab3396da5054f71fc9ac0029315d8bdc4efd2e0f23</originalsourceid><addsrcrecordid>eNqFkUFPGzEQha0KVALtT2jlE4LDFs86u-s9VVEELVIEkQq9Wl57rLpKvKntRfQP8LvxJgGOHCxLo-_N6L1HyBdg34BBffGLiVYUdVWLMwbnjEHbFvCBTEA0vOAt8AMyeUWOyHGMfzNUsbr8SI4AmlKIUkzI0w0OoUdveh2cR2qctRjQJ6eS6z3tLU1_kC5u5mpJN6GPSSWkWnmNgWpcrehqlK2V8ym_uKXxcRMwxlGvvKF28Ppl2e_r5Xa2nM1nSxpQ4yb1IX4ih1atIn7e_yfk_urybv6zWNz-uJ7PFoXmNaSi09gZ1kxrVALLamprZo1VquO8rY2qWB41YHWrNGNly6EyojN6itaUyGzJT8jpbm-28m_AmOTaxdGG8tgPUTYlh2nDWQarHaiz5xjQyk1waxX-S2ByLEBuC5BjupKB3BYgIeu-7g8M3RrNm2qfeAa-7wDMNh8cBhm1wxyncTmNJE3v3jnxDEwmmDg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>72314730</pqid></control><display><type>article</type><title>Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Juarranz, Marı́a G. ; Bolaños, Oscar ; Gutiérrez-Cañas, Irene ; Lerner, Ethan A. ; Robberecht, Patrick ; Carmena, Marı́a J. ; Prieto, Juan C. ; Rodrı́guez-Henche, Nieves</creator><creatorcontrib>Juarranz, Marı́a G. ; Bolaños, Oscar ; Gutiérrez-Cañas, Irene ; Lerner, Ethan A. ; Robberecht, Patrick ; Carmena, Marı́a J. ; Prieto, Juan C. ; Rodrı́guez-Henche, Nieves</creatorcontrib><description>The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC 1, VPAC 1, and VPAC 2) with a major role for VPAC 1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.</description><identifier>ISSN: 0898-6568</identifier><identifier>EISSN: 1873-3913</identifier><identifier>DOI: 10.1016/S0898-6568(01)00199-1</identifier><identifier>PMID: 11728828</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Adenylyl Cyclases - metabolism ; Binding, Competitive ; cAMP ; Cell Differentiation ; Culture Media, Serum-Free ; Cyclic AMP - biosynthesis ; Dose-Response Relationship, Drug ; Humans ; Male ; Neurites - ultrastructure ; Neuroendocrine cells ; Neurons - cytology ; Neurons - metabolism ; Neuropeptides - pharmacology ; Neurosecretory Systems - cytology ; Neurosecretory Systems - metabolism ; PACAP receptors ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Prostate cancer ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I ; Receptors, Pituitary Hormone - genetics ; Receptors, Pituitary Hormone - metabolism ; Receptors, Pituitary Hormone - physiology ; Receptors, Vasoactive Intestinal Peptide - genetics ; Receptors, Vasoactive Intestinal Peptide - metabolism ; Receptors, Vasoactive Intestinal Peptide - physiology ; Receptors, Vasoactive Intestinal Peptide, Type II ; Receptors, Vasoactive Intestinal Polypeptide, Type I ; RNA, Neoplasm - biosynthesis ; Transcription, Genetic ; Transdifferentiation ; Tumor Cells, Cultured ; Vasoactive Intestinal Peptide - pharmacology ; VIP receptors</subject><ispartof>Cellular signalling, 2001-12, Vol.13 (12), p.887-894</ispartof><rights>2001 Elsevier Science Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c361t-bcebd0746ea8e254f60fdfaab3396da5054f71fc9ac0029315d8bdc4efd2e0f23</citedby><cites>FETCH-LOGICAL-c361t-bcebd0746ea8e254f60fdfaab3396da5054f71fc9ac0029315d8bdc4efd2e0f23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0898656801001991$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11728828$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Juarranz, Marı́a G.</creatorcontrib><creatorcontrib>Bolaños, Oscar</creatorcontrib><creatorcontrib>Gutiérrez-Cañas, Irene</creatorcontrib><creatorcontrib>Lerner, Ethan A.</creatorcontrib><creatorcontrib>Robberecht, Patrick</creatorcontrib><creatorcontrib>Carmena, Marı́a J.</creatorcontrib><creatorcontrib>Prieto, Juan C.</creatorcontrib><creatorcontrib>Rodrı́guez-Henche, Nieves</creatorcontrib><title>Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors</title><title>Cellular signalling</title><addtitle>Cell Signal</addtitle><description>The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC 1, VPAC 1, and VPAC 2) with a major role for VPAC 1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.</description><subject>Adenylyl Cyclases - metabolism</subject><subject>Binding, Competitive</subject><subject>cAMP</subject><subject>Cell Differentiation</subject><subject>Culture Media, Serum-Free</subject><subject>Cyclic AMP - biosynthesis</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Male</subject><subject>Neurites - ultrastructure</subject><subject>Neuroendocrine cells</subject><subject>Neurons - cytology</subject><subject>Neurons - metabolism</subject><subject>Neuropeptides - pharmacology</subject><subject>Neurosecretory Systems - cytology</subject><subject>Neurosecretory Systems - metabolism</subject><subject>PACAP receptors</subject><subject>Pituitary Adenylate Cyclase-Activating Polypeptide</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide</subject><subject>Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I</subject><subject>Receptors, Pituitary Hormone - genetics</subject><subject>Receptors, Pituitary Hormone - metabolism</subject><subject>Receptors, Pituitary Hormone - physiology</subject><subject>Receptors, Vasoactive Intestinal Peptide - genetics</subject><subject>Receptors, Vasoactive Intestinal Peptide - metabolism</subject><subject>Receptors, Vasoactive Intestinal Peptide - physiology</subject><subject>Receptors, Vasoactive Intestinal Peptide, Type II</subject><subject>Receptors, Vasoactive Intestinal Polypeptide, Type I</subject><subject>RNA, Neoplasm - biosynthesis</subject><subject>Transcription, Genetic</subject><subject>Transdifferentiation</subject><subject>Tumor Cells, Cultured</subject><subject>Vasoactive Intestinal Peptide - pharmacology</subject><subject>VIP receptors</subject><issn>0898-6568</issn><issn>1873-3913</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFPGzEQha0KVALtT2jlE4LDFs86u-s9VVEELVIEkQq9Wl57rLpKvKntRfQP8LvxJgGOHCxLo-_N6L1HyBdg34BBffGLiVYUdVWLMwbnjEHbFvCBTEA0vOAt8AMyeUWOyHGMfzNUsbr8SI4AmlKIUkzI0w0OoUdveh2cR2qctRjQJ6eS6z3tLU1_kC5u5mpJN6GPSSWkWnmNgWpcrehqlK2V8ym_uKXxcRMwxlGvvKF28Ppl2e_r5Xa2nM1nSxpQ4yb1IX4ih1atIn7e_yfk_urybv6zWNz-uJ7PFoXmNaSi09gZ1kxrVALLamprZo1VquO8rY2qWB41YHWrNGNly6EyojN6itaUyGzJT8jpbm-28m_AmOTaxdGG8tgPUTYlh2nDWQarHaiz5xjQyk1waxX-S2ByLEBuC5BjupKB3BYgIeu-7g8M3RrNm2qfeAa-7wDMNh8cBhm1wxyncTmNJE3v3jnxDEwmmDg</recordid><startdate>20011201</startdate><enddate>20011201</enddate><creator>Juarranz, Marı́a G.</creator><creator>Bolaños, Oscar</creator><creator>Gutiérrez-Cañas, Irene</creator><creator>Lerner, Ethan A.</creator><creator>Robberecht, Patrick</creator><creator>Carmena, Marı́a J.</creator><creator>Prieto, Juan C.</creator><creator>Rodrı́guez-Henche, Nieves</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20011201</creationdate><title>Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors</title><author>Juarranz, Marı́a G. ; Bolaños, Oscar ; Gutiérrez-Cañas, Irene ; Lerner, Ethan A. ; Robberecht, Patrick ; Carmena, Marı́a J. ; Prieto, Juan C. ; Rodrı́guez-Henche, Nieves</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c361t-bcebd0746ea8e254f60fdfaab3396da5054f71fc9ac0029315d8bdc4efd2e0f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adenylyl Cyclases - metabolism</topic><topic>Binding, Competitive</topic><topic>cAMP</topic><topic>Cell Differentiation</topic><topic>Culture Media, Serum-Free</topic><topic>Cyclic AMP - biosynthesis</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Male</topic><topic>Neurites - ultrastructure</topic><topic>Neuroendocrine cells</topic><topic>Neurons - cytology</topic><topic>Neurons - metabolism</topic><topic>Neuropeptides - pharmacology</topic><topic>Neurosecretory Systems - cytology</topic><topic>Neurosecretory Systems - metabolism</topic><topic>PACAP receptors</topic><topic>Pituitary Adenylate Cyclase-Activating Polypeptide</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide</topic><topic>Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I</topic><topic>Receptors, Pituitary Hormone - genetics</topic><topic>Receptors, Pituitary Hormone - metabolism</topic><topic>Receptors, Pituitary Hormone - physiology</topic><topic>Receptors, Vasoactive Intestinal Peptide - genetics</topic><topic>Receptors, Vasoactive Intestinal Peptide - metabolism</topic><topic>Receptors, Vasoactive Intestinal Peptide - physiology</topic><topic>Receptors, Vasoactive Intestinal Peptide, Type II</topic><topic>Receptors, Vasoactive Intestinal Polypeptide, Type I</topic><topic>RNA, Neoplasm - biosynthesis</topic><topic>Transcription, Genetic</topic><topic>Transdifferentiation</topic><topic>Tumor Cells, Cultured</topic><topic>Vasoactive Intestinal Peptide - pharmacology</topic><topic>VIP receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Juarranz, Marı́a G.</creatorcontrib><creatorcontrib>Bolaños, Oscar</creatorcontrib><creatorcontrib>Gutiérrez-Cañas, Irene</creatorcontrib><creatorcontrib>Lerner, Ethan A.</creatorcontrib><creatorcontrib>Robberecht, Patrick</creatorcontrib><creatorcontrib>Carmena, Marı́a J.</creatorcontrib><creatorcontrib>Prieto, Juan C.</creatorcontrib><creatorcontrib>Rodrı́guez-Henche, Nieves</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cellular signalling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Juarranz, Marı́a G.</au><au>Bolaños, Oscar</au><au>Gutiérrez-Cañas, Irene</au><au>Lerner, Ethan A.</au><au>Robberecht, Patrick</au><au>Carmena, Marı́a J.</au><au>Prieto, Juan C.</au><au>Rodrı́guez-Henche, Nieves</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors</atitle><jtitle>Cellular signalling</jtitle><addtitle>Cell Signal</addtitle><date>2001-12-01</date><risdate>2001</risdate><volume>13</volume><issue>12</issue><spage>887</spage><epage>894</epage><pages>887-894</pages><issn>0898-6568</issn><eissn>1873-3913</eissn><abstract>The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC 1, VPAC 1, and VPAC 2) with a major role for VPAC 1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>11728828</pmid><doi>10.1016/S0898-6568(01)00199-1</doi><tpages>8</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0898-6568
ispartof Cellular signalling, 2001-12, Vol.13 (12), p.887-894
issn 0898-6568
1873-3913
language eng
recordid cdi_proquest_miscellaneous_72314730
source MEDLINE; Elsevier ScienceDirect Journals
subjects Adenylyl Cyclases - metabolism
Binding, Competitive
cAMP
Cell Differentiation
Culture Media, Serum-Free
Cyclic AMP - biosynthesis
Dose-Response Relationship, Drug
Humans
Male
Neurites - ultrastructure
Neuroendocrine cells
Neurons - cytology
Neurons - metabolism
Neuropeptides - pharmacology
Neurosecretory Systems - cytology
Neurosecretory Systems - metabolism
PACAP receptors
Pituitary Adenylate Cyclase-Activating Polypeptide
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Receptors, Pituitary Hormone - genetics
Receptors, Pituitary Hormone - metabolism
Receptors, Pituitary Hormone - physiology
Receptors, Vasoactive Intestinal Peptide - genetics
Receptors, Vasoactive Intestinal Peptide - metabolism
Receptors, Vasoactive Intestinal Peptide - physiology
Receptors, Vasoactive Intestinal Peptide, Type II
Receptors, Vasoactive Intestinal Polypeptide, Type I
RNA, Neoplasm - biosynthesis
Transcription, Genetic
Transdifferentiation
Tumor Cells, Cultured
Vasoactive Intestinal Peptide - pharmacology
VIP receptors
title Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T10%3A00%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Neuroendocrine%20differentiation%20of%20the%20LNCaP%20prostate%20cancer%20cell%20line%20maintains%20the%20expression%20and%20function%20of%20VIP%20and%20PACAP%20receptors&rft.jtitle=Cellular%20signalling&rft.au=Juarranz,%20Mar%C4%B1%CC%81a%20G.&rft.date=2001-12-01&rft.volume=13&rft.issue=12&rft.spage=887&rft.epage=894&rft.pages=887-894&rft.issn=0898-6568&rft.eissn=1873-3913&rft_id=info:doi/10.1016/S0898-6568(01)00199-1&rft_dat=%3Cproquest_cross%3E72314730%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=72314730&rft_id=info:pmid/11728828&rft_els_id=S0898656801001991&rfr_iscdi=true