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href="https://www.academia.edu/108498837/A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment"><img alt="Research paper thumbnail of A crosstalk between HIF-1a and LOX in the tumor microenvironment" class="work-thumbnail" src="https://attachments.academia-assets.com/106864580/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498837/A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment">A crosstalk between HIF-1a and LOX in the tumor microenvironment</a></div><div class="wp-workCard_item"><span>Ejc Supplements</span><span>, Jul 1, 2008</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="e8d80541371afc72c98fe43ebe7adcec" class="wp-workCard--action" rel="nofollow" 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Microenvironment","grobid_abstract":"Materials and Methods: Expression of HIF-1alpha was assayed by Werstern Blotting and qPCR. Transfection of siRNA against HIF-1alpha was done to demonstrate its transcriptional activity. A pull down assay using as bait the oxygen binding domain of HIF-1 was used to assay PHD activity. Results: Here, we demonstrate that exposure of T84 colon cancer cells to C1845 bacteria induces the expression of HIF-1, a key transcription factor involved in VEGF expression. In contrast to hypoxia which inhibits the activity of prolyl hydroxylases (PHD) and as a consequence stabilizes HIF-1alpha protein, C1845 bacteria do not inhibit PHD activity but rather induce translational mechanisms. C1845 stimulation of HIF-1alpha required the binding of F1845 adhesin to the apical DAF/CD55 receptor. HIF-1alpha expression was inhibited by treating the cells with inhibitors of Src like tyrosine kinase, MAP kinase and phosphatidylinsositol 3-kinase signaling pathways. These inhibitors also blocked the C1845-induced phosphorylation of the translational regulatory protein p70 S6 kinase thus providing a mechanism for the modulation of HIF-1alpha protein synthesis. In addition to VEGF, C1845 bacteria induce the expression of BNIP3, a major regulator of autophagy. Autophagy is a process by which cytoplasmic organelles can be catabolized to provide macromolecules for energy generation under conditions of nutrient starvation. Conclusion: Thus we propose that C1845-induced HIF1alpha expression could promote the survival of human colon cancer cell.","publication_date":{"day":1,"month":7,"year":2008,"errors":{}},"publication_name":"Ejc Supplements","grobid_abstract_attachment_id":106864580},"translated_abstract":null,"internal_url":"https://www.academia.edu/108498837/A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment","translated_internal_url":"","created_at":"2023-10-23T06:01:46.789-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":106864580,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864580/thumbnails/1.jpg","file_name":"s1359-634928082971240-020231023-1-6tpq78.pdf","download_url":"https://www.academia.edu/attachments/106864580/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"A_crosstalk_between_HIF_1a_and_LOX_in_th.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864580/s1359-634928082971240-020231023-1-6tpq78-libre.pdf?1698067607=\u0026response-content-disposition=attachment%3B+filename%3DA_crosstalk_between_HIF_1a_and_LOX_in_th.pdf\u0026Expires=1733011076\u0026Signature=P4dX~hay5RpGnSokQ6h~aWuZzkRlM-WpzPEuTE8FsAWXvDgiy4hYRqP0aRn4T3qUw2Vo7~5qzo0033kcE8Xp2DE8kOXXrYO5bQrILHkk-lITFwwBbkQA50bOlZX5SlFndzTRIAm06EKoY4Osv9Br~MbTaScTRGXOHM1x0yHzT681bCCin1-lEGy1kT8CZo8ppCnizc~Fba4oxhM6AruuqGWk7OLRuk28cfjd4E5IzxdcwCjIgx7LNnDojG6rCkaQ2h5IQxrP8JGAhXvGemgkHuyvk~VPz2CLLr7muv~E822VJeZyQj0a0pS52ZG5zZ2vKqjkmQ-E6m337rcQQhODvw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment","translated_slug":"","page_count":1,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":106864580,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864580/thumbnails/1.jpg","file_name":"s1359-634928082971240-020231023-1-6tpq78.pdf","download_url":"https://www.academia.edu/attachments/106864580/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"A_crosstalk_between_HIF_1a_and_LOX_in_th.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864580/s1359-634928082971240-020231023-1-6tpq78-libre.pdf?1698067607=\u0026response-content-disposition=attachment%3B+filename%3DA_crosstalk_between_HIF_1a_and_LOX_in_th.pdf\u0026Expires=1733011076\u0026Signature=P4dX~hay5RpGnSokQ6h~aWuZzkRlM-WpzPEuTE8FsAWXvDgiy4hYRqP0aRn4T3qUw2Vo7~5qzo0033kcE8Xp2DE8kOXXrYO5bQrILHkk-lITFwwBbkQA50bOlZX5SlFndzTRIAm06EKoY4Osv9Br~MbTaScTRGXOHM1x0yHzT681bCCin1-lEGy1kT8CZo8ppCnizc~Fba4oxhM6AruuqGWk7OLRuk28cfjd4E5IzxdcwCjIgx7LNnDojG6rCkaQ2h5IQxrP8JGAhXvGemgkHuyvk~VPz2CLLr7muv~E822VJeZyQj0a0pS52ZG5zZ2vKqjkmQ-E6m337rcQQhODvw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":62710,"name":"Tumor microenvironment","url":"https://www.academia.edu/Documents/in/Tumor_microenvironment"},{"id":452367,"name":"Crosstalk","url":"https://www.academia.edu/Documents/in/Crosstalk"}],"urls":[{"id":34959156,"url":"https://doi.org/10.1016/s1359-6349(08)71240-0"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498836"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498836/Hypoxie_et_croissance_tumorale"><img alt="Research paper thumbnail of Hypoxie et croissance tumorale" class="work-thumbnail" src="https://attachments.academia-assets.com/106864579/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498836/Hypoxie_et_croissance_tumorale">Hypoxie et croissance tumorale</a></div><div class="wp-workCard_item"><span>Journal De Radiologie</span><span>, Sep 1, 2004</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="371284acbf7f22b43a4b0c3776e78538" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864579,"asset_id":108498836,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864579/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498836"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498836"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498836; 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Connaître la néo-angiogenèse tumorale. comprendre les liens entre hypoxie et angiogenèse. Connaître le principe des traitements anti-angiogéniques en cancérologie. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498832"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498832/531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression"><img alt="Research paper thumbnail of 531 Synergy between HIF1a and LOX is critical for tumour progression" class="work-thumbnail" src="https://attachments.academia-assets.com/106864576/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498832/531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression">531 Synergy between HIF1a and LOX is critical for tumour progression</a></div><div class="wp-workCard_item"><span>Ejc Supplements</span><span>, Jun 1, 2010</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="71b0de8139770373485ac592cafdbcb3" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864576,"asset_id":108498832,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864576/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498832"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498832"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498832; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498832]").text(description); $(".js-view-count[data-work-id=108498832]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498832; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498832']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 108498832, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "71b0de8139770373485ac592cafdbcb3" } } $('.js-work-strip[data-work-id=108498832]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498832,"title":"531 Synergy between HIF1a and LOX is critical for tumour progression","translated_title":"","metadata":{"publisher":"Elsevier BV","grobid_abstract":"UV as well as to chemotherapeutics. In the present study, we examined the role of Myh1 in cisplatin-treated lung carcinoma cells. Methods: A panel of small cell lung carcinoma (SCLC: H82, H69, U1285 and U1906) and non small cell lung carcinoma (NSCLC: A549, U1810, H23, H125 and H661) cell lines with different cisplatin sensitivity were analyzed for their basal level of Myh1 using western blotting. Myh1 localization and expression after cisplatin treatment in NSCLC cells was analyzed in cytosolic and nuclear fractions using western blotting, and was confirmed by immunofluorescence analysis. To assess the role of Myh1 in cisplatin-induced apoptotic signaling, siRNA to Myh1 was used and caspase-3 activity examined prior and post cisplatin treatment using flow cytometry. Results: Western blot analysis of Myh1 in the lung cancer cell line panel revealed heterogenous Myh1 expression. In the NSCLC cell line U1810, a relatively cisplatin resistant NSCLC, cisplatin treatment was found to cause an increase in Myh1 both in cytosol and nucleus. This was evident already at 30 min post cisplatin addition and still evident at 2h. Moreover, immunofluorescence analysis of Myh1 after cisplatin treatment of U1810 cells revealed relocalization of Myh1 into nuclear foci. Finally, siRNA to Myh1 was found to increase cisplatin-induced caspase-3 activity in NSCLC U1810 cells. Conclusion: Our data suggest that Myh1 is stabilized by cisplatin treatment in NSCLC cells and can act as a negative regulator of cisplatin-induced apoptotic signaling in this tumour type. 528 Sarcoma cell lines express stem-cell associated features","publication_date":{"day":1,"month":6,"year":2010,"errors":{}},"publication_name":"Ejc Supplements","grobid_abstract_attachment_id":106864576},"translated_abstract":null,"internal_url":"https://www.academia.edu/108498832/531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression","translated_internal_url":"","created_at":"2023-10-23T06:01:44.489-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":106864576,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864576/thumbnails/1.jpg","file_name":"s1359-634928102971332-x20231023-1-k9ceiu.pdf","download_url":"https://www.academia.edu/attachments/106864576/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"531_Synergy_between_HIF1a_and_LOX_is_cri.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864576/s1359-634928102971332-x20231023-1-k9ceiu-libre.pdf?1698067608=\u0026response-content-disposition=attachment%3B+filename%3D531_Synergy_between_HIF1a_and_LOX_is_cri.pdf\u0026Expires=1733011076\u0026Signature=GWasQqOJdjAiYzfUJfrfE0NZV0LNsugCmWUfKUapQpFKvGlT1u0Qh64rhNDd0JKuBJeeIvLPVCTGRSKNR0rfI7aRCzqndXzaLETwX6CtnFNVwSn1YNmTvXHaO-ufDZZHcHmKtjkszhRQrPHQ8Y3G4v1F5wPk-f~~mW8rImAozgrezXTNYNvE0kUNK1yabUiKsprGbce8th0z2xKflZvy3I0yI~lvmFnB3iwXDUu~sMlsyRimyPt6KvFubtUBm208LEtngnAR6g2QeLYkqM5j5GiHp5iATabmTsh6N5F0koNk4Zj2OpnZmgqK4k3cPuChyrwzeYFZVceWdyyfbK4sFA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression","translated_slug":"","page_count":2,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":106864576,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864576/thumbnails/1.jpg","file_name":"s1359-634928102971332-x20231023-1-k9ceiu.pdf","download_url":"https://www.academia.edu/attachments/106864576/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"531_Synergy_between_HIF1a_and_LOX_is_cri.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864576/s1359-634928102971332-x20231023-1-k9ceiu-libre.pdf?1698067608=\u0026response-content-disposition=attachment%3B+filename%3D531_Synergy_between_HIF1a_and_LOX_is_cri.pdf\u0026Expires=1733011076\u0026Signature=GWasQqOJdjAiYzfUJfrfE0NZV0LNsugCmWUfKUapQpFKvGlT1u0Qh64rhNDd0JKuBJeeIvLPVCTGRSKNR0rfI7aRCzqndXzaLETwX6CtnFNVwSn1YNmTvXHaO-ufDZZHcHmKtjkszhRQrPHQ8Y3G4v1F5wPk-f~~mW8rImAozgrezXTNYNvE0kUNK1yabUiKsprGbce8th0z2xKflZvy3I0yI~lvmFnB3iwXDUu~sMlsyRimyPt6KvFubtUBm208LEtngnAR6g2QeLYkqM5j5GiHp5iATabmTsh6N5F0koNk4Zj2OpnZmgqK4k3cPuChyrwzeYFZVceWdyyfbK4sFA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"}],"urls":[{"id":34959151,"url":"https://doi.org/10.1016/s1359-6349(10)71332-x"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498831"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498831/Hypoxia_Autophagy_and_Tumour_Metabolism"><img alt="Research paper thumbnail of Hypoxia, Autophagy and Tumour Metabolism" class="work-thumbnail" src="https://attachments.academia-assets.com/106864577/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498831/Hypoxia_Autophagy_and_Tumour_Metabolism">Hypoxia, Autophagy and Tumour Metabolism</a></div><div class="wp-workCard_item"><span>Ejc Supplements</span><span>, Jul 1, 2008</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5353ba6e1ea0cee925ded5cdf2571104" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864577,"asset_id":108498831,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864577/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498831"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498831"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498831; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5353ba6e1ea0cee925ded5cdf2571104" } } $('.js-work-strip[data-work-id=108498831]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498831,"title":"Hypoxia, Autophagy and Tumour Metabolism","translated_title":"","metadata":{"publisher":"Elsevier BV","grobid_abstract":"has long been recognized, progress in identifying susceptibility genes has been slow. To identify genetic factors that modify disease risk, we conducted a genome-wide association study of lung cancer. The initial phase constituted an analysis of 317,139 SNPs in 1,989 lung cancer cases and 2,625 controls from 6 central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (p=9x10-10). This locus was replicated in 5 separate lung cancer studies comprising an additional 2,518 lung cancer cases and 4,752 controls (p=5x10-20 overall), and it was found to account for 14% of lung cancer cases (Hung et al, Nature 2008). The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3, and CHRNB4). This effect has been identified in two other studies (Thorgeirsson et al, Nature 2008; Amos et al, Nat Gen 2008). The interpretations and implications of these results will be discussed. Finally, we have since extended our genome-wide study of lung cancer by including two further studies comprising an additional 750 cases and 800 controls. We subsequently replicated the top 31 independent findings in a further 4 studies comprising 3339 lung cancer cases and 6064 controls (total 5911 cases and 9416 controls). After pooling the genome-wide and replication phase results, two additional variants were strongly associated with lung cancer, suggesting new susceptibility loci.","publication_date":{"day":1,"month":7,"year":2008,"errors":{}},"publication_name":"Ejc Supplements","grobid_abstract_attachment_id":106864577},"translated_abstract":null,"internal_url":"https://www.academia.edu/108498831/Hypoxia_Autophagy_and_Tumour_Metabolism","translated_internal_url":"","created_at":"2023-10-23T06:01:44.240-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":106864577,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864577/thumbnails/1.jpg","file_name":"s1359-634928082971423-x20231023-1-1uwims.pdf","download_url":"https://www.academia.edu/attachments/106864577/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Hypoxia_Autophagy_and_Tumour_Metabolism.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864577/s1359-634928082971423-x20231023-1-1uwims-libre.pdf?1698067608=\u0026response-content-disposition=attachment%3B+filename%3DHypoxia_Autophagy_and_Tumour_Metabolism.pdf\u0026Expires=1733011076\u0026Signature=Z6YFk2uk5pcM9Pf9VcZP8g8digxKx4psKEwAI4mLhkWoXDIQRsBrn~QS2PVVQbJBVGzJtovIfxnFRie~t5yftV-NS2viW8qq5sQcEGzWbGpX1KfPOt0187E9ZDX4bzTKbQDXk2MADRvxZrrOfWRDAKxLufLfFa89d6KANy5toprFgmz2YFqwGkYkQh8n52imIbs-b45KcqzTsWOUTLAYQXLye-k3GUue~~-hPMZDOJXn8qxqSoWDDT2Od6VF7IRKYNXQ2VlrO-jltTXsj0HVC8XYRxHq3obe~dTG9koCqRvulMd~07D8a2dTAgzCla3YWXNo6gnhuA8QcKyCplvZQw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Hypoxia_Autophagy_and_Tumour_Metabolism","translated_slug":"","page_count":1,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":106864577,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864577/thumbnails/1.jpg","file_name":"s1359-634928082971423-x20231023-1-1uwims.pdf","download_url":"https://www.academia.edu/attachments/106864577/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Hypoxia_Autophagy_and_Tumour_Metabolism.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864577/s1359-634928082971423-x20231023-1-1uwims-libre.pdf?1698067608=\u0026response-content-disposition=attachment%3B+filename%3DHypoxia_Autophagy_and_Tumour_Metabolism.pdf\u0026Expires=1733011076\u0026Signature=Z6YFk2uk5pcM9Pf9VcZP8g8digxKx4psKEwAI4mLhkWoXDIQRsBrn~QS2PVVQbJBVGzJtovIfxnFRie~t5yftV-NS2viW8qq5sQcEGzWbGpX1KfPOt0187E9ZDX4bzTKbQDXk2MADRvxZrrOfWRDAKxLufLfFa89d6KANy5toprFgmz2YFqwGkYkQh8n52imIbs-b45KcqzTsWOUTLAYQXLye-k3GUue~~-hPMZDOJXn8qxqSoWDDT2Od6VF7IRKYNXQ2VlrO-jltTXsj0HVC8XYRxHq3obe~dTG9koCqRvulMd~07D8a2dTAgzCla3YWXNo6gnhuA8QcKyCplvZQw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":523,"name":"Chemistry","url":"https://www.academia.edu/Documents/in/Chemistry"},{"id":3770,"name":"Metabolism","url":"https://www.academia.edu/Documents/in/Metabolism"},{"id":17923,"name":"Autophagy","url":"https://www.academia.edu/Documents/in/Autophagy"},{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"}],"urls":[{"id":34959150,"url":"https://doi.org/10.1016/s1359-6349(08)71423-x"}]}, dispatcherData: dispatcherData }); 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However, the impact and origin of this pool of HIF-1a, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1a stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1a stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1a accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70 S6K phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O 2 levels, only slightly impacts upon the mTOR pathway under low cell density conditions. 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href="https://www.academia.edu/108498828/The_HIF_1_Inducible_Lysyl_Oxidase_Activates_HIF_1_via_the_Akt_Pathway_in_a_Positive_Regulation_Loop_and_Synergizes_with_HIF_1_in_Promoting_Tumor_Cell_Growth"><img alt="Research paper thumbnail of The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth" class="work-thumbnail" src="https://attachments.academia-assets.com/106864574/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498828/The_HIF_1_Inducible_Lysyl_Oxidase_Activates_HIF_1_via_the_Akt_Pathway_in_a_Positive_Regulation_Loop_and_Synergizes_with_HIF_1_in_Promoting_Tumor_Cell_Growth">The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth</a></div><div class="wp-workCard_item"><span>Cancer Research</span><span>, Mar 1, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="6108a1401fa5e9e704cb8ecd8169b685" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864574,"asset_id":108498828,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864574/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498828"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa 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$('.js-work-strip[data-work-id=108498828]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498828,"title":"The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth","translated_title":"","metadata":{"publisher":"American Association for Cancer Research","grobid_abstract":"Adaptation to hypoxia is a driving force for tumor progression that leads to therapy resistance and poor clinical outcome. Hypoxic responses are mainly mediated by hypoxia-inducible transcription factor-1 (HIF-1). One critical HIF-1 target mediating tumor progression is lysyl oxidase (LOX), which catalyzes cross-linking of collagens and elastin in the extracellular matrix, thereby regulating tissue tensile strength. Paradoxically, LOX has been reported to be both upregulated and downregulated in cancer cells, especially in colorectal cancer. Thus, we hypothesized that LOX might regulate expression of HIF-1 to create a self-timing regulatory circuit. Using human colorectal carcinoma cell lines in which HIF-1 and LOX expression could be modulated, we showed that LOX induction enhanced HIF-1 expression, whereas LOX silencing reduced it. Mechanistic investigations revealed that LOX activated the PI3K (phosphoinositide 3-kinase)-Akt signaling pathway, thereby upregulating HIF-1a protein synthesis in a manner requiring LOX-mediated hydrogen peroxide production. Consistent with these results, cancer cell proliferation was stimulated by secreted and active LOX in an HIF-1a-dependent fashion. Furthermore, nude mice xenograft assays established that HIF-1 potentiated LOX action on tumor growth in vivo. Taken together, these findings provide compelling evidence that LOX and HIF-1 act in synergy to foster tumor formation, and they suggest that HIF-1/LOX mutual regulation is a pivotal mechanism in the adaptation of tumor cells to hypoxia. Cancer Res; 71(5); 1647-57. Ó2011 AACR.","publication_date":{"day":1,"month":3,"year":2011,"errors":{}},"publication_name":"Cancer Research","grobid_abstract_attachment_id":106864574},"translated_abstract":null,"internal_url":"https://www.academia.edu/108498828/The_HIF_1_Inducible_Lysyl_Oxidase_Activates_HIF_1_via_the_Akt_Pathway_in_a_Positive_Regulation_Loop_and_Synergizes_with_HIF_1_in_Promoting_Tumor_Cell_Growth","translated_internal_url":"","created_at":"2023-10-23T06:01:43.501-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":106864574,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864574/thumbnails/1.jpg","file_name":"81ec417e5ef767513212c2a2fd8270c12945.pdf","download_url":"https://www.academia.edu/attachments/106864574/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"The_HIF_1_Inducible_Lysyl_Oxidase_Activa.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864574/81ec417e5ef767513212c2a2fd8270c12945-libre.pdf?1698067616=\u0026response-content-disposition=attachment%3B+filename%3DThe_HIF_1_Inducible_Lysyl_Oxidase_Activa.pdf\u0026Expires=1733011076\u0026Signature=SlfGzont-UYsdEjcDeIFT9QpjotOO4Kdja1FJM8Fyy1i8nmKHGRs2Xv~lKhsLmx3allrOrKuDNyqfRGDvCAZZ-PHJrkD8NvQGx7-cO6wqf2k89omh79r5xr~CMyGDwlBQLxnvsQldHPr~R-YunSq0dvTjxZOF1QymelIqyspxg6v~PraaP3rDcFnAiy7u78oTA7mtEsA8ZaHoTjmyC-bYhaOwVqBGkg8doC79UJ2G6QU-dKGWvfVtjdB8kyoUaFl7zCy-6IPR2rwZFVoKXVhQpnetQ4v9TTGtfpJfukVpz0LQ2nNca8EEKwvW9dGvCAEX9mISeO94X94zlVvdFxU7A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"The_HIF_1_Inducible_Lysyl_Oxidase_Activates_HIF_1_via_the_Akt_Pathway_in_a_Positive_Regulation_Loop_and_Synergizes_with_HIF_1_in_Promoting_Tumor_Cell_Growth","translated_slug":"","page_count":12,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":106864574,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864574/thumbnails/1.jpg","file_name":"81ec417e5ef767513212c2a2fd8270c12945.pdf","download_url":"https://www.academia.edu/attachments/106864574/download_file?st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"The_HIF_1_Inducible_Lysyl_Oxidase_Activa.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864574/81ec417e5ef767513212c2a2fd8270c12945-libre.pdf?1698067616=\u0026response-content-disposition=attachment%3B+filename%3DThe_HIF_1_Inducible_Lysyl_Oxidase_Activa.pdf\u0026Expires=1733011076\u0026Signature=SlfGzont-UYsdEjcDeIFT9QpjotOO4Kdja1FJM8Fyy1i8nmKHGRs2Xv~lKhsLmx3allrOrKuDNyqfRGDvCAZZ-PHJrkD8NvQGx7-cO6wqf2k89omh79r5xr~CMyGDwlBQLxnvsQldHPr~R-YunSq0dvTjxZOF1QymelIqyspxg6v~PraaP3rDcFnAiy7u78oTA7mtEsA8ZaHoTjmyC-bYhaOwVqBGkg8doC79UJ2G6QU-dKGWvfVtjdB8kyoUaFl7zCy-6IPR2rwZFVoKXVhQpnetQ4v9TTGtfpJfukVpz0LQ2nNca8EEKwvW9dGvCAEX9mISeO94X94zlVvdFxU7A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":6021,"name":"Cancer","url":"https://www.academia.edu/Documents/in/Cancer"},{"id":7710,"name":"Biology","url":"https://www.academia.edu/Documents/in/Biology"},{"id":12071,"name":"Immunohistochemistry","url":"https://www.academia.edu/Documents/in/Immunohistochemistry"},{"id":22255,"name":"Cancer Research","url":"https://www.academia.edu/Documents/in/Cancer_Research"},{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction"},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice"},{"id":295271,"name":"Protein kinase B","url":"https://www.academia.edu/Documents/in/Protein_kinase_B"},{"id":782251,"name":"Cell Proliferation","url":"https://www.academia.edu/Documents/in/Cell_Proliferation"},{"id":1579513,"name":"Tumor Progression","url":"https://www.academia.edu/Documents/in/Tumor_Progression"},{"id":1810445,"name":"Gene expression profiling","url":"https://www.academia.edu/Documents/in/Gene_expression_profiling"},{"id":1954130,"name":"Cell Growth","url":"https://www.academia.edu/Documents/in/Cell_Growth"},{"id":2044562,"name":"lysyl oxidase ","url":"https://www.academia.edu/Documents/in/lysyl_oxidase"},{"id":2440562,"name":"Colorectal Neoplasms","url":"https://www.academia.edu/Documents/in/Colorectal_Neoplasms"},{"id":3067128,"name":"reverse transcriptase polymerase chain reaction","url":"https://www.academia.edu/Documents/in/reverse_transcriptase_polymerase_chain_reaction"}],"urls":[{"id":34959147,"url":"https://aacrjournals.org/cancerres/article-pdf/71/5/1647/2664483/1647.pdf"}]}, dispatcherData: dispatcherData }); 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As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1A subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1A possesses two transcriptional activation domains [TAD; NH 2-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1A that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygensensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO 2 .","publication_date":{"day":1,"month":4,"year":2006,"errors":{}},"publication_name":"Cancer 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data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498826/Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting"><img alt="Research paper thumbnail of Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498826/Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting">Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting</a></div><div class="wp-workCard_item"><span>Therapeutic Drug Monitoring</span><span>, Oct 1, 2022</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, ...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. Results: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. Conclusions: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498826"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498826"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498826; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498826]").text(description); $(".js-view-count[data-work-id=108498826]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498826; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498826']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 108498826, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=108498826]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498826,"title":"Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting","translated_title":"","metadata":{"abstract":"Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. Results: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. Conclusions: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.","publisher":"Lippincott Williams \u0026 Wilkins","publication_date":{"day":1,"month":10,"year":2022,"errors":{}},"publication_name":"Therapeutic Drug Monitoring"},"translated_abstract":"Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. Results: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. Conclusions: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.","internal_url":"https://www.academia.edu/108498826/Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting","translated_internal_url":"","created_at":"2023-10-23T06:01:42.952-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[],"slug":"Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting","translated_slug":"","page_count":null,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[],"research_interests":[{"id":524,"name":"Analytical Chemistry","url":"https://www.academia.edu/Documents/in/Analytical_Chemistry"},{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":47953,"name":"Predictability","url":"https://www.academia.edu/Documents/in/Predictability"},{"id":58380,"name":"Therapeutic drug monitoring","url":"https://www.academia.edu/Documents/in/Therapeutic_drug_monitoring"},{"id":64336,"name":"Population","url":"https://www.academia.edu/Documents/in/Population"},{"id":1032783,"name":"Bayesian Probability","url":"https://www.academia.edu/Documents/in/Bayesian_Probability"},{"id":1322524,"name":"Clozapine","url":"https://www.academia.edu/Documents/in/Clozapine"},{"id":2618916,"name":"Dosing","url":"https://www.academia.edu/Documents/in/Dosing"},{"id":3789884,"name":"Pharmacology and pharmaceutical sciences","url":"https://www.academia.edu/Documents/in/Pharmacology_and_pharmaceutical_sciences"}],"urls":[{"id":34959145,"url":"https://doi.org/10.1097/ftd.0000000000000987"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498825"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498825/HIF_1_master_and_commander_of_the_hypoxic_world"><img alt="Research paper thumbnail of HIF-1: master and commander of the hypoxic world" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498825/HIF_1_master_and_commander_of_the_hypoxic_world">HIF-1: master and commander of the hypoxic world</a></div><div class="wp-workCard_item"><span>Biochemical Pharmacology</span><span>, Sep 1, 2004</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O2 concentrations.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498825"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498825"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498825; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498825]").text(description); $(".js-view-count[data-work-id=108498825]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498825; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498825']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 108498825, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=108498825]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498825,"title":"HIF-1: master and commander of the hypoxic world","translated_title":"","metadata":{"abstract":"The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O2 concentrations.","publisher":"Elsevier BV","publication_date":{"day":1,"month":9,"year":2004,"errors":{}},"publication_name":"Biochemical Pharmacology"},"translated_abstract":"The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. 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data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/87613681/The_Asparaginyl_Hydroxylase_Factor_Inhibiting_HIF_1%CE%B1_Is_an_Essential_Regulator_of_Metabolism"><img alt="Research paper thumbnail of The Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential Regulator of Metabolism" class="work-thumbnail" src="https://attachments.academia-assets.com/91774994/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/87613681/The_Asparaginyl_Hydroxylase_Factor_Inhibiting_HIF_1%CE%B1_Is_an_Essential_Regulator_of_Metabolism">The Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential Regulator of Metabolism</a></div><div class="wp-workCard_item"><span>Cell Metabolism</span><span>, 2010</span></div><div class="wp-workCard_item 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Hydroxylation of HIF-α proteins by FIH blocks association of HIFs with the transcriptional co-activators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene, and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, improved glucose and lipid homeostasis, and are resistant to high fat diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, enhanced insulin sensitivity, and are also protected against high fat diet-induced weight gain. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="80530138"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/80530138/Activation_of_HIF_1%CE%B1_in_exponentially_growing_cells_via_hypoxic_stimulation_is_independent_of_the_Akt_mTOR_pathway"><img alt="Research paper thumbnail of Activation of HIF-1α in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway" class="work-thumbnail" src="https://attachments.academia-assets.com/86881093/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/80530138/Activation_of_HIF_1%CE%B1_in_exponentially_growing_cells_via_hypoxic_stimulation_is_independent_of_the_Akt_mTOR_pathway">Activation of HIF-1α in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway</a></div><div class="wp-workCard_item"><span>Journal of Cellular Physiology</span><span>, 2009</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="7fb5e2fd8f825cd8b63b9bf7851ce1e7" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":86881093,"asset_id":80530138,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/86881093/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="80530138"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="80530138"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 80530138; 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However, the impact and origin of this pool of HIF-1a, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1a stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1a stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1a accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70 S6K phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O 2 levels, only slightly impacts upon the mTOR pathway under low cell density conditions. Thus, activation of HIF-1a in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway whereas HIF-1a activation obtained in high confluency is totally dependent on mTOR pathway as rapamycin totally impaired (i) HIF-1a stabilization and (ii) mRNA levels of CA9 and BNIP3, two HIF-target genes.","publication_date":{"day":null,"month":null,"year":2009,"errors":{}},"publication_name":"Journal of Cellular Physiology","grobid_abstract_attachment_id":86881093},"translated_abstract":null,"internal_url":"https://www.academia.edu/80530138/Activation_of_HIF_1%CE%B1_in_exponentially_growing_cells_via_hypoxic_stimulation_is_independent_of_the_Akt_mTOR_pathway","translated_internal_url":"","created_at":"2022-06-02T05:38:38.727-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":86881093,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/86881093/thumbnails/1.jpg","file_name":"jcp.2158420220602-1-1u5dx11.pdf","download_url":"https://www.academia.edu/attachments/86881093/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Activation_of_HIF_1_in_exponentially_gr.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/86881093/jcp.2158420220602-1-1u5dx11-libre.pdf?1654174521=\u0026response-content-disposition=attachment%3B+filename%3DActivation_of_HIF_1_in_exponentially_gr.pdf\u0026Expires=1733011077\u0026Signature=IWsvG-rdXZc-cEKZ8zDsAJGDtUQZwq6fUiHfiwoizkSIylIoYywf26cQ~JHH5vl6RGe70tryAIyFCOmC~jdUsNJkYpEfGgOyk3fWVU4g2b00Fe4y3tRC4RVDbsxQO~8XUsqR63DKWYE7s1oB0R5Kz0J2gS3vAg4wniLv75SZ962JjinWrzu0B64hhlVXWM5ilYVRWIwj7ismC2Lxe6pZ5R5fZd6-NiIufMSp6TYEebaoJBKxzCAaOyepaAR2PI2i-qmkrilvB4l1dUf2AYUGydQszFv7S0WzEPr6AFNzGMLHV6lNHQfdGyZdaetCkV7x8ydEwnq2qz0hjGGJz2~SSQ__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Activation_of_HIF_1α_in_exponentially_growing_cells_via_hypoxic_stimulation_is_independent_of_the_Akt_mTOR_pathway","translated_slug":"","page_count":8,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":86881093,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/86881093/thumbnails/1.jpg","file_name":"jcp.2158420220602-1-1u5dx11.pdf","download_url":"https://www.academia.edu/attachments/86881093/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Activation_of_HIF_1_in_exponentially_gr.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/86881093/jcp.2158420220602-1-1u5dx11-libre.pdf?1654174521=\u0026response-content-disposition=attachment%3B+filename%3DActivation_of_HIF_1_in_exponentially_gr.pdf\u0026Expires=1733011077\u0026Signature=IWsvG-rdXZc-cEKZ8zDsAJGDtUQZwq6fUiHfiwoizkSIylIoYywf26cQ~JHH5vl6RGe70tryAIyFCOmC~jdUsNJkYpEfGgOyk3fWVU4g2b00Fe4y3tRC4RVDbsxQO~8XUsqR63DKWYE7s1oB0R5Kz0J2gS3vAg4wniLv75SZ962JjinWrzu0B64hhlVXWM5ilYVRWIwj7ismC2Lxe6pZ5R5fZd6-NiIufMSp6TYEebaoJBKxzCAaOyepaAR2PI2i-qmkrilvB4l1dUf2AYUGydQszFv7S0WzEPr6AFNzGMLHV6lNHQfdGyZdaetCkV7x8ydEwnq2qz0hjGGJz2~SSQ__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":13827,"name":"Cell Biology","url":"https://www.academia.edu/Documents/in/Cell_Biology"},{"id":51121,"name":"RNA interference","url":"https://www.academia.edu/Documents/in/RNA_interference"},{"id":57808,"name":"Cell line","url":"https://www.academia.edu/Documents/in/Cell_line"},{"id":60915,"name":"Cellular","url":"https://www.academia.edu/Documents/in/Cellular"},{"id":69424,"name":"Protein Kinases","url":"https://www.academia.edu/Documents/in/Protein_Kinases"},{"id":177688,"name":"Cellular Physiology","url":"https://www.academia.edu/Documents/in/Cellular_Physiology"},{"id":186234,"name":"Medical Physiology","url":"https://www.academia.edu/Documents/in/Medical_Physiology"},{"id":295271,"name":"Protein kinase B","url":"https://www.academia.edu/Documents/in/Protein_kinase_B"},{"id":422325,"name":"HeLa cells","url":"https://www.academia.edu/Documents/in/HeLa_cells"},{"id":782251,"name":"Cell Proliferation","url":"https://www.academia.edu/Documents/in/Cell_Proliferation"},{"id":1150115,"name":"Sirolimus","url":"https://www.academia.edu/Documents/in/Sirolimus"},{"id":1193624,"name":"Oxygen Consumption","url":"https://www.academia.edu/Documents/in/Oxygen_Consumption"},{"id":2796077,"name":"Cell count","url":"https://www.academia.edu/Documents/in/Cell_count"},{"id":3214915,"name":"Cricetinae","url":"https://www.academia.edu/Documents/in/Cricetinae"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> </div><div class="profile--tab_content_container js-tab-pane tab-pane" data-section-id="12858751" id="papers"><div class="js-work-strip profile--work_container" data-work-id="108498837"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498837/A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment"><img alt="Research paper thumbnail of A crosstalk between HIF-1a and LOX in the tumor microenvironment" class="work-thumbnail" src="https://attachments.academia-assets.com/106864580/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498837/A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment">A crosstalk between HIF-1a and LOX in the tumor microenvironment</a></div><div class="wp-workCard_item"><span>Ejc Supplements</span><span>, Jul 1, 2008</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="e8d80541371afc72c98fe43ebe7adcec" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864580,"asset_id":108498837,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864580/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498837"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498837"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498837; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498837]").text(description); $(".js-view-count[data-work-id=108498837]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498837; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498837']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 108498837, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); 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Transfection of siRNA against HIF-1alpha was done to demonstrate its transcriptional activity. A pull down assay using as bait the oxygen binding domain of HIF-1 was used to assay PHD activity. Results: Here, we demonstrate that exposure of T84 colon cancer cells to C1845 bacteria induces the expression of HIF-1, a key transcription factor involved in VEGF expression. In contrast to hypoxia which inhibits the activity of prolyl hydroxylases (PHD) and as a consequence stabilizes HIF-1alpha protein, C1845 bacteria do not inhibit PHD activity but rather induce translational mechanisms. C1845 stimulation of HIF-1alpha required the binding of F1845 adhesin to the apical DAF/CD55 receptor. HIF-1alpha expression was inhibited by treating the cells with inhibitors of Src like tyrosine kinase, MAP kinase and phosphatidylinsositol 3-kinase signaling pathways. These inhibitors also blocked the C1845-induced phosphorylation of the translational regulatory protein p70 S6 kinase thus providing a mechanism for the modulation of HIF-1alpha protein synthesis. In addition to VEGF, C1845 bacteria induce the expression of BNIP3, a major regulator of autophagy. Autophagy is a process by which cytoplasmic organelles can be catabolized to provide macromolecules for energy generation under conditions of nutrient starvation. Conclusion: Thus we propose that C1845-induced HIF1alpha expression could promote the survival of human colon cancer cell.","publication_date":{"day":1,"month":7,"year":2008,"errors":{}},"publication_name":"Ejc Supplements","grobid_abstract_attachment_id":106864580},"translated_abstract":null,"internal_url":"https://www.academia.edu/108498837/A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment","translated_internal_url":"","created_at":"2023-10-23T06:01:46.789-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":106864580,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864580/thumbnails/1.jpg","file_name":"s1359-634928082971240-020231023-1-6tpq78.pdf","download_url":"https://www.academia.edu/attachments/106864580/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"A_crosstalk_between_HIF_1a_and_LOX_in_th.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864580/s1359-634928082971240-020231023-1-6tpq78-libre.pdf?1698067607=\u0026response-content-disposition=attachment%3B+filename%3DA_crosstalk_between_HIF_1a_and_LOX_in_th.pdf\u0026Expires=1733011076\u0026Signature=P4dX~hay5RpGnSokQ6h~aWuZzkRlM-WpzPEuTE8FsAWXvDgiy4hYRqP0aRn4T3qUw2Vo7~5qzo0033kcE8Xp2DE8kOXXrYO5bQrILHkk-lITFwwBbkQA50bOlZX5SlFndzTRIAm06EKoY4Osv9Br~MbTaScTRGXOHM1x0yHzT681bCCin1-lEGy1kT8CZo8ppCnizc~Fba4oxhM6AruuqGWk7OLRuk28cfjd4E5IzxdcwCjIgx7LNnDojG6rCkaQ2h5IQxrP8JGAhXvGemgkHuyvk~VPz2CLLr7muv~E822VJeZyQj0a0pS52ZG5zZ2vKqjkmQ-E6m337rcQQhODvw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"A_crosstalk_between_HIF_1a_and_LOX_in_the_tumor_microenvironment","translated_slug":"","page_count":1,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":106864580,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864580/thumbnails/1.jpg","file_name":"s1359-634928082971240-020231023-1-6tpq78.pdf","download_url":"https://www.academia.edu/attachments/106864580/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"A_crosstalk_between_HIF_1a_and_LOX_in_th.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864580/s1359-634928082971240-020231023-1-6tpq78-libre.pdf?1698067607=\u0026response-content-disposition=attachment%3B+filename%3DA_crosstalk_between_HIF_1a_and_LOX_in_th.pdf\u0026Expires=1733011076\u0026Signature=P4dX~hay5RpGnSokQ6h~aWuZzkRlM-WpzPEuTE8FsAWXvDgiy4hYRqP0aRn4T3qUw2Vo7~5qzo0033kcE8Xp2DE8kOXXrYO5bQrILHkk-lITFwwBbkQA50bOlZX5SlFndzTRIAm06EKoY4Osv9Br~MbTaScTRGXOHM1x0yHzT681bCCin1-lEGy1kT8CZo8ppCnizc~Fba4oxhM6AruuqGWk7OLRuk28cfjd4E5IzxdcwCjIgx7LNnDojG6rCkaQ2h5IQxrP8JGAhXvGemgkHuyvk~VPz2CLLr7muv~E822VJeZyQj0a0pS52ZG5zZ2vKqjkmQ-E6m337rcQQhODvw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":62710,"name":"Tumor microenvironment","url":"https://www.academia.edu/Documents/in/Tumor_microenvironment"},{"id":452367,"name":"Crosstalk","url":"https://www.academia.edu/Documents/in/Crosstalk"}],"urls":[{"id":34959156,"url":"https://doi.org/10.1016/s1359-6349(08)71240-0"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498836"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498836/Hypoxie_et_croissance_tumorale"><img alt="Research paper thumbnail of Hypoxie et croissance tumorale" class="work-thumbnail" src="https://attachments.academia-assets.com/106864579/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498836/Hypoxie_et_croissance_tumorale">Hypoxie et croissance tumorale</a></div><div class="wp-workCard_item"><span>Journal De Radiologie</span><span>, Sep 1, 2004</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="371284acbf7f22b43a4b0c3776e78538" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864579,"asset_id":108498836,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864579/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498836"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498836"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498836; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "371284acbf7f22b43a4b0c3776e78538" } } $('.js-work-strip[data-work-id=108498836]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498836,"title":"Hypoxie et croissance tumorale","translated_title":"","metadata":{"publisher":"Elsevier BV","grobid_abstract":"lundi 4 octobre Séances scientifiques et thématiques Angiogenèse tumorale et imagerie Séance organisée par l'Interface Imagerie-Biologie Responsable : Charles-André Cuenod l \" Objectifs pédagogiques Appréhender les évolutions technologiques à court ou moyen terme et mesurer leur impact pratique, organisationnel et économique. Connaître la néo-angiogenèse tumorale. comprendre les liens entre hypoxie et angiogenèse. Connaître le principe des traitements anti-angiogéniques en cancérologie. 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href="https://www.academia.edu/108498833/Hypoxia_Inducible_Carbonic_Anhydrase_IX_and_XII_Promote_Tumor_Cell_Growth_by_Counteracting_Acidosis_through_the_Regulation_of_the_Intracellular_pH"><img alt="Research paper thumbnail of Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH" class="work-thumbnail" src="https://attachments.academia-assets.com/106864557/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498833/Hypoxia_Inducible_Carbonic_Anhydrase_IX_and_XII_Promote_Tumor_Cell_Growth_by_Counteracting_Acidosis_through_the_Regulation_of_the_Intracellular_pH">Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH</a></div><div class="wp-workCard_item"><span>Cancer Research</span><span>, Dec 31, 2008</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="1ed319135c03f79d4c870d80a2c8f326" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864557,"asset_id":108498833,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864557/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498833"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498832"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498832/531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression"><img alt="Research paper thumbnail of 531 Synergy between HIF1a and LOX is critical for tumour progression" class="work-thumbnail" src="https://attachments.academia-assets.com/106864576/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498832/531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression">531 Synergy between HIF1a and LOX is critical for tumour progression</a></div><div class="wp-workCard_item"><span>Ejc Supplements</span><span>, Jun 1, 2010</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="71b0de8139770373485ac592cafdbcb3" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864576,"asset_id":108498832,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864576/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498832"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498832"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498832; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498832]").text(description); $(".js-view-count[data-work-id=108498832]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498832; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498832']"); 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$('.js-work-strip[data-work-id=108498832]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498832,"title":"531 Synergy between HIF1a and LOX is critical for tumour progression","translated_title":"","metadata":{"publisher":"Elsevier BV","grobid_abstract":"UV as well as to chemotherapeutics. In the present study, we examined the role of Myh1 in cisplatin-treated lung carcinoma cells. Methods: A panel of small cell lung carcinoma (SCLC: H82, H69, U1285 and U1906) and non small cell lung carcinoma (NSCLC: A549, U1810, H23, H125 and H661) cell lines with different cisplatin sensitivity were analyzed for their basal level of Myh1 using western blotting. Myh1 localization and expression after cisplatin treatment in NSCLC cells was analyzed in cytosolic and nuclear fractions using western blotting, and was confirmed by immunofluorescence analysis. To assess the role of Myh1 in cisplatin-induced apoptotic signaling, siRNA to Myh1 was used and caspase-3 activity examined prior and post cisplatin treatment using flow cytometry. Results: Western blot analysis of Myh1 in the lung cancer cell line panel revealed heterogenous Myh1 expression. In the NSCLC cell line U1810, a relatively cisplatin resistant NSCLC, cisplatin treatment was found to cause an increase in Myh1 both in cytosol and nucleus. This was evident already at 30 min post cisplatin addition and still evident at 2h. Moreover, immunofluorescence analysis of Myh1 after cisplatin treatment of U1810 cells revealed relocalization of Myh1 into nuclear foci. Finally, siRNA to Myh1 was found to increase cisplatin-induced caspase-3 activity in NSCLC U1810 cells. Conclusion: Our data suggest that Myh1 is stabilized by cisplatin treatment in NSCLC cells and can act as a negative regulator of cisplatin-induced apoptotic signaling in this tumour type. 528 Sarcoma cell lines express stem-cell associated features","publication_date":{"day":1,"month":6,"year":2010,"errors":{}},"publication_name":"Ejc Supplements","grobid_abstract_attachment_id":106864576},"translated_abstract":null,"internal_url":"https://www.academia.edu/108498832/531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression","translated_internal_url":"","created_at":"2023-10-23T06:01:44.489-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":106864576,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864576/thumbnails/1.jpg","file_name":"s1359-634928102971332-x20231023-1-k9ceiu.pdf","download_url":"https://www.academia.edu/attachments/106864576/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"531_Synergy_between_HIF1a_and_LOX_is_cri.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864576/s1359-634928102971332-x20231023-1-k9ceiu-libre.pdf?1698067608=\u0026response-content-disposition=attachment%3B+filename%3D531_Synergy_between_HIF1a_and_LOX_is_cri.pdf\u0026Expires=1733011076\u0026Signature=GWasQqOJdjAiYzfUJfrfE0NZV0LNsugCmWUfKUapQpFKvGlT1u0Qh64rhNDd0JKuBJeeIvLPVCTGRSKNR0rfI7aRCzqndXzaLETwX6CtnFNVwSn1YNmTvXHaO-ufDZZHcHmKtjkszhRQrPHQ8Y3G4v1F5wPk-f~~mW8rImAozgrezXTNYNvE0kUNK1yabUiKsprGbce8th0z2xKflZvy3I0yI~lvmFnB3iwXDUu~sMlsyRimyPt6KvFubtUBm208LEtngnAR6g2QeLYkqM5j5GiHp5iATabmTsh6N5F0koNk4Zj2OpnZmgqK4k3cPuChyrwzeYFZVceWdyyfbK4sFA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"531_Synergy_between_HIF1a_and_LOX_is_critical_for_tumour_progression","translated_slug":"","page_count":2,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":106864576,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/106864576/thumbnails/1.jpg","file_name":"s1359-634928102971332-x20231023-1-k9ceiu.pdf","download_url":"https://www.academia.edu/attachments/106864576/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"531_Synergy_between_HIF1a_and_LOX_is_cri.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/106864576/s1359-634928102971332-x20231023-1-k9ceiu-libre.pdf?1698067608=\u0026response-content-disposition=attachment%3B+filename%3D531_Synergy_between_HIF1a_and_LOX_is_cri.pdf\u0026Expires=1733011076\u0026Signature=GWasQqOJdjAiYzfUJfrfE0NZV0LNsugCmWUfKUapQpFKvGlT1u0Qh64rhNDd0JKuBJeeIvLPVCTGRSKNR0rfI7aRCzqndXzaLETwX6CtnFNVwSn1YNmTvXHaO-ufDZZHcHmKtjkszhRQrPHQ8Y3G4v1F5wPk-f~~mW8rImAozgrezXTNYNvE0kUNK1yabUiKsprGbce8th0z2xKflZvy3I0yI~lvmFnB3iwXDUu~sMlsyRimyPt6KvFubtUBm208LEtngnAR6g2QeLYkqM5j5GiHp5iATabmTsh6N5F0koNk4Zj2OpnZmgqK4k3cPuChyrwzeYFZVceWdyyfbK4sFA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"}],"urls":[{"id":34959151,"url":"https://doi.org/10.1016/s1359-6349(10)71332-x"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498831"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498831/Hypoxia_Autophagy_and_Tumour_Metabolism"><img alt="Research paper thumbnail of Hypoxia, Autophagy and Tumour Metabolism" class="work-thumbnail" src="https://attachments.academia-assets.com/106864577/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498831/Hypoxia_Autophagy_and_Tumour_Metabolism">Hypoxia, Autophagy and Tumour Metabolism</a></div><div class="wp-workCard_item"><span>Ejc Supplements</span><span>, Jul 1, 2008</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5353ba6e1ea0cee925ded5cdf2571104" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864577,"asset_id":108498831,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864577/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498831"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498831"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498831; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5353ba6e1ea0cee925ded5cdf2571104" } } $('.js-work-strip[data-work-id=108498831]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498831,"title":"Hypoxia, Autophagy and Tumour Metabolism","translated_title":"","metadata":{"publisher":"Elsevier BV","grobid_abstract":"has long been recognized, progress in identifying susceptibility genes has been slow. To identify genetic factors that modify disease risk, we conducted a genome-wide association study of lung cancer. The initial phase constituted an analysis of 317,139 SNPs in 1,989 lung cancer cases and 2,625 controls from 6 central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (p=9x10-10). This locus was replicated in 5 separate lung cancer studies comprising an additional 2,518 lung cancer cases and 4,752 controls (p=5x10-20 overall), and it was found to account for 14% of lung cancer cases (Hung et al, Nature 2008). The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3, and CHRNB4). This effect has been identified in two other studies (Thorgeirsson et al, Nature 2008; Amos et al, Nat Gen 2008). The interpretations and implications of these results will be discussed. Finally, we have since extended our genome-wide study of lung cancer by including two further studies comprising an additional 750 cases and 800 controls. We subsequently replicated the top 31 independent findings in a further 4 studies comprising 3339 lung cancer cases and 6064 controls (total 5911 cases and 9416 controls). 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However, the impact and origin of this pool of HIF-1a, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1a stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1a stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1a accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70 S6K phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O 2 levels, only slightly impacts upon the mTOR pathway under low cell density conditions. 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href="https://www.academia.edu/108498828/The_HIF_1_Inducible_Lysyl_Oxidase_Activates_HIF_1_via_the_Akt_Pathway_in_a_Positive_Regulation_Loop_and_Synergizes_with_HIF_1_in_Promoting_Tumor_Cell_Growth"><img alt="Research paper thumbnail of The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth" class="work-thumbnail" src="https://attachments.academia-assets.com/106864574/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498828/The_HIF_1_Inducible_Lysyl_Oxidase_Activates_HIF_1_via_the_Akt_Pathway_in_a_Positive_Regulation_Loop_and_Synergizes_with_HIF_1_in_Promoting_Tumor_Cell_Growth">The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth</a></div><div class="wp-workCard_item"><span>Cancer Research</span><span>, Mar 1, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="6108a1401fa5e9e704cb8ecd8169b685" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864574,"asset_id":108498828,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864574/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498828"><a class="js-profile-work-strip-edit-button" 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$('.js-work-strip[data-work-id=108498828]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498828,"title":"The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth","translated_title":"","metadata":{"publisher":"American Association for Cancer Research","grobid_abstract":"Adaptation to hypoxia is a driving force for tumor progression that leads to therapy resistance and poor clinical outcome. Hypoxic responses are mainly mediated by hypoxia-inducible transcription factor-1 (HIF-1). One critical HIF-1 target mediating tumor progression is lysyl oxidase (LOX), which catalyzes cross-linking of collagens and elastin in the extracellular matrix, thereby regulating tissue tensile strength. Paradoxically, LOX has been reported to be both upregulated and downregulated in cancer cells, especially in colorectal cancer. Thus, we hypothesized that LOX might regulate expression of HIF-1 to create a self-timing regulatory circuit. Using human colorectal carcinoma cell lines in which HIF-1 and LOX expression could be modulated, we showed that LOX induction enhanced HIF-1 expression, whereas LOX silencing reduced it. Mechanistic investigations revealed that LOX activated the PI3K (phosphoinositide 3-kinase)-Akt signaling pathway, thereby upregulating HIF-1a protein synthesis in a manner requiring LOX-mediated hydrogen peroxide production. Consistent with these results, cancer cell proliferation was stimulated by secreted and active LOX in an HIF-1a-dependent fashion. Furthermore, nude mice xenograft assays established that HIF-1 potentiated LOX action on tumor growth in vivo. Taken together, these findings provide compelling evidence that LOX and HIF-1 act in synergy to foster tumor formation, and they suggest that HIF-1/LOX mutual regulation is a pivotal mechanism in the adaptation of tumor cells to hypoxia. Cancer Res; 71(5); 1647-57. Ó2011 AACR.","publication_date":{"day":1,"month":3,"year":2011,"errors":{}},"publication_name":"Cancer 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Research","url":"https://www.academia.edu/Documents/in/Cancer_Research"},{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction"},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice"},{"id":295271,"name":"Protein kinase B","url":"https://www.academia.edu/Documents/in/Protein_kinase_B"},{"id":782251,"name":"Cell Proliferation","url":"https://www.academia.edu/Documents/in/Cell_Proliferation"},{"id":1579513,"name":"Tumor Progression","url":"https://www.academia.edu/Documents/in/Tumor_Progression"},{"id":1810445,"name":"Gene expression profiling","url":"https://www.academia.edu/Documents/in/Gene_expression_profiling"},{"id":1954130,"name":"Cell Growth","url":"https://www.academia.edu/Documents/in/Cell_Growth"},{"id":2044562,"name":"lysyl oxidase ","url":"https://www.academia.edu/Documents/in/lysyl_oxidase"},{"id":2440562,"name":"Colorectal Neoplasms","url":"https://www.academia.edu/Documents/in/Colorectal_Neoplasms"},{"id":3067128,"name":"reverse transcriptase polymerase chain reaction","url":"https://www.academia.edu/Documents/in/reverse_transcriptase_polymerase_chain_reaction"}],"urls":[{"id":34959147,"url":"https://aacrjournals.org/cancerres/article-pdf/71/5/1647/2664483/1647.pdf"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498827"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498827/The_Oxygen_Sensor_Factor_Inhibiting_Hypoxia_Inducible_Factor_1_Controls_Expression_of_Distinct_Genes_through_the_Bifunctional_Transcriptional_Character_of_Hypoxia_Inducible_Factor_1%CE%B1"><img alt="Research paper thumbnail of The Oxygen Sensor Factor-Inhibiting Hypoxia-Inducible Factor-1 Controls Expression of Distinct Genes through the Bifunctional Transcriptional Character of Hypoxia-Inducible Factor-1α" class="work-thumbnail" src="https://attachments.academia-assets.com/106864555/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498827/The_Oxygen_Sensor_Factor_Inhibiting_Hypoxia_Inducible_Factor_1_Controls_Expression_of_Distinct_Genes_through_the_Bifunctional_Transcriptional_Character_of_Hypoxia_Inducible_Factor_1%CE%B1">The Oxygen Sensor Factor-Inhibiting Hypoxia-Inducible Factor-1 Controls Expression of Distinct Genes through the Bifunctional Transcriptional Character of Hypoxia-Inducible Factor-1α</a></div><div class="wp-workCard_item"><span>Cancer Research</span><span>, Apr 1, 2006</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="30c98d7ec9e895784084cb5e8f69d1c9" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":106864555,"asset_id":108498827,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/106864555/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Niw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper 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As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1A subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1A possesses two transcriptional activation domains [TAD; NH 2-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1A that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygensensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO 2 .","publication_date":{"day":1,"month":4,"year":2006,"errors":{}},"publication_name":"Cancer 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data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498826/Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting"><img alt="Research paper thumbnail of Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498826/Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting">Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting</a></div><div class="wp-workCard_item"><span>Therapeutic Drug Monitoring</span><span>, Oct 1, 2022</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, ...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. Results: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. Conclusions: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498826"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498826"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498826; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498826]").text(description); $(".js-view-count[data-work-id=108498826]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498826; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498826']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 108498826, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=108498826]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498826,"title":"Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting","translated_title":"","metadata":{"abstract":"Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. Results: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. Conclusions: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.","publisher":"Lippincott Williams \u0026 Wilkins","publication_date":{"day":1,"month":10,"year":2022,"errors":{}},"publication_name":"Therapeutic Drug Monitoring"},"translated_abstract":"Background: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. Methods: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. Results: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. Conclusions: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.","internal_url":"https://www.academia.edu/108498826/Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting","translated_internal_url":"","created_at":"2023-10-23T06:01:42.952-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[],"slug":"Towards_Precision_Dosing_of_Clozapine_in_Schizophrenia_External_Evaluation_of_Population_Pharmacokinetic_Models_and_Bayesian_Forecasting","translated_slug":"","page_count":null,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[],"research_interests":[{"id":524,"name":"Analytical Chemistry","url":"https://www.academia.edu/Documents/in/Analytical_Chemistry"},{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":47953,"name":"Predictability","url":"https://www.academia.edu/Documents/in/Predictability"},{"id":58380,"name":"Therapeutic drug monitoring","url":"https://www.academia.edu/Documents/in/Therapeutic_drug_monitoring"},{"id":64336,"name":"Population","url":"https://www.academia.edu/Documents/in/Population"},{"id":1032783,"name":"Bayesian Probability","url":"https://www.academia.edu/Documents/in/Bayesian_Probability"},{"id":1322524,"name":"Clozapine","url":"https://www.academia.edu/Documents/in/Clozapine"},{"id":2618916,"name":"Dosing","url":"https://www.academia.edu/Documents/in/Dosing"},{"id":3789884,"name":"Pharmacology and pharmaceutical sciences","url":"https://www.academia.edu/Documents/in/Pharmacology_and_pharmaceutical_sciences"}],"urls":[{"id":34959145,"url":"https://doi.org/10.1097/ftd.0000000000000987"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="108498825"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/108498825/HIF_1_master_and_commander_of_the_hypoxic_world"><img alt="Research paper thumbnail of HIF-1: master and commander of the hypoxic world" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/108498825/HIF_1_master_and_commander_of_the_hypoxic_world">HIF-1: master and commander of the hypoxic world</a></div><div class="wp-workCard_item"><span>Biochemical Pharmacology</span><span>, Sep 1, 2004</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O2 concentrations.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="108498825"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="108498825"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 108498825; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=108498825]").text(description); $(".js-view-count[data-work-id=108498825]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 108498825; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='108498825']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 108498825, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=108498825]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":108498825,"title":"HIF-1: master and commander of the hypoxic world","translated_title":"","metadata":{"abstract":"The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O2 concentrations.","publisher":"Elsevier BV","publication_date":{"day":1,"month":9,"year":2004,"errors":{}},"publication_name":"Biochemical Pharmacology"},"translated_abstract":"The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O2 level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O2 concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O2 homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. 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data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/87613681/The_Asparaginyl_Hydroxylase_Factor_Inhibiting_HIF_1%CE%B1_Is_an_Essential_Regulator_of_Metabolism"><img alt="Research paper thumbnail of The Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential Regulator of Metabolism" class="work-thumbnail" src="https://attachments.academia-assets.com/91774994/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/87613681/The_Asparaginyl_Hydroxylase_Factor_Inhibiting_HIF_1%CE%B1_Is_an_Essential_Regulator_of_Metabolism">The Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential Regulator of Metabolism</a></div><div class="wp-workCard_item"><span>Cell Metabolism</span><span>, 2010</span></div><div class="wp-workCard_item 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{"id":87613681,"title":"The Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential Regulator of Metabolism","translated_title":"","metadata":{"publisher":"Elsevier BV","grobid_abstract":"Factor Inhibiting HIF-1α (FIH) is an asparaginal hydroxylase. Hydroxylation of HIF-α proteins by FIH blocks association of HIFs with the transcriptional co-activators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene, and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, improved glucose and lipid homeostasis, and are resistant to high fat diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, enhanced insulin sensitivity, and are also protected against high fat diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.","publication_date":{"day":null,"month":null,"year":2010,"errors":{}},"publication_name":"Cell Metabolism","grobid_abstract_attachment_id":91774994},"translated_abstract":null,"internal_url":"https://www.academia.edu/87613681/The_Asparaginyl_Hydroxylase_Factor_Inhibiting_HIF_1%CE%B1_Is_an_Essential_Regulator_of_Metabolism","translated_internal_url":"","created_at":"2022-09-30T04:10:05.145-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":66249376,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[],"downloadable_attachments":[{"id":91774994,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/91774994/thumbnails/1.jpg","file_name":"pmc2893150.pdf","download_url":"https://www.academia.edu/attachments/91774994/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"The_Asparaginyl_Hydroxylase_Factor_Inhib.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/91774994/pmc2893150-libre.pdf?1664538535=\u0026response-content-disposition=attachment%3B+filename%3DThe_Asparaginyl_Hydroxylase_Factor_Inhib.pdf\u0026Expires=1733011077\u0026Signature=eImOX3kZb3PP77iDSMH5QMahjjsySCVWhvCswjc2w4TYJ9RoTEQoab1YFG-VP9D90i5Dc4S1irj9AZtpoEVAHmxsaKa4ZkdLWs-mBtrtX1aPhg1eD1S5WH5QYZM~Ta9tjETHgGthinPg6zyFk9SLsBGmBRFGAmpYt33sPTNcIP47JlKgwWOeB-XAeWsGPzJh0DWdtQmsfd7GzPGGdZiktvQwQ0pr6NLZwpxgc5OogNQGUiSFlou5XN4IPzOdwIBSWLuOYJ3Ca-eUnhmnntayOZOLbKGEAW-biEK1XGcof3e3aCvzdwnfuQoEwXzamLMSNupr2AxZOank-0VzIUl9ZA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"The_Asparaginyl_Hydroxylase_Factor_Inhibiting_HIF_1α_Is_an_Essential_Regulator_of_Metabolism","translated_slug":"","page_count":26,"language":"en","content_type":"Work","owner":{"id":66249376,"first_name":"Frederic","middle_initials":null,"last_name":"Dayan","page_name":"FredericDayan","domain_name":"independent","created_at":"2017-07-09T00:13:11.221-07:00","display_name":"Frederic Dayan","url":"https://independent.academia.edu/FredericDayan"},"attachments":[{"id":91774994,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/91774994/thumbnails/1.jpg","file_name":"pmc2893150.pdf","download_url":"https://www.academia.edu/attachments/91774994/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"The_Asparaginyl_Hydroxylase_Factor_Inhib.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/91774994/pmc2893150-libre.pdf?1664538535=\u0026response-content-disposition=attachment%3B+filename%3DThe_Asparaginyl_Hydroxylase_Factor_Inhib.pdf\u0026Expires=1733011077\u0026Signature=eImOX3kZb3PP77iDSMH5QMahjjsySCVWhvCswjc2w4TYJ9RoTEQoab1YFG-VP9D90i5Dc4S1irj9AZtpoEVAHmxsaKa4ZkdLWs-mBtrtX1aPhg1eD1S5WH5QYZM~Ta9tjETHgGthinPg6zyFk9SLsBGmBRFGAmpYt33sPTNcIP47JlKgwWOeB-XAeWsGPzJh0DWdtQmsfd7GzPGGdZiktvQwQ0pr6NLZwpxgc5OogNQGUiSFlou5XN4IPzOdwIBSWLuOYJ3Ca-eUnhmnntayOZOLbKGEAW-biEK1XGcof3e3aCvzdwnfuQoEwXzamLMSNupr2AxZOank-0VzIUl9ZA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":7710,"name":"Biology","url":"https://www.academia.edu/Documents/in/Biology"},{"id":26327,"name":"Medicine","url":"https://www.academia.edu/Documents/in/Medicine"},{"id":71289,"name":"Glucose","url":"https://www.academia.edu/Documents/in/Glucose"},{"id":71400,"name":"Insulin","url":"https://www.academia.edu/Documents/in/Insulin"},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice"},{"id":154388,"name":"Hyperventilation","url":"https://www.academia.edu/Documents/in/Hyperventilation"},{"id":184609,"name":"Lipid metabolism","url":"https://www.academia.edu/Documents/in/Lipid_metabolism"},{"id":244814,"name":"Clinical Sciences","url":"https://www.academia.edu/Documents/in/Clinical_Sciences"},{"id":295465,"name":"Fatty Liver","url":"https://www.academia.edu/Documents/in/Fatty_Liver"},{"id":705414,"name":"Regulator","url":"https://www.academia.edu/Documents/in/Regulator"},{"id":1141692,"name":"Weight Gain","url":"https://www.academia.edu/Documents/in/Weight_Gain"},{"id":1152182,"name":"Asparagine","url":"https://www.academia.edu/Documents/in/Asparagine"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology"},{"id":2348526,"name":"Dietary fats","url":"https://www.academia.edu/Documents/in/Dietary_fats"},{"id":2832672,"name":"cell metabolism","url":"https://www.academia.edu/Documents/in/cell_metabolism"},{"id":3789880,"name":"Medical biochemistry and metabolomics","url":"https://www.academia.edu/Documents/in/Medical_biochemistry_and_metabolomics"}],"urls":[{"id":24329753,"url":"https://api.elsevier.com/content/article/PII:S1550413110000690?httpAccept=text/xml"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="80530138"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/80530138/Activation_of_HIF_1%CE%B1_in_exponentially_growing_cells_via_hypoxic_stimulation_is_independent_of_the_Akt_mTOR_pathway"><img alt="Research paper thumbnail of Activation of HIF-1α in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway" class="work-thumbnail" src="https://attachments.academia-assets.com/86881093/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/80530138/Activation_of_HIF_1%CE%B1_in_exponentially_growing_cells_via_hypoxic_stimulation_is_independent_of_the_Akt_mTOR_pathway">Activation of HIF-1α in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway</a></div><div class="wp-workCard_item"><span>Journal of Cellular Physiology</span><span>, 2009</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="7fb5e2fd8f825cd8b63b9bf7851ce1e7" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":86881093,"asset_id":80530138,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/86881093/download_file?st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzQ3Nyw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="80530138"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="80530138"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 80530138; 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However, the impact and origin of this pool of HIF-1a, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1a stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1a stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1a accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70 S6K phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O 2 levels, only slightly impacts upon the mTOR pathway under low cell density conditions. 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