{"response":{"docs":[{"system_create_dtsi":"2017-10-27T02:31:50Z","system_modified_dtsi":"2018-08-01T18:36:53Z","has_model_ssim":["Article"],"id":"bc386t218","accessControl_ssim":["c91331db-617b-4f94-ae8c-b34824a36652"],"hasRelatedMediaFragment_ssim":["bc386t22j"],"hasRelatedImage_ssim":["bc386t22j"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Lack of Communication Rusts and Ages Stem Cells"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Landes Bio Science "],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Cancelas, Jose A.","Taniguchi, E."],"publisher_tesim":["Landes Bio Science "],"description_tesim":["Not Available."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2012-09-01"],"source_tesim":["Landes Bio Science "],"thumbnail_path_ss":"/downloads/bc386t22j?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t22j"],"file_set_ids_ssim":["bc386t22j"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"LACK OF COMMUNICATION RUSTS AND AGES STEM CELLS","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t218"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697087855610822656,"timestamp":"2021-04-15T06:45:00.581Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:41Z","system_modified_dtsi":"2018-08-01T18:36:51Z","has_model_ssim":["Article"],"id":"bc386t17p","accessControl_ssim":["5d36fa68-f895-4b5c-806f-3a1ca9ee812c"],"hasRelatedMediaFragment_ssim":["bc386t18z"],"hasRelatedImage_ssim":["bc386t18z"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Insertional Mutagenesis Identifies a STAT3/Arid1b/ b-catenin Pathway Driving Neurofibroma Initiation"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Wu et al. map an Nf1-Stat3-Arid1b/ b-catenin pathway that initiates Neurofibromatosis type 1 (Nf1) neurofibromas, using unbiased insertional mutagenesis screening. Stat3 transcriptionally represses Gsk3b and Arid1b, thereby activating b-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance. Stat3-mediated modification plays a role in early tumorigenesis."],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Spinner, R. J.","Ratner, N.","Largaespada, D. A.","Keng, V.","Patmore, D. M.","Wu, J.","Cancelas, Jose A."],"publisher_tesim":["Cell Reports"],"description_tesim":["Wu et al. map an Nf1-Stat3-Arid1b/ b-catenin pathway that initiates\nNeurofibromatosis type 1 (Nf1) neurofibromas, using unbiased\ninsertional mutagenesis screening. Stat3 transcriptionally represses Gsk3b and Arid1b, thereby activating b-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance.\nStat3-mediated modification plays a role in early tumorigenesis."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2016-02"],"source_tesim":["Wu et al. map an Nf1-Stat3-Arid1b/ b-catenin pathway that initiates Neurofibromatosis type 1 (Nf1) neurofibromas, using unbiased insertional mutagenesis screening. Stat3 transcriptionally represses Gsk3b and Arid1b, thereby activating b-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance. Stat3-mediated modification plays a role in early tumorigenesis."],"thumbnail_path_ss":"/downloads/bc386t18z?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t18z"],"file_set_ids_ssim":["bc386t18z"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"INSERTIONAL MUTAGENESIS IDENTIFIES A STAT3ARID1B BCATENIN PATHWAY DRIVING NEUROFIBROMA INITIATION","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t17p"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697108570496040960,"timestamp":"2021-04-15T12:14:15.834Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:35Z","system_modified_dtsi":"2018-08-01T18:36:52Z","has_model_ssim":["Article"],"id":"bc386t154","accessControl_ssim":["6e878354-fc4f-4bd4-a562-4360c50abe48"],"hasRelatedMediaFragment_ssim":["bc386t16d"],"hasRelatedImage_ssim":["bc386t16d"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["PM-18 EGFR-STAT3 Activates B-Catenin Signaling to Drive Neurofibroma Initiation in Nf1, and Plays a Role in Tumor Maintenance"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE Nancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1, Edwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James R. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose A. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David A. Largaespada2; 1 Cincinnati Children’s, Cincinnati, OH, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3 Mayo Clinic, Rochester, MN, USA; 4 Massachusetts General Hospital, Boston, MA, USA; 5 National Cancer Institute Pediatric Branch, Bethesda, MD, USA; 6 New York University School of Medicine, New York, NY, USA To identify genes and signaling pathways that drive peripheral nerve tumor initiationand growth beyond the Ras-MAPK pathwaywe used unbiased insertional mutagenesis screening. We identified Stat3 as a potential driver of Neurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented neurofibroma formation, and self-renewal of tumor initiating cells. Genetic gain- and loss-of-function identified EGFR as the major upstream regulator of P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation; IL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/ Stat3 inhibitor reduced established neurofibroma growth, supporting an additional role for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream of Stat3, we identified b-catenin, and b-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and b-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ b-catenin pathway inhibition in neurofibroma therapeutic trials. Supported by: NIH R01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a DAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.). The American Cancer Society (IRG-67-003-44) supported J.R.F."],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Schwartz, E. B.","Ratner, N.","Largaespada, D. A.","Cancelas, Jose A.","Stemmer-Rachamimov, A. O."],"publisher_tesim":["Neuro-Oncology"],"description_tesim":["PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO\nDRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A\nROLE IN TUMOR MAINTENANCE\nNancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1,\nEdwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James\nR. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose\nA. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David\nA. Largaespada2;\n1\nCincinnati Children’s, Cincinnati, OH, USA; 2\nUniversity of\nMinnesota, Minneapolis, MN, USA; 3\nMayo Clinic, Rochester, MN, USA; 4\nMassachusetts General Hospital, Boston, MA, USA; 5\nNational Cancer\nInstitute Pediatric Branch, Bethesda, MD, USA; 6\nNew York University School\nof Medicine, New York, NY, USA\nTo identify genes and signaling pathways that drive peripheral nerve tumor\ninitiationand growth beyond the Ras-MAPK pathwaywe used unbiased insertional\nmutagenesis screening. We identified Stat3 as a potential driver of\nNeurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3\nin Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented\nneurofibroma formation, and self-renewal of tumor initiating cells. Genetic\ngain- and loss-of-function identified EGFR as the major upstream regulator\nof P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation;\nIL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/\nStat3 inhibitor reduced established neurofibroma growth, supporting an additional\nrole for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream\nof Stat3, we identified b-catenin, and b-catenin expression rescued\nphenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and\nb-catenin were strongly correlated in NF1 human plexiform neurofibromas.\nThe data support testing of JAK/STAT inhibition and Wnt/ b-catenin\npathway inhibition in neurofibroma therapeutic trials. Supported by: NIH\nR01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a\nDAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State\nUniversity Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.).\nThe American Cancer Society (IRG-67-003-44) supported J.R.F."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2014-11"],"source_tesim":["PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE Nancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1, Edwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James R. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose A. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David A. Largaespada2; 1 Cincinnati Children’s, Cincinnati, OH, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3 Mayo Clinic, Rochester, MN, USA; 4 Massachusetts General Hospital, Boston, MA, USA; 5 National Cancer Institute Pediatric Branch, Bethesda, MD, USA; 6 New York University School of Medicine, New York, NY, USA To identify genes and signaling pathways that drive peripheral nerve tumor initiationand growth beyond the Ras-MAPK pathwaywe used unbiased insertional mutagenesis screening. We identified Stat3 as a potential driver of Neurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented neurofibroma formation, and self-renewal of tumor initiating cells. Genetic gain- and loss-of-function identified EGFR as the major upstream regulator of P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation; IL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/ Stat3 inhibitor reduced established neurofibroma growth, supporting an additional role for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream of Stat3, we identified b-catenin, and b-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and b-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ b-catenin pathway inhibition in neurofibroma therapeutic trials. Supported by: NIH R01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a DAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.). The American Cancer Society (IRG-67-003-44) supported J.R.F."],"thumbnail_path_ss":"/downloads/bc386t16d?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t16d"],"file_set_ids_ssim":["bc386t16d"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"PM18 EGFRSTAT3 ACTIVATES BCATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1 AND PLAYS A ROLE IN TUMOR MAINTENANCE","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t154"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697125337642565632,"timestamp":"2021-04-15T16:40:46.232Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:31Z","system_modified_dtsi":"2018-08-01T18:36:51Z","has_model_ssim":["Article"],"id":"bc386t13k","accessControl_ssim":["4d06e4fe-452c-4112-9019-e24ceb8ced29"],"hasRelatedMediaFragment_ssim":["bc386t14v"],"hasRelatedImage_ssim":["bc386t14v"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Overnight, room temperature hold of whole blood followed by 42-day storage of red blood cells in additive solution-7"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Overnight, room temperature hold of whole blood followed by 42-day storage of red blood cells in additive solution-7"],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Szczerpiorkowski, Z. M.","Whitley, P.","Maes, L. A.","Dumont, L. J.","Cancelas, Jose A.","Zia, M.","Hess, J. R.","Rugg, N.","Herschel, L."],"publisher_tesim":["Transfusion"],"description_tesim":["Overnight, room temperature hold\n(ONH) of whole blood before component processing\noffers several benefits. This study evaluated the storage\nand in vivo recovery characteristics of ONH red blood\ncells (RBCs) stored in additive solution-7 (AS-7)."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2014-10"],"source_tesim":["Overnight, room temperature hold of whole blood followed by 42-day storage of red blood cells in additive solution-7"],"thumbnail_path_ss":"/downloads/bc386t14v?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t14v"],"file_set_ids_ssim":["bc386t14v"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"OVERNIGHT ROOM TEMPERATURE HOLD OF WHOLE BLOOD FOLLOWED BY 42DAY STORAGE OF RED BLOOD CELLS IN ADDITIVE SOLUTION7","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t13k"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697073437089988608,"timestamp":"2021-04-15T02:55:50.008Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:27Z","system_modified_dtsi":"2018-08-01T18:36:55Z","has_model_ssim":["Article"],"id":"bc386t111","accessControl_ssim":["88e34224-a0e1-4419-af18-4ca2a861ad97"],"hasRelatedMediaFragment_ssim":["bc386t129"],"hasRelatedImage_ssim":["bc386t129"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Vasculopathy associated hyperangiotensinemia mobilizes hematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Vasculopathy associated hyperangiotensinemia mobilizes hematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation"],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Inagami, T.","Hill, S. E.","Wellendorf, A. M.","Perumbeti, A.","Nayak, R. C.","Bezold, K. Y.","Zheng, Y.","Chang, K. H.","Pirman, M.","Loberg, A.","Cancelas, Jose A.","Roy, S.","Malik, P.","Starnes, J.","Zhou, X."],"publisher_tesim":["Nature Communication"],"description_tesim":["Patients in organ failure of vascular origin have increased circulating hematopoietic stem cells and\nprogenitors (HSC/P). Plasma levels of angiotensin II (Ang-II), are commonly increased in\nvasculopathies. Hyperangiotensinemia results in activation of a very distinct Ang-II receptor set,\nRho-family GTPase members, and actin in bone marrow endothelial cells (BMEC) and HSC/P,\nwhich results in decreased membrane integrin activation in both BMEC and HSC/P, and in HSC/P\nde-adhesion and mobilization. The Ang-II effect can be reversed pharmacologically and\ngenetically by inhibiting Ang-II production or signaling through BMEC AT2R, HSCP AT1R/\nAT2R or HSC/P RhoA, but not by interfering with other vascular tone mediators.\nHyperangiotensinemia and high counts of circulating HSC/P seen in sickle cell disease (SCD) as a\nresult of vascular damage, is significantly decreased by Ang-II inhibitors. Our data define for the\nfirst time the role of Ang-II HSC/P traffic regulation and redefine the hematopoietic consequences\nof anti-angiotensin therapy in SCD."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2015-01"],"source_tesim":["Vasculopathy associated hyperangiotensinemia mobilizes hematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation"],"thumbnail_path_ss":"/downloads/bc386t129?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t129"],"file_set_ids_ssim":["bc386t129"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"VASCULOPATHY ASSOCIATED HYPERANGIOTENSINEMIA MOBILIZES HEMATOPOIETIC STEM CELLSPROGENITORS THROUGH ENDOTHELIAL AT2R AND CYTOSKELETAL DYSREGULATION","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t111"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697103323650326528,"timestamp":"2021-04-15T10:50:52.053Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:23Z","system_modified_dtsi":"2018-08-01T18:36:55Z","has_model_ssim":["Article"],"id":"bc386t090","accessControl_ssim":["1ccf01ad-da31-40b5-a0b4-9f22bc0db581"],"hasRelatedMediaFragment_ssim":["bc386t10r"],"hasRelatedImage_ssim":["bc386t10r"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-kB Gene Network"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-kB Gene Network"],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Komurov, K.","Maciejewski, J. P.","Bolanos, L.","Grimes, H. L.","Cancelas, Jose A.","Chen, X.","Barker, B.","Weirauch, M. T.","Jerez, A.","Liu, X.","Makishima, H.","Christie, S.","Starczynowski, D. T.","Rao, D. S.","Fang, J."],"publisher_tesim":["Cell Reports"],"description_tesim":["Chromosome 5q deletions (del[5q]) are common in\nhigh-risk (HR) myelodysplastic syndrome (MDS) and\nacute myeloid leukemia (AML); however, the gene\nregulatory networks that sustain these aggressive\ndiseases are unknown. Reduced miR-146a expression\nin del(5q) HR MDS/AML and miR-146a/ hematopoietic\nstem/progenitor cells (HSPCs) results in\nTRAF6/NF-kB activation. Increased survival and proliferation\nof HSPCs from miR-146alow HR MDS/AML is\nsustained by a neighboring haploid gene, SQSTM1\n(p62), expressed from the intact 5q allele. Overexpression\nof p62 from the intact allele occurs through\nNF-kB-dependent feedforward signaling mediated\nby miR-146a deficiency. p62 is necessary for\nTRAF6-mediated NF-kB signaling, as disrupting the\np62-TRAF6 signaling complex results in cell-cycle arrest\nand apoptosis of MDS/AML cells. Thus, del(5q)\nHR MDS/AML employs an intrachromosomal gene\nnetwork involving loss of miR-146a and haploid overexpression\nof p62 via NF-kB to sustain TRAF6/NF-kB\nsignaling for cell survival and proliferation. Interfering\nwith the p62-TRAF6 signaling complex represents a\ntherapeutic option in miR-146a-deficient and aggressive\ndel(5q) MDS/AML."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2014-09"],"source_tesim":["Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-kB Gene Network"],"thumbnail_path_ss":"/downloads/bc386t10r?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t10r"],"file_set_ids_ssim":["bc386t10r"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"MYELOID MALIGNANCIES WITH CHROMOSOME 5Q DELETIONS ACQUIRE A DEPENDENCY ON AN INTRACHROMOSOMAL NFKB GENE NETWORK","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t090"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697085740469452800,"timestamp":"2021-04-15T06:11:23.425Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:18Z","system_modified_dtsi":"2018-08-01T18:36:54Z","has_model_ssim":["Article"],"id":"bc386t07f","accessControl_ssim":["199961fe-7545-4e66-987e-4522e8c9138e"],"hasRelatedMediaFragment_ssim":["bc386t08q"],"hasRelatedImage_ssim":["bc386t08q"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Pathogenesis of ELANE-Mutant Severe Neutropenia Revealed by Induced Pluripotent Stem Cells"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells"],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Lutzko, C.","Mehta, P.","Kalfa, T.","Aronow, B. J.","Myers, K.","Grimes, H. L.","Horwitz, M.","Cancelas, Jose A.","Valencia, C. A.","Trump, L.","Nayak, R. C."],"publisher_tesim":["The Journal of Clinical Investigation"],"description_tesim":["Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which\nencodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered\nthe understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN\npatient–derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that\nrecapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte\ndeath and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein\nresponse/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues\nthe dysgranulopoietic defect in SCN patient–derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In\ncontrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular\nNE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and\npromoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes\nNE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the\npotential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to\ncorrect NE mislocalization."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2015-07"],"source_tesim":["Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells"],"thumbnail_path_ss":"/downloads/bc386t08q?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t08q"],"file_set_ids_ssim":["bc386t08q"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"PATHOGENESIS OF ELANEMUTANT SEVERE NEUTROPENIA REVEALED BY INDUCED PLURIPOTENT STEM CELLS","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t07f"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697079758815232000,"timestamp":"2021-04-15T04:36:18.875Z","score":0.00049999997},{"system_create_dtsi":"2017-10-27T02:31:13Z","system_modified_dtsi":"2018-08-01T18:36:54Z","has_model_ssim":["Article"],"id":"bc386t05w","accessControl_ssim":["aa4e940c-86e9-4afe-9c54-7c92942af259"],"hasRelatedMediaFragment_ssim":["bc386t065"],"hasRelatedImage_ssim":["bc386t065"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["P62 is Required for Stem Cell/Progenitor Retention through Inhahvition of IKK/NF-kB/CcI14 Signaling at the Bone Marrow Macrophage-Osteoblast Niche"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["p62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-kB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche"],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Moscat, J.","Nayak, R. 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