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Article ; Online: Epithelial-mesenchymal transition and plasticity in the developmental basis of cancer and fibrosis.

Runyan, Raymond B / Savagner, Pierre

Developmental dynamics : an official publication of the American Association of Anatomists

2018 Volume 247, Issue 3, Page(s) 330–331

MeSH term(s)	Epithelial-Mesenchymal Transition ; Fibrosis/etiology ; Fibrosis/pathology ; Humans ; Neoplasms/etiology ; Neoplasms/pathology
Language	English
Publishing date	2018-02-14
Publishing country	United States
Document type	Editorial
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.24620
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Article ; Online: Letter to the Editor.

Runyan, Raymond B / Selmin, Ornella I / Smith, Susan M / Freeman, Jennifer L

Birth defects research

2019 Volume 111, Issue 16, Page(s) 1234–1236

MeSH term(s)	Animals ; Drinking Water ; Heart Defects, Congenital ; Rats ; Rats, Sprague-Dawley ; Trichloroethylene
Chemical Substances	Drinking Water ; Trichloroethylene (290YE8AR51)
Language	English
Publishing date	2019-08-05
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2104792-3
ISSN	2472-1727
ISSN (online)	2472-1727
DOI	10.1002/bdr2.1573
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Article: HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart

Chen, Sheri / Lencinas, Alejandro / Nunez, Martha / Selmin, Ornella I / Runyan, Raymond B

Environmental science. 2020 Mar. 27, v. 22, no. 3

2020

Abstract: In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern ... ...

Abstract	In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 μM Benfluorex, 5 μM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.
Keywords	RNA ; agonists ; antagonists ; cardiotoxicity ; chick embryos ; chickens ; chicks ; drinking water ; heart ; heart abnormalities ; metabolism ; mice ; quantitative polymerase chain reaction ; toxicity ; transcription (genetics) ; trichloroethylene
Language	English
Dates of publication	2020-0327
Size	p. 824-832.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2703814-2
ISSN	2050-7895 ; 2050-7887
ISSN (online)	2050-7895
ISSN	2050-7887
DOI	10.1039/c9em00597h
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart.

Chen, Sheri / Lencinas, Alejandro / Nunez, Martha / Selmin, Ornella I / Runyan, Raymond B

Environmental science. Processes & impacts

2020 Volume 22, Issue 3, Page(s) 824–832

Abstract	In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 μM Benfluorex, 5 μM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.
MeSH term(s)	Animals ; Female ; Heart/embryology ; Hepatocyte Nuclear Factor 4/genetics ; Mice ; Pregnancy ; Trichloroethylene/toxicity
Chemical Substances	Hepatocyte Nuclear Factor 4 ; Trichloroethylene (290YE8AR51)
Language	English
Publishing date	2020-03-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2703814-2
ISSN	2050-7895 ; 2050-7887
ISSN (online)	2050-7895
ISSN	2050-7887
DOI	10.1039/c9em00597h
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Article ; Online: Cartilage Oligomeric Matrix Protein, COMP may be a Better Prognostic Marker Than CEACAM5 and Correlates With Colon Cancer Molecular Subtypes, Tumor Aggressiveness and Overall Survival.

Wusterbarth, Emily / Chen, Yuliang / Jecius, Hunter / Krall, Erika / Runyan, Raymond B / Pandey, Ritu / Nfonsam, Valentine

The Journal of surgical research

2021 Volume 270, Page(s) 169–177

Abstract: Background: New tumor biomarkers are needed to improve the management of colon cancer (CC), the second leading cause of cancer-related deaths in the United States. Carcinoembryonic Antigen (CEA), the translated protein of carcinoembryonic antigen- ... ...

Abstract	Background: New tumor biomarkers are needed to improve the management of colon cancer (CC), the second leading cause of cancer-related deaths in the United States. Carcinoembryonic Antigen (CEA), the translated protein of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) gene, is used as a biomarker for CC. Cartilage Oligomeric Matrix Protein (COMP) is overexpressed in CC compared to normal colon tissues. This study aims to evaluate the expression of COMP by disease stage, consensus molecular subtype (CMS), its impact on disease outcomes, and comparison to CEACAM5. Materials and methods: RNA-seq data from 456 CC The Cancer Genome Atlas samples and 41 matching control samples were analyzed for COMP expression and CEACAM5 expression. We stratified tumor samples by stage (I-IV), subtype (CMS1-CMS4), tumor location, and Kirsten RAt Sarcoma (KRAS) mutant status and three quartiles were established based on COMP expression. Kaplan Meier survival outcomes were evaluated. Results: COMP expression was significantly higher in tumor samples, with elevation of expression occurring in stage I and significantly increasing in stage IV. Increased COMP expression occurs in CMS4 with relatively low expression in CMS3. No significant expression difference was attributed to tumor location and KRAS mutant status. Compared to CEACAM5, COMP was a stronger molecular marker across stages and subtypes. CMS4 was associated with the high COMP expression, and higher levels of COMP were associated with poorer overall survival, disease-specific survival, and tumor progression-free intervals. CMS2 and 3 were associated with low expression and better survival. Conclusion: COMP is a potential molecular biomarker for CC and may be superior to CEA as an indicator of CC.
MeSH term(s)	Biomarkers, Tumor/genetics ; Carcinoembryonic Antigen ; Cartilage Oligomeric Matrix Protein/genetics ; Cell Adhesion Molecules ; Colonic Neoplasms/pathology ; GPI-Linked Proteins/genetics ; Humans ; Prognosis
Chemical Substances	Biomarkers, Tumor ; CEACAM5 protein, human ; Carcinoembryonic Antigen ; Cartilage Oligomeric Matrix Protein ; Cell Adhesion Molecules ; GPI-Linked Proteins
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2021.09.007
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Article ; Online: Epicardial placement of human placental membrane protects from heart injury in a swine model of myocardial infarction.

Skaria, Rinku S / Lopez-Pier, Marissa A / Kathuria, Brij S / Leber, Christian J / Langlais, Paul R / Aras, Shravan G / Khalpey, Zain I / Hitscherich, Pamela G / Chnari, Evangelia / Long, Marc / Churko, Jared M / Runyan, Raymond B / Konhilas, John P

Physiological reports

2023 Volume 11, Issue 20, Page(s) e15838

Abstract: Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood-flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective ... ...

Abstract	Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood-flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective strategies remain limited to prevent or attenuate IRI. We hypothesized that epicardial placement of human placental amnion/chorion (HPAC) grafts will protect against IRI. Using a clinically relevant model of IRI, swine were subjected to 45 min percutaneous ischemia followed with (MI + HPAC, n = 3) or without (MI only, n = 3) HPAC. Cardiac function was assessed by echocardiography, and regional punch biopsies were collected 14 days post-operatively. A deep phenotyping approach was implemented by using histological interrogation and incorporating global proteomics and transcriptomics in nonischemic, ischemic, and border zone biopsies. Our results established HPAC limited the extent of cardiac injury by 50% (11.0 ± 2.0% vs. 22.0 ± 3.0%, p = 0.039) and preserved ejection fraction in HPAC-treated swine (46.8 ± 2.7% vs. 35.8 ± 4.5%, p = 0.014). We present comprehensive transcriptome and proteome profiles of infarct (IZ), border (BZ), and remote (RZ) zone punch biopsies from swine myocardium during the proliferative cardiac repair phase 14 days post-MI. Both HPAC-treated and untreated tissues showed regional dynamic responses, whereas only HPAC-treated IZ revealed active immune and extracellular matrix remodeling. Decreased endoplasmic reticulum (ER)-dependent protein secretion and increased antiapoptotic and anti-inflammatory responses were measured in HPAC-treated biopsies. We provide quantitative evidence HPAC reduced cardiac injury from MI in a preclinical swine model, establishing a potential new therapeutic strategy for IRI. Minimizing the impact of MI remains a central clinical challenge. We present a new strategy to attenuate post-MI cardiac injury using HPAC in a swine model of IRI. Placement of HPAC membrane on the heart following MI minimizes ischemic damage, preserves cardiac function, and promotes anti-inflammatory signaling pathways.
MeSH term(s)	Pregnancy ; Swine ; Humans ; Female ; Animals ; Placenta/metabolism ; Myocardial Infarction/pathology ; Myocardium/metabolism ; Heart Injuries/drug therapy ; Heart Injuries/metabolism ; Heart Injuries/pathology ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal
Chemical Substances	Anti-Inflammatory Agents
Language	English
Publishing date	2023-10-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.15838
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Article ; Online: Study of the Expression Transition of Cardiac Myosin Using Polarization-Dependent SHG Microscopy.

Yuan, Cai / Zhao, Xiaolei / Wang, Zhonghai / Borg, Thomas K / Ye, Tong / Khalpey, Zain I / Runyan, Raymond B / Shao, Yonghong / Gao, Bruce Z

Biophysical journal

2020 Volume 118, Issue 5, Page(s) 1058–1066

Abstract: Detection of the transition between the two myosin isoforms α- and β-myosin in living cardiomyocytes is essential for understanding cardiac physiology and pathology. In this study, the differences in symmetry of polarization spectra obtained from α- and ... ...

Abstract	Detection of the transition between the two myosin isoforms α- and β-myosin in living cardiomyocytes is essential for understanding cardiac physiology and pathology. In this study, the differences in symmetry of polarization spectra obtained from α- and β-myosin in various mammalian ventricles and propylthiouracil-treated rats are explored through polarization-dependent second harmonic generation microscopy. Here, we report for the, to our knowledge, first time that α- and β-myosin, as protein crystals, possess different symmetries: the former has C6 symmetry, and the latter has C3v. A single-sarcomere line scan further demonstrated that the differences in polarization-spectrum symmetry between α- and β-myosin came from their head regions: the head and neck domains of α- and β-myosin account for the differences in symmetry. In addition, the dynamic transition of the polarization spectrum from C6 to C3v line profile was observed in a cell culture in which norepinephrine induced an α- to β-myosin transition.
MeSH term(s)	Animals ; Cardiac Myosins ; Myocytes, Cardiac ; Myosins ; Rats ; Sarcomeres ; Ventricular Myosins
Chemical Substances	Cardiac Myosins (EC 3.6.1.-) ; Ventricular Myosins (EC 3.6.1.-) ; Myosins (EC 3.6.4.1)
Language	English
Publishing date	2020-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2019.12.030
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Runx2-I is an Early Regulator of Epithelial-Mesenchymal Cell Transition in the Chick Embryo.

Tavares, Andre L P / Brown, Jessie A / Ulrich, Emily C / Dvorak, Katerina / Runyan, Raymond B

Developmental dynamics : an official publication of the American Association of Anatomists

2017 Volume 247, Issue 3, Page(s) 542–554

Abstract: Background: Although normally linked to bone and cartilage development, the Runt-related transcription factor, RUNX2, was reported in the mouse heart during development of the valves. We examined RUNX2 expression and function in the developing avian ... ...

Abstract	Background: Although normally linked to bone and cartilage development, the Runt-related transcription factor, RUNX2, was reported in the mouse heart during development of the valves. We examined RUNX2 expression and function in the developing avian heart as it related to the epithelial-mesenchymal transition (EMT) in the atrioventricular canal. EMT can be separated into an activation stage involving hypertrophy and cell separation and an invasion stage where cells invade the extracellular matrix. The localization and activity of RUNX2 was explored in relation to these steps in the heart. As RUNX2 was also reported in cancer tissues, we examined its expression in the progression of esophageal cancer in staged tissues. Results: A specific isoform, RUNX2-I, is present and required for EMT by endothelia of the atrioventricular canal. Knockdown of RUNX2-I inhibits the cell-cell separation that is characteristic of initial activation of EMT. Loss of RUNX2-I altered expression of EMT markers to a greater extent during activation than during subsequent cell invasion. Transforming growth factor beta 2 (TGFβ2) mediates activation during cardiac endothelial EMT. Consistent with a role in activation, RUNX2-I is regulated by TGFβ2 and its activity is independent of similarly expressed Snai2 in regulation of EMT. Examination of RUNX2 expression in esophageal cancer showed its upregulation concomitant with the development of dysplasia and continued expression in adenocarcinoma. Conclusions: These data introduce the RUNX2-I isoform as a critical early transcription factor mediating EMT in the developing heart after induction by TGFβ2. Its expression in tumor tissue suggests a similar role for RUNX2 in the EMT of metastasis. Developmental Dynamics 247:542-554, 2018. © 2017 Wiley Periodicals, Inc.
MeSH term(s)	Animals ; Chick Embryo ; Chickens ; Core Binding Factor Alpha 1 Subunit/genetics ; Core Binding Factor Alpha 1 Subunit/physiology ; Epithelial-Mesenchymal Transition ; Neoplasms/metabolism ; Protein Isoforms ; Transcriptional Activation ; Transforming Growth Factor beta
Chemical Substances	Core Binding Factor Alpha 1 Subunit ; Protein Isoforms ; Transforming Growth Factor beta
Language	English
Publishing date	2017-07-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.24539
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Article ; Online: COMP Gene Coexpresses With EMT Genes and Is Associated With Poor Survival in Colon Cancer Patients.

Nfonsam, Valentine N / Nfonsam, Landry E / Chen, Debbie / Omesiete, Pamela N / Cruz, Alejandro / Runyan, Raymond B / Jandova, Jana

The Journal of surgical research

2018 Volume 233, Page(s) 297–303

Abstract: Background: About 1.2 million new cases of colon cancer (CC) and 0.6 million deaths are reported every year, establishing CC as an important contributor to worldwide cancer morbidity and mortality. Although the overall incidence and mortality of CC have ...

Abstract	Background: About 1.2 million new cases of colon cancer (CC) and 0.6 million deaths are reported every year, establishing CC as an important contributor to worldwide cancer morbidity and mortality. Although the overall incidence and mortality of CC have declined over the past 3 decades, the number of early-onset colon cancer ([EOCC], patients <50 y old) continues to rise alarmingly. These young patients are often diagnosed at a more advanced stage and tend to have poor survival. Our recently published data showed that the cartilage oligomeric matrix protein (COMP) is overexpressed in early-onset colon cancer patients. COMP is also reported in several cancers to coexpress with epithelial-mesenchymal transition (EMT) transcription factors. Given the role of EMT in cancer metastasis and cell invasion, we assessed the correlation between COMP gene expression and EMT gene expression in CC, and COMP's relationship to patient survival. Methods: mRNA expression of COMP was compared to that of EMT markers using the UCSC Cancer Genomics Browser. Survival analysis was performed using the UCSC Xena Browser for cancer genomics. Results: Expression analysis revealed coexpression of COMP with the EMT markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP9, and COL1A1. Samples that were more mesenchymal had higher expression levels of COMP and EMT markers, thus suggesting a potential role of COMP in EMT. Patients with increased COMP expression presented with poorer overall survival compared to patients with no change or reduced COMP expression (P = 0.02). Conclusions: These findings reveal COMP as a potential biomarker for CC especially in more aggressive CC and CC in young patients, with a likely role in EMT during tumor metastasis and invasion, and a contributing factor to patient survival.
MeSH term(s)	Adenocarcinoma/mortality ; Adenocarcinoma/pathology ; Age of Onset ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/metabolism ; Cartilage Oligomeric Matrix Protein/metabolism ; Colon/pathology ; Colonic Neoplasms/mortality ; Colonic Neoplasms/pathology ; Databases, Factual/statistics & numerical data ; Datasets as Topic ; Epithelial-Mesenchymal Transition/genetics ; Female ; Gene Expression Profiling ; Humans ; Male ; Middle Aged ; Neoplasm Invasiveness/pathology ; Survival Analysis
Chemical Substances	Biomarkers, Tumor ; COMP protein, human ; Cartilage Oligomeric Matrix Protein
Language	English
Publishing date	2018-09-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2018.08.021
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Article ; Online: Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart.

Harris, Alondra P / Ismail, Kareem A / Nunez, Martha / Martopullo, Ira / Lencinas, Alejandro / Selmin, Ornella I / Runyan, Raymond B

Toxicology letters

2018 Volume 285, Page(s) 113–120

Abstract: Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. ...

Abstract	Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.
MeSH term(s)	Animals ; Chick Embryo ; Dose-Response Relationship, Drug ; Echocardiography ; Environmental Pollutants/toxicity ; Fenfluramine/analogs & derivatives ; Fenfluramine/pharmacology ; Genes, Reporter ; Heart/diagnostic imaging ; Heart/drug effects ; Heart/embryology ; Hep G2 Cells ; Hepatocyte Nuclear Factor 4/agonists ; Hepatocyte Nuclear Factor 4/genetics ; Humans ; Myocardium/metabolism ; Transcription, Genetic/drug effects ; Trichloroethylene/toxicity
Chemical Substances	Environmental Pollutants ; HNF4A protein, human ; Hepatocyte Nuclear Factor 4 ; Trichloroethylene (290YE8AR51) ; Fenfluramine (2DS058H2CF) ; benfluorex (403FO0NQG3)
Language	English
Publishing date	2018-01-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	433788-8
ISSN	1879-3169 ; 0378-4274
ISSN (online)	1879-3169
ISSN	0378-4274
DOI	10.1016/j.toxlet.2017.12.027
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