16 results on '"Pease DR"'
Search Results
2. Updated cutaneous T-cell lymphoma TNMB staging criteria fail to identify patients with Sézary syndrome with low blood burden.
- Author
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Chrisman LP, Trimark PF, Pang Y, Pease DR, Martinez-Escala ME, Nguyen WQ, Fernandez R, Griffin TL, Ayanruoh L, Hooper MJ, Zhou XA, Fu L, Wolniak KL, and Guitart J
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Practice Guidelines as Topic, Sezary Syndrome pathology, Sezary Syndrome diagnosis, Sezary Syndrome blood, Neoplasm Staging, Lymphoma, T-Cell, Cutaneous diagnosis, Lymphoma, T-Cell, Cutaneous pathology, Lymphoma, T-Cell, Cutaneous blood, Skin Neoplasms pathology, Skin Neoplasms blood, Skin Neoplasms diagnosis
- Abstract
Comparison of the 2007 EORTC/ISCL and the 2022 EORTC/ISCL/USCLC blood staging guidelines for cutaneous T-cell lymphoma at a single institution reveals the newer guidelines fail to detect a subset of patients with Sézary syndrome with low blood burden., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
- View/download PDF
3. Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.
- Author
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Giammona A, De Vellis C, Crivaro E, Maresca L, Amoriello R, Ricci F, Anichini G, Pietrobono S, Pease DR, Fernandez-Zapico ME, Ballerini C, and Stecca B
- Subjects
- Animals, Mice, Humans, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Melanoma, Experimental metabolism, Cell Line, Tumor, Dendritic Cells immunology, Dendritic Cells metabolism, Mice, Inbred C57BL, Tumor Microenvironment, Zinc Finger Protein GLI1 metabolism, Zinc Finger Protein GLI1 genetics, Myeloid-Derived Suppressor Cells metabolism, Myeloid-Derived Suppressor Cells immunology, Melanoma pathology, Melanoma metabolism, Melanoma immunology, Melanoma genetics
- Abstract
Background: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored., Methods: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays., Results: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8., Conclusion: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1., (© 2024. The Author(s).)
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- 2024
- Full Text
- View/download PDF
4. KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis.
- Author
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Sigafoos AN, Tolosa EJ, Carr RM, Fernandez-Barrena MG, Almada LL, Pease DR, Hogenson TL, Raja Arul GL, Mousavi F, Sen S, Vera RE, Marks DL, Flores LF, LaRue-Nolan KC, Wu C, Bamlet WR, Vrabel AM, Sicotte H, Schenk EL, Smyrk TC, Zhang L, Rabe KG, Oberg AL, Zaphiropoulos PG, Chevet E, Graham RP, Hagen CE, di Magliano MP, Elsawa SF, Pin CL, Mao J, McWilliams RR, and Fernandez-Zapico ME
- Subjects
- Animals, Humans, Mice, Carcinogenesis, Cell Line, Tumor, Histones metabolism, Histones genetics, Mice, Transgenic, Promoter Regions, Genetic genetics, Transcription, Genetic, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal metabolism, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Zinc Finger Protein Gli2 genetics, Zinc Finger Protein Gli2 metabolism
- Abstract
Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth-promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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5. SUFU promotes GLI activity in a Hedgehog-independent manner in pancreatic cancer.
- Author
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Paradise BD, Gainullin VG, Almada LL, Sigafoos AN, Sen S, Vera RE, Raja Arul GL, Toruner M, Pease DR, Gonzalez AL, Mentucci FM, Grasso DH, and Fernandez-Zapico ME
- Subjects
- Humans, Zinc Finger Protein GLI1 genetics, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism, Proto-Oncogene Proteins c-bcl-2, Pancreatic Neoplasms, Repressor Proteins genetics, Repressor Proteins metabolism, Pancreatic Neoplasms genetics
- Abstract
Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2023
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6. GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.
- Author
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Almada LL, Barroso K, Sen S, Toruner M, Sigafoos AN, Raja Arul GL, Pease DR, Vera RE, Olson RLO, Auner HW, Pedeux R, Iovanna JL, Chevet E, and Fernandez-Zapico ME
- Subjects
- Zinc Finger Protein GLI1 genetics, Zinc Finger Protein GLI1 metabolism, Valosin Containing Protein genetics, Valosin Containing Protein metabolism, Transcription Factors genetics, Transcription Factors metabolism, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Adenosine Triphosphatases genetics, Adenosine Triphosphatases metabolism
- Abstract
Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process., Competing Interests: Declaration of competing interest EC is a founding member of Thabor Tx (https://www.thabor-tx.com/). The other authors declare that they have no competing interests with the contents of this article., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2023
- Full Text
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7. SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may contribute to increased arrhythmic risk in COVID-19.
- Author
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Clemens DJ, Ye D, Zhou W, Kim CSJ, Pease DR, Navaratnarajah CK, Barkhymer A, Tester DJ, Nelson TJ, Cattaneo R, Schneider JW, and Ackerman MJ
- Subjects
- Humans, Myocytes, Cardiac metabolism, Spike Glycoprotein, Coronavirus metabolism, Calcium metabolism, Furin metabolism, Pandemics, SARS-CoV-2 metabolism, Arrhythmias, Cardiac metabolism, Action Potentials physiology, Long QT Syndrome metabolism, Induced Pluripotent Stem Cells, COVID-19 metabolism
- Abstract
Background: SARS-CoV-2-mediated COVID-19 may cause sudden cardiac death (SCD). Factors contributing to this increased risk of potentially fatal arrhythmias include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs. However, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown., Objective: To assess the cellular and electrophysiological effects of direct SARS-CoV-2 infection of the heart using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)., Methods: hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator., Results: Transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; P<0.0001) consistent with increased cell size. The APD90 was prolonged significantly from 419±26 ms (n = 10) in untransfected hiPSC-CMs to 590±67 ms (n = 10; P<0.05) in CoV-2 S-mEm-transfected hiPSC-CMs. CoV-2 S-induced syncytia displayed delayed afterdepolarizations, erratic beating frequency, and calcium handling abnormalities including calcium sparks, large "tsunami"-like waves, and increased calcium transient amplitude. After furin protease inhibitor treatment or mutating the CoV-2 S furin cleavage site, cell-cell fusion was no longer evident and Ca2+ handling returned to normal., Conclusion: The SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte's repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic., Competing Interests: Dr. Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, LQT Therapeutics, Medtronic, and Thryv Therapeutics. Dr. Ackerman and Mayo Clinic are involved in equity/intellectual property/royalty relationships with AliveCor, Anumana, ARMGO Pharma, Pfizer, and UpToDate. The consulting activities are all modest, and none of these entities have contributed to this study in any manner. Dr. Roberto Cattaneo is a consultant for the Merck Research Laboratories (scientific input). This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Clemens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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8. Highly Efficient SARS-CoV-2 Infection of Human Cardiomyocytes: Spike Protein-Mediated Cell Fusion and Its Inhibition.
- Author
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Navaratnarajah CK, Pease DR, Halfmann PJ, Taye B, Barkhymer A, Howell KG, Charlesworth JE, Christensen TA, Kawaoka Y, Cattaneo R, and Schneider JW
- Subjects
- Animals, Cathepsin B metabolism, Cell Fusion, Chlorocebus aethiops, Embryonic Stem Cells metabolism, Exocytosis, Humans, Induced Pluripotent Stem Cells metabolism, Microscopy, Confocal, Serine Endopeptidases metabolism, Vero Cells, Viral Proteins metabolism, Virus Internalization, Virus Replication, COVID-19 virology, Myocytes, Cardiac virology, SARS-CoV-2, Spike Glycoprotein, Coronavirus metabolism
- Abstract
Severe cardiovascular complications can occur in coronavirus disease of 2019 (COVID-19) patients. Cardiac damage is attributed mostly to the aberrant host response to acute respiratory infection. However, direct infection of cardiac tissue by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also occurs. We examined here the cardiac tropism of SARS-CoV-2 in spontaneously beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These cardiomyocytes express the angiotensin-converting enzyme 2 (ACE2) receptor but not the transmembrane protease serine 2 (TMPRSS2) that mediates spike protein cleavage in the lungs. Nevertheless, SARS-CoV-2 infection of hiPSC-CMs was prolific; viral transcripts accounted for about 88% of total mRNA. In the cytoplasm of infected hiPSC-CMs, smooth-walled exocytic vesicles contained numerous 65- to 90-nm particles with canonical ribonucleocapsid structures, and virus-like particles with knob-like spikes covered the cell surface. To better understand how SARS-CoV-2 spreads in hiPSC-CMs, we engineered an expression vector coding for the spike protein with a monomeric emerald-green fluorescent protein fused to its cytoplasmic tail (S-mEm). Proteolytic processing of S-mEm and the parental spike were equivalent. Live cell imaging tracked spread of S-mEm cell-to-cell and documented formation of syncytia. A cell-permeable, peptide-based molecule that blocks the catalytic site of furin and furin-like proteases abolished cell fusion. A spike mutant with the single amino acid change R682S that disrupts the multibasic furin cleavage motif was fusion inactive. Thus, SARS-CoV-2 replicates efficiently in hiPSC-CMs and furin, and/or furin-like-protease activation of its spike protein is required for fusion-based cytopathology. This hiPSC-CM platform enables target-based drug discovery in cardiac COVID-19. IMPORTANCE Cardiac complications frequently observed in COVID-19 patients are tentatively attributed to systemic inflammation and thrombosis, but viral replication has occasionally been confirmed in cardiac tissue autopsy materials. We developed an in vitro model of SARS-CoV-2 spread in myocardium using induced pluripotent stem cell-derived cardiomyocytes. In these highly differentiated cells, viral transcription levels exceeded those previously documented in permissive transformed cell lines. To better understand the mechanisms of SARS-CoV-2 spread, we expressed a fluorescent version of its spike protein that allowed us to characterize a fusion-based cytopathic effect. A mutant of the spike protein with a single amino acid mutation in the furin/furin-like protease cleavage site lost cytopathic function. Of note, the fusion activities of the spike protein of other coronaviruses correlated with the level of cardiovascular complications observed in infections with the respective viruses. These data indicate that SARS-CoV-2 may cause cardiac damage by fusing cardiomyocytes.
- Published
- 2021
- Full Text
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9. mTOR-Dependent ARID1A Degradation: A New Twist in the Genetic-Epigenetic Interplay Driving Hepatocellular Carcinoma.
- Author
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Pease DR and Fernandez-Zapico ME
- Subjects
- DNA-Binding Proteins, Epigenesis, Genetic, Humans, Oncogenes, TOR Serine-Threonine Kinases genetics, Transcription Factors genetics, Carcinoma, Hepatocellular genetics, Liver Neoplasms genetics
- Abstract
The importance of the cross-talk between the genetic and epigenetic alterations promoting cancer development is well understood; however, the molecular details underlying the mechanism of how oncogenic signaling remodels the epigenome to generate a procancer transcriptome require further elucidation. The study by Zhang and colleagues in this issue of Cancer Research reveals a novel role for oncogenic mTOR signaling leading to the degradation of a prominent chromatin remodeler, ARID1a, establishing an altered, protumor chromatin landscape in hepatocellular carcinoma (HCC) controlling tumor deve-lopment and treatment resistance. These findings highlight oncogenic effects on chromatin remodelers as an important factor in both HCC pathobiology and therapeutic response. As strategies for cancer therapy begin to move in an increasingly individualized direction, increased knowledge into the impact of restoring the function of chromatin remodelers on response to therapy is warranted. See related article by Zhang et al., p. 5652 ., (©2021 American Association for Cancer Research.)
- Published
- 2021
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10. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity.
- Author
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Park J, Daniels J, Wartewig T, Ringbloom KG, Martinez-Escala ME, Choi S, Thomas JJ, Doukas PG, Yang J, Snowden C, Law C, Lee Y, Lee K, Zhang Y, Conran C, Tegtmeyer K, Mo SH, Pease DR, Jothishankar B, Kwok PY, Abdulla FR, Pro B, Louissaint A, Boggon TJ, Sosman J, Guitart J, Rao D, Ruland J, and Choi J
- Subjects
- Animals, Cells, Cultured, Forkhead Box Protein M1 genetics, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, Mice, Mutation, Oncogenes, Tumor Suppressor Protein p53 genetics, Lymphoma, T-Cell, Cutaneous genetics, Transcriptome
- Abstract
Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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11. Author Correction: Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.
- Author
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Schneider JW, Oommen S, Qureshi MY, Goetsch SC, Pease DR, Sundsbak RS, Guo W, Sun M, Sun H, Kuroyanagi H, Webster DA, Coutts AW, Holst KA, Edwards BS, Newville N, Hathcock MA, Melkamu T, Briganti F, Wei W, Romanelli MG, Fahrenkrug SC, Frantz DE, Olson TM, Steinmetz LM, Carlson DF, and Nelson TJ
- Published
- 2021
- Full Text
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12. Cutaneous T-cell lymphoma after chronic exposure to hydrochlorothiazide: pharmacovigilance analysis from the RADAR (Research on Adverse Drug events And Reports) Program.
- Author
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Pease DR, Martinez-Escala ME, Jimenez J, Guitart J, West DP, and Nardone B
- Subjects
- Databases, Factual, Humans, Hydrochlorothiazide adverse effects, Pharmacovigilance, Drug-Related Side Effects and Adverse Reactions, Lymphoma, T-Cell, Cutaneous, Skin Neoplasms
- Published
- 2021
- Full Text
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13. Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.
- Author
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Schneider JW, Oommen S, Qureshi MY, Goetsch SC, Pease DR, Sundsbak RS, Guo W, Sun M, Sun H, Kuroyanagi H, Webster DA, Coutts AW, Holst KA, Edwards BS, Newville N, Hathcock MA, Melkamu T, Briganti F, Wei W, Romanelli MG, Fahrenkrug SC, Frantz DE, Olson TM, Steinmetz LM, Carlson DF, and Nelson TJ
- Subjects
- Alleles, Animals, Cardiomyopathy, Dilated physiopathology, Cellular Reprogramming, Disease Models, Animal, Female, Gene Editing, Humans, Male, Mutation genetics, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, RNA, Messenger genetics, Sarcoplasmic Reticulum genetics, Sarcoplasmic Reticulum metabolism, Secretory Vesicles genetics, Secretory Vesicles metabolism, Swine, Cardiomyopathy, Dilated genetics, Myocardium metabolism, RNA-Binding Proteins genetics, Ribonucleoproteins genetics
- Abstract
Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.
- Published
- 2020
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14. Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas.
- Author
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Daniels J, Doukas PG, Escala MEM, Ringbloom KG, Shih DJH, Yang J, Tegtmeyer K, Park J, Thomas JJ, Selli ME, Altunbulakli C, Gowthaman R, Mo SH, Jothishankar B, Pease DR, Pro B, Abdulla FR, Shea C, Sahni N, Gru AA, Pierce BG, Louissaint A Jr, Guitart J, and Choi J
- Subjects
- Amino Acid Sequence, Antigens, CD1d metabolism, Chromatin Assembly and Disassembly, Epitopes immunology, Genome, Human, HEK293 Cells, Humans, Lymph Nodes pathology, Models, Biological, Mutation genetics, Phenotype, Principal Component Analysis, Signal Transduction, Skin pathology, Transcription, Genetic, Transcriptome genetics, Lymphoma, T-Cell, Cutaneous genetics, Lymphoma, T-Cell, Cutaneous pathology, Receptors, Antigen, T-Cell, gamma-delta metabolism, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Primary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.
- Published
- 2020
- Full Text
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15. Inflammatory bowel disease events after exposure to interleukin 17 inhibitors secukinumab and ixekizumab: Postmarketing analysis from the RADAR ("Research on Adverse Drug events And Reports") program.
- Author
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Orrell KA, Murphrey M, Kelm RC, Lee HH, Pease DR, Laumann AE, West DP, and Nardone B
- Subjects
- Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Australia, Canada, Databases, Factual, Disease Progression, Female, Humans, Inflammatory Bowel Diseases physiopathology, Male, Risk Assessment, Adverse Drug Reaction Reporting Systems, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Inflammatory Bowel Diseases chemically induced
- Published
- 2018
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16. P21-activated kinase 2 is essential in maintenance of peripheral Foxp3 + regulatory T cells.
- Author
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Choi J, Pease DR, Chen S, Zhang B, and Phee H
- Subjects
- Animals, Biomarkers, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation immunology, Forkhead Transcription Factors metabolism, Gene Knockdown Techniques, Homeostasis, Interleukin-17 metabolism, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Mice, Mice, Transgenic, Phosphorylation, Receptors, Antigen, T-Cell, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, Th17 Cells immunology, Th17 Cells metabolism, p21-Activated Kinases, T-Lymphocytes, Regulatory metabolism
- Abstract
The p21-activated kinase 2 (Pak2), an effector molecule of the Rho family GTPases Rac and Cdc42, regulates diverse functions of T cells. Previously, we showed that Pak2 is required for development and maturation of T cells in the thymus, including thymus-derived regulatory T (Treg) cells. However, whether Pak2 is required for the functions of various subsets of peripheral T cells, such as naive CD4 and helper T-cell subsets including Foxp3
+ Treg cells, is unknown. To determine the role of Pak2 in CD4 T cells in the periphery, we generated inducible Pak2 knockout (KO) mice, in which Pak2 was deleted in CD4 T cells acutely by administration of tamoxifen. Temporal deletion of Pak2 greatly reduced the number of Foxp3+ Treg cells, while minimally affecting the homeostasis of naive CD4 T cells. Pak2 was required for proliferation and Foxp3 expression of Foxp3+ Treg cells upon T-cell receptor and interleukin-2 stimulation, differentiation of in vitro induced Treg cells, and activation of naive CD4 T cells. Together, Pak2 is essential in maintaining the peripheral Treg cell pool by providing proliferation and maintenance signals to Foxp3+ Treg cells., (© 2018 The Authors. Immunology Published by John Wiley & Sons Ltd.)- Published
- 2018
- Full Text
- View/download PDF
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