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Arterial Thrombotic Complications of Tyrosine Kinase Inhibitors.
Wu MD, Moslehi JJ, Lindner JR
(2021) Arterioscler Thromb Vasc Biol 41: 3-10
MeSH Terms: Animals, Antineoplastic Agents, Arterial Occlusive Diseases, Humans, Molecular Targeted Therapy, Neoplasms, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Risk Assessment, Risk Factors, Thrombosis
Show Abstract · Added January 23, 2021
Abnormal expression or function of several classes of kinases contribute to the development of many types of solid and hematologic malignancies. TKs (tyrosine kinases) in particular play a role in tumor growth, metastasis, neovascularization, suppression of immune surveillance, and drug resistance. TKIs (tyrosine kinase inhibitors) targeted to TKs such as BCR-ABL1, VEGF receptors, PDGF receptors, have transformed therapy of certain forms of cancer by providing excellent efficacy with relatively low adverse event rates. Yet some of these agents have been associated with high rates of vascular events, presumably from prothrombotic complications that result in myocardial infarction, stroke, and critical limb ischemia. This review describes the scope of the problem evidenced by clinical experience with some of the most commonly used TKIs, with a focus on TKIs targeted to the BCR-ABL1 (breakpoint cluster region-Abelson 1) translocation. We also discuss the potential mechanisms responsible for arterial thrombotic complications that could lead to mitigation strategies or unique TK targeting strategies to reduce adverse event rates without compromising efficacy.
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11 MeSH Terms
T-B Lymphocyte Interactions Promote Type 1 Diabetes Independently of SLAM-Associated Protein.
Bonami RH, Nyhoff LE, McNitt DH, Hulbert C, Felton JL, Kendall PL, Thomas JW
(2020) J Immunol 205: 3263-3276
MeSH Terms: Animals, Autoantibodies, B-Lymphocytes, Cell Communication, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Mice, Mice, Inbred NOD, Mice, Transgenic, Signaling Lymphocytic Activation Molecule Associated Protein, Th1 Cells
Show Abstract · Added December 1, 2020
Signaling lymphocytic activation molecule-associated protein (SAP), a critical intracellular signaling molecule for T-B lymphocyte interactions, drives T follicular helper (Tfh) cell development in germinal centers (GCs). High-affinity islet autoantibodies predict type 1 diabetes (T1D) but do not cause β cell destruction. This paradox intimates Tfh cells as key pathologic effectors, consistent with an observed Tfh signature in T1D. To understand how fully developed Tfh (GC Tfh) contribute to different autoimmune processes, we investigated the role of SAP in T1D and autoantibody-mediated arthritis. Whereas spontaneous arthritis depended on in the autoantibody-mediated K/BxN model, organized insulitis and diabetes onset were unabated, despite a blocked anti-insulin vaccine response in -deficient NOD mice. GC Tfh and GC B cell development were blocked by loss of in K/BxN mice. In contrast, although GC B cell formation was markedly reduced in -deficient NOD mice, T cells with a GC Tfh phenotype were found at disease sites. CXCR3 CCR6 (Tfh1) subset bias was observed among GC Tfh cells infiltrating the pancreas of NOD mice, which was enhanced by loss of NOD T cells override requirement to undergo activation and proliferation in response to Ag presentation, demonstrating the potential for productive cognate T-B lymphocyte interactions in T1D-prone mice. We find that is essential when autoantibody-driven immune complexes promote inflammation but is not required for effective organ-specific autoimmune attack. Thus, Tfh induced in classic GC reactions are dispensable for T1D, but the autoimmune process in the NOD model retains pathogenic Tfh without .
Copyright © 2020 by The American Association of Immunologists, Inc.
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11 MeSH Terms
Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngeneic murine models of ovarian cancer.
Hoover AA, Hufnagel DH, Harris W, Bullock K, Glass EB, Liu E, Barham W, Crispens MA, Khabele D, Giorgio TD, Wilson AJ, Yull FE
(2020) BMC Cancer 20: 970
MeSH Terms: Animals, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Female, Humans, Macrophages, Mice, Mice, Transgenic, NF-kappa B, Signal Transduction
Show Abstract · Added January 29, 2021
BACKGROUND - New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-κB) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown. Therefore, we aimed to investigate the therapeutic potential of increasing macrophage NF-κB activity in immunocompetent mouse models of ovarian cancer.
METHODS - We have generated a transgenic mouse model, termed IKFM, which allows doxycycline-inducible overexpression of a constitutively active form of IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to evaluate effects of increasing macrophage NF-κB activity in syngeneic murine TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in established tumors, and 2) during tumor implantation and early tumor growth. Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor were collected at sacrifice. Populations of macrophages and T cells within solid tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value < 0.05 was considered statistically significant.
RESULTS - Increased expression of the cIKK2 transgene in TAMs from IKFM mice was confirmed at the mRNA and protein levels. Tumors from IKFM mice, regardless of the timing of doxycycline (dox) administration, demonstrated greater necrosis and immune infiltration than control tumors. Analysis of IKFM ascites and tumors showed sustained shifts in macrophage populations away from the M2 and towards the anti-tumor M1 phenotype. There were also increased tumor-infiltrating CD3/CD8 T cells in IKFM mice, accompanied by higher levels of CXCL9, a T cell activating factor secreted by macrophages, in IKFM ascitic fluid.
CONCLUSIONS - In syngeneic ovarian cancer models, increased canonical NF-κB signaling in macrophages promoted anti-tumor TAM phenotypes and increased cytotoxic T cell infiltration, which was sufficient to limit tumor progression. This may present a novel translational approach for ovarian cancer treatment, with the potential to increase responses to T cell-directed therapy in future studies.
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11 MeSH Terms
A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis.
Zhou D, Jiang Y, Zhong X, Cox NJ, Liu C, Gamazon ER
(2020) Nat Genet 52: 1239-1246
MeSH Terms: Animals, Gene Expression Profiling, Genetic Association Studies, Humans, Lipoproteins, LDL, Mendelian Randomization Analysis, Mice, Models, Genetic, Multifactorial Inheritance, Predictive Value of Tests
Show Abstract · Added October 7, 2020
Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches.
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10 MeSH Terms
A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin.
Kondo J, Huh WJ, Franklin JL, Heinrich MC, Rubin BP, Coffey RJ
(2020) J Pathol 252: 441-450
MeSH Terms: Animals, Biomarkers, Tumor, Disease Models, Animal, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Mice, Muscle, Smooth, Mutation, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-kit, Receptor, Platelet-Derived Growth Factor alpha
Show Abstract · Added September 25, 2020
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gut. GISTs are thought to arise solely from interstitial cells of Cajal (ICC), a KIT-positive population that controls gut motility. Activating gain-of-function mutations in KIT and PDGFRA are the most frequent driver events, and most of these tumors are responsive to the tyrosine kinase inhibitor imatinib. Less common drivers include mutant BRAF and these tumors are resistant to imatinib. A mouse model of GIST was recently reported using Etv1, the master transcriptional regulator of ICC-intramuscular (IM) and ICC-myenteric (MY), to induce mutant Braf expression. ICC hyperplasia was observed in Etv1 ;Braf mice but loss of Trp53 was required for development of GIST. We identified previously expression of the pan-ErbB negative regulator, LRIG1, in two distinct subclasses of ICC [ICC-deep muscular plexus (DMP) in small intestine and ICC-submucosal plexus (SMP) in colon] and that LRIG1 regulated their development from smooth muscle cell progenitors. Using Lrig1 to induce Braf , we observed ICC hyperplasia beyond the confines of ICC-DMP and ICC-SMP expression, suggesting smooth muscle cells as the cell-of-origin. To examine this possibility, we selectively activated Braf in smooth muscle cells. Myh11 ;Braf mice developed not only ICC hyperplasia but also GIST and in the absence of Trp53 disruption. In addition to providing a simpler model for mutant Braf GIST, these results provide conclusive evidence for smooth muscle cells as an alternative cell-of-origin for GIST. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
© 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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11 MeSH Terms
Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity.
Miller JM, Meki MH, Ou Q, George SA, Gams A, Abouleisa RRE, Tang XL, Ahern BM, Giridharan GA, El-Baz A, Hill BG, Satin J, Conklin DJ, Moslehi J, Bolli R, Ribeiro AJS, Efimov IR, Mohamed TMA
(2020) Toxicol Appl Pharmacol 406: 115213
MeSH Terms: Adult, Aged, Animals, Antineoplastic Agents, Apoptosis, Cardiotoxicity, Cardiotoxins, Doxorubicin, Female, Heart, Humans, Induced Pluripotent Stem Cells, Male, Middle Aged, Models, Biological, Swine, Tissue Culture Techniques, Trastuzumab
Show Abstract · Added September 29, 2020
The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1-1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.
Copyright © 2020 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Succinate Produced by Intestinal Microbes Promotes Specification of Tuft Cells to Suppress Ileal Inflammation.
Banerjee A, Herring CA, Chen B, Kim H, Simmons AJ, Southard-Smith AN, Allaman MM, White JR, Macedonia MC, Mckinley ET, Ramirez-Solano MA, Scoville EA, Liu Q, Wilson KT, Coffey RJ, Washington MK, Goettel JA, Lau KS
(2020) Gastroenterology 159: 2101-2115.e5
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Chemoreceptor Cells, Crohn Disease, DNA, Bacterial, Disease Models, Animal, Feces, Female, Gastrointestinal Microbiome, Humans, Ileitis, Ileum, Intestinal Mucosa, Male, Mice, Mice, Knockout, Protective Factors, RNA, Ribosomal, 16S, RNA-Seq, Single-Cell Analysis, Succinic Acid
Show Abstract · Added September 17, 2020
BACKGROUND & AIMS - Countries endemic for parasitic infestations have a lower incidence of Crohn's disease (CD) than nonendemic countries, and there have been anecdotal reports of the beneficial effects of helminths in CD patients. Tuft cells in the small intestine sense and direct the immune response against eukaryotic parasites. We investigated the activities of tuft cells in patients with CD and mouse models of intestinal inflammation.
METHODS - We used microscopy to quantify tuft cells in intestinal specimens from patients with ileal CD (n = 19), healthy individuals (n = 14), and TNF mice, which develop Crohn's-like ileitis. We performed single-cell RNA sequencing, mass spectrometry, and microbiome profiling of intestinal tissues from wild-type and Atoh1-knockout mice, which have expansion of tuft cells, to study interactions between microbes and tuft cell populations. We assessed microbe dependence of tuft cell populations using microbiome depletion, organoids, and microbe transplant experiments. We used multiplex imaging and cytokine assays to assess alterations in inflammatory response following expansion of tuft cells with succinate administration in TNF and anti-CD3E CD mouse models.
RESULTS - Inflamed ileal tissues from patients and mice had reduced numbers of tuft cells, compared with healthy individuals or wild-type mice. Expansion of tuft cells was associated with increased expression of genes that regulate the tricarboxylic acid cycle, which resulted from microbe production of the metabolite succinate. Experiments in which we manipulated the intestinal microbiota of mice revealed the existence of an ATOH1-independent population of tuft cells that was sensitive to metabolites produced by microbes. Administration of succinate to mice expanded tuft cells and reduced intestinal inflammation in TNF mice and anti-CD3E-treated mice, increased GATA3 cells and type 2 cytokines (IL22, IL25, IL13), and decreased RORGT cells and type 17 cytokines (IL23) in a tuft cell-dependent manner.
CONCLUSIONS - We found that tuft cell expansion reduced chronic intestinal inflammation in mice. Strategies to expand tuft cells might be developed for treatment of CD.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Casein Kinase 1α as a Regulator of Wnt-Driven Cancer.
Shen C, Nayak A, Melendez RA, Wynn DT, Jackson J, Lee E, Ahmed Y, Robbins DJ
(2020) Int J Mol Sci 21:
MeSH Terms: Animals, Antineoplastic Agents, Casein Kinase Ialpha, Enzyme Activators, Humans, Neoplasms, Wnt Signaling Pathway
Show Abstract · Added August 24, 2020
Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.
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7 MeSH Terms
Nuclear Regulation of Wnt/β-Catenin Signaling: It's a Complex Situation.
Anthony CC, Robbins DJ, Ahmed Y, Lee E
(2020) Genes (Basel) 11:
MeSH Terms: Active Transport, Cell Nucleus, Animals, Cell Nucleus, Gene Expression Regulation, Developmental, Humans, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added August 10, 2020
Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway-nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes.
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7 MeSH Terms
Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D.
DelGiorno KE, Chung CY, Vavinskaya V, Maurer HC, Novak SW, Lytle NK, Ma Z, Giraddi RR, Wang D, Fang L, Naeem RF, Andrade LR, Ali WH, Tseng H, Tsui C, Gubbala VB, Ridinger-Saison M, Ohmoto M, Erikson GA, O'Connor C, Shokhirev MN, Hah N, Urade Y, Matsumoto I, Kaech SM, Singh PK, Manor U, Olive KP, Wahl GM
(2020) Gastroenterology 159: 1866-1881.e8
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Ceruletide, Disease Models, Animal, Energy Metabolism, Fibrosis, Humans, Interleukins, Intramolecular Oxidoreductases, Mice, Transgenic, Mutation, Octamer Transcription Factors, Pancreas, Pancreatic Neoplasms, Pancreatitis, Prostaglandin D2, Proto-Oncogene Proteins p21(ras), Time Factors, Transcription Factors
Show Abstract · Added March 13, 2021
BACKGROUND & AIMS - Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells because of the lack of animal models. We investigated the role of tuft cells in pancreatic tumorigenesis.
METHODS - We performed studies with LSL-Kras;Ptf1a mice (KC; develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice; do not develop tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice) and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA-sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasia (PanIN), 19 patients with intraductal papillary mucinous neoplasms (IPMNs), and 197 patients with PDA.
RESULTS - Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells after administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of prostaglandin D, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury after administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and intraductal papillary mucinous neoplasm had gene expression signatures associated with tuft cells and increased expression of Hpgds messenger RNA compared with PDA.
CONCLUSIONS - In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of prostaglandin D. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms