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1
Horn, Lucas, Haiyan Qin, Kristen Fousek, Masafumi Iida, Dallas Flies, Ronald Copeland, Zachary Cusumano, et al. "570 Blockade of the inhibitory collagen receptor LAIR-1, PD-L1, and TGF-β promotes anti-tumor activity through T cell activation and myeloid cell polarization." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A599. http://dx.doi.org/10.1136/jitc-2021-sitc2021.570.
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BackgroundLeukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an immune inhibitory receptor that binds collagen-like domains commonly found in extracellular matrix (ECM) collagens and complement component C1q. LAIR-1 is expressed on several immune cell types including activated T cells, B cells, NK cells, dendritic cells, and macrophages. Numerous cancer types including gastric, colon, ovarian, bladder, and others, upregulate collagens which enhances tumor growth, metastases, and invasion while actively suppressing antitumor immunity. While a soluble decoy, LAIR-2, is expressed in humans and competes with LAIR-1 for binding of collagen domains, excess LAIR ligands in the tumor often result in an immune suppressive environment.MethodsHere, we report on a novel immunotherapy approach combining NC410, a novel fusion protein consisting of two LAIR-2 molecules grafted on to an IgG1 antibody backbone, capable of targeting the tumor ECM and blocking LAIR-1 signaling; and bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β ”trap”) fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti–PD-L1).ResultsWe have demonstrated that the combination of NC410 and bintrafusp alfa more effectively controls in vivo tumor growth of the collagen rich MC38 colon and EMT6 mammary carcinomas compared to either monotherapy. We demonstrate that this potent anti-tumor immune response is propagated through the synergy of activated tumor infiltrating lymphocytes and a repolarization of myeloid cells in the tumor microenvironment. MC38 tumors treated with the combination of NC410 plus bintrafusp alfa contained higher numbers of infiltrating T cells, NK cells, and M1 polarized macrophages.ConclusionsThis study highlights the synergy of reshaping the large suppressive myeloid cell populations often present in tumors with activation of adaptive T-cell immune responses dampened by checkpoint inhibition. The results also provide the rationale for the future evaluation of this combination therapy in the clinic.
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Horn, Lucas, Linjie Tian, Dallas Flies, Linda Liu, Solomon Langermann, Jeffrey Schlom, and Claudia Palena. "445 Blockade of the inhibitory collagen receptor LAIR-1 with NC410, a LAIR2-Fc fusion protein, enhances anti-tumor activity of the bifunctional fusion protein bintrafusp alfa." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A471. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0445.
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BackgroundLAIR-1 is an immune inhibitory receptor expressed on several immune cell types including activated T cells, B cells, NK cells, macrophages, and dendritic cells. The ligands for LAIR-1 contain collagen-like domains which are commonly found in extracellular matrix collagens and complement component C1q. In numerous cancer types, including gastric, colon, ovarian, bladder, and others, upregulation of collagens has been shown to enhance tumor growth, metastases, and invasion while actively suppressing antitumor immunity. Although humans produce a natural, soluble decoy, LAIR-2, that competes with LAIR-1 for binding of collagen domains, excess LAIR ligands in the tumor often result in an immune suppressive environment.MethodsHere, we report on a novel immunotherapy approach which combined NC410, a LAIR-2-Fc fusion protein capable of blocking LAIR-1 signaling, and bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β ‘trap’) fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti–PD-L1).ResultsWe demonstrate that the combination of NC410 and bintrafusp alfa more effectively controls in vivo tumor growth of the collagen rich MC38 colon carcinoma compared to either monotherapy. We hypothesize that this potent anti-tumor immune response is propagated through the synergy of activated tumor infiltrating lymphocytes and a repolarization of macrophages towards a tumoricidal phenotype. MC38 tumors treated with the combination of NC410/Bintrafusp alfa contained higher numbers of infiltrating CD4+ and CD8+ T cells and higher numbers of CD38+ and MHCII+ M1 polarized macrophages.ConclusionsThis study highlights the synergy of reshaping the large suppressive myeloid cell populations often present in tumors with activation of adaptive T-cell immune responses dampened by checkpoint inhibition. The results also provide the rationale for the future evaluation of this combination therapy in the clinic.AcknowledgementsBintrafusp alfa was kindly provided by EMD Serono under a CRADA with the NCI.Trial RegistrationN/AEthics ApprovalMice were maintained under pathogen-free conditions in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care guidelines. All animal studies were approved by the NIH Intramural Animal Care and Use Committee under protocol LTIB-038.ConsentN/A
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Barreto, Deirisa Lopes, Annemieke M. Coester, Dirk G. Struijk, and Raymond T. Krediet. "Can Effluent Matrix Metalloproteinase 2 and Plasminogen Activator Inhibitor 1 be Used as Biomarkers of Peritoneal Membrane Alterations in Peritoneal Dialysis Patients?" Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 33, no. 5 (September 2013): 529–37. http://dx.doi.org/10.3747/pdi.2012.01063.
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BackgroundPeritoneal effluent contains clinically relevant substances derived from intraperitoneal production or transperitoneal transport, or both. The glycoproteinase matrix metalloproteinase 2 (MMP-2) cleaves denatured collagen and complements other collagenases in the degradation of fibrillar collagens. Elevated intraperitoneal levels of plasminogen activator inhibitor 1 (PAI-1) have been demonstrated to be present in patients with intra-abdominal adhesions. The aim of the present study was therefore to investigate the potential for effluent MMP-2 and PAI-1 to be used as markers of the development of peritoneal alterations. In addition, MMP-2 was analyzed in previously frozen effluent samples from a uremic rat model, in which data concerning the severity of peritoneal fibrosis were available.MethodsThis prospective, single-center cohort study included 86 incident peritoneal dialysis (PD) patients. All patients were treated solely with biocompatible dialysis solutions and underwent a standard peritoneal permeability analysis (SPA). The presence of local MMP-2 and PAI-1 production and the relationships between those markers and peritoneal transport parameters were analyzed. Furthermore, effluent interleukin 6 was analyzed as a marker of local inflammation.ResultsMedian effluent levels of 21.4 ng/mL for MMP-2 and 0.9 ng/mL for PAI-1 were found. The median dialysate appearance rates were 218.8 ng/min for MMP-2 and 9.6 ng/min for PAI-1. Local peritoneal production averaged 90% of effluent MMP-2 concentration and 74% of effluent PAI-1 concentration. Furthermore, correlations between peritoneal transport parameters and MMP-2 and PAI-1 were observed. Longitudinal follow-up showed no change for MMP-2 ( p = 0.37), but a tendency for PAI-1 to increase with the duration of PD ( p < 0.001). In rats, a significant relationship was present between the extent of peritoneal fibrosis and the appearance rate of MMP-2 ( r = 0.64, p = 0.03).ConclusionsThe foregoing data illustrate the potential of effluent MMP-2 and PAI-1 as biomarkers of peritoneal modifications, especially fibrosis; however, the components of peritoneal transport and local production should be clearly distinguished in every patient.
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Feng, Chao, Xi Wang, Yuting Tao, Yuanliang Xie, Zhiyong Lai, Zhijian Li, Jiaxin Hu, et al. "Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer." Cancers 13, no. 21 (October 29, 2021): 5440. http://dx.doi.org/10.3390/cancers13215440.
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Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an integrated combination of mass cytometry and imaging mass cytometry was used to analyze tumor cells, immune cells, and TME spatial characteristics of 44 MIBC patients. We detected tumor and immune cell clusters with abnormal phenotypes. In particular, we identified a previously overlooked cancer stem-like cell cluster (ALDH+PD-L1+ER-β−) that was strongly associated with poor prognosis. We elucidated the different spatial architectures of immune cells (excluded, infiltrated, and deserted) and tumor-associated collagens (curved, stretched, directionally distributed, and chaotic) in the MIBC TME. The present study is the first to provide in-depth insight into the complexity of the MIBC TME at the single-cell level. Our results will improve the general understanding of the heterogeneous characteristics of MIBC, potentially facilitating patient stratification and personalized therapy.
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Komiya, Takefumi, Jun Zhang, Prakash C. Neupane, Kathan Mehta, and Chao Hui Huang. "Combination of atezolizumab and pirfenidone in second-line and beyond NSCLC: A phase I/II study." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS2678. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps2678.
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TPS2678 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis significantly improved patient outcomes in stage IV non-small cell lung cancer (NSCLC). However, these patients will eventually develop resistance and progression. There is a need to identify novel treatment options. Poor response to PD-L1 antibody was correlated with increase in cancer-associated fibroblasts (CAF), which is known to interact with cytotoxic T cells (CTLs) by suppressing their function in a manner similar to regulatory T cells (Tregs). Production of cytokines by CAFs leads to impaired antitumor immunity by impairing CTL function (TGF beta) and prevent recruitment/mobilization of CTLs into tumors. These effects suggesting that CAF can be a therapeutic target in lung cancer resistant to checkpoint inhibitors. Pirfenidone (P) is approved to treat pulmonary fibrosis with anti-fibrotic effect by blocking the differentiation of fibroblasts into CAFs and suppress the production of TGF beta and TGF beta-induced signaling pathways/collagens. Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (CD80), both of which function as inhibitory receptors expressed on T cells. We proposed a phase I/II trial to test the combination of atezolizumab (A) with P in patients with recurrent non-small cell lung cancer (NSCLC) after progression with CPI. The primary objective of phase I is to determine the maximum tolerated (MTD) dose of P in combination with A and assess the safety and tolerability of this combination. The secondary objective is to determine the efficacy of AP in all NSCLC participants treated in this study. Exploratory objectives include the measurement of circulating levels of TGF beta and research in expression of CAF related proteins. Methods: The initial phase I will enroll 3 patients using P at 801 mg po TID. A will be at 1200mg iv every 3 weeks. If there is ≤ 1 DLT, the study will proceed to phase II If there are 2- 3 DLT, P will be reduced to 534 mg TID. If there is ≤ 1 DLT, then this dose will proceed to phase II. If there is 2-3 DLT, then the study will be terminated. The phase II will enroll 16 patients to assess efficacy. Main inclusion criteria are patients with recurrent NSCLC after progression with first-line therapy CPI with or without chemotherapy, measurable disease, ECOG 0-2, and adequate organ function. Clinical trial information: NCT04467723.
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Broz, Marina T., Marco DeSimone, Emily Ko, Roberta Piras, and Jlenia Guarnerio. "Abstract A29: Uncovering transcriptional signatures of drug resistant tumor cells: Mechanisms of therapeutic resistance and opportunities for combination therapies." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A29. http://dx.doi.org/10.1158/2326-6074.tumimm22-a29.
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Abstract Soft tissue sarcomas (STS) are tumors of mesenchymal origin and include multiple sub-types such as undifferentiated pleomorphic sarcoma (UPS) which is the most frequent classification of STS. UPS is one of the most aggressive and recurrent sarcomas. The current standard of care for UPS patients remains surgical resection, radiotherapy, and chemotherapy, but many patients still develop recurrent tumors after these interventions. In addition, anti-PD-1 therapy has only been successful in a small fraction of patients with high levels of tumor infiltrating B and T cells, while immune excluded tumors showed poor responses. To understand why these tumors are frequently recurrent, it is essential to understand the characteristics of resistant tumor cells following standard treatment regimens in both immune excluded and immune infiltrated tumor microenvironments. We generated multiple mouse models that reflect the genetic alterations frequently found in patients via overexpression of oncogenes Ccne1 or Vgll3 in p53KO mesenchymal stem cells. Classification of the immune microenvironment of these models revealed that these driver genetics promote an immune excluded or immune infiltrated tumor microenvironment, respectively. We leveraged these two tumor models to understand the mechanisms of therapeutic resistance to common agents doxorubicin or anti-PD-1. We found that despite higher levels of baseline tumor infiltrating lymphocytes in Vgll3 tumors, anti-PD-1 failed to reduce tumor growth. Doxorubicin treatment resulted in a modest reduction of tumor volume in Ccne1 tumors, and more significantly in immune infiltrated Vgll3 tumors. To understand the transcriptional profiles of resistant tumor cells we harnessed single-cell RNA-sequencing (scRNA-seq) to characterize the least responsive model to determine if treatments had an impact on tumor cell expression profiles and which tumor clusters persist after treatment. scRNA-seq analysis revealed that different clusters of tumor cells were differently affected by anti-PD-1 and doxorubicin. While doxorubicin mainly affected tumor cells expressing collagens and matrix associated adhesion proteins, treatment with anti-PD-1 selectively reduced tumor cells enriched in interferon signaling pathways. Interestingly, tumor cells expressing high levels of extracellular matrix (ECM) remodeling genes remained unaffected and, in some cases, were enriched under both treatments. These results may suggest that tumor cells capable of ECM remodeling may shield tumor cells from chemotherapy agents and immune cells from immune checkpoint inhibitors and promote tumor recurrence. Therefore, these results highlight the need for investigation of combination therapies targeting extracellular matrix proteins in addition to immune checkpoint blockade. Citation Format: Marina T Broz, Marco DeSimone, Emily Ko, Roberta Piras, Jlenia Guarnerio. Uncovering transcriptional signatures of drug resistant tumor cells: Mechanisms of therapeutic resistance and opportunities for combination therapies [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A29.
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Huang, Tao, Caroline Bonnans, Maria Jose Costa, Azita Tabrizi, Jing-Tyan Ma, Jingjing Xie, Heyu Chen, et al. "304 Antagonistic antibodies targeting LAIR1 enhance T lymphocyte activation and promote inflammatory phenotypes in myeloid cells." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A327. http://dx.doi.org/10.1136/jitc-2021-sitc2021.304.
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BackgroundThe Leukocyte Associated Immunoglobulin-like Receptor 1 (LAIR1) is an immune inhibitory transmembrane glycoprotein expressed on lymphocytes and myeloid cells. The known ligands for LAIR1 are proteins containing collagen-like domains including collagen, complement component 1q (C1q), and stromal protein Colec12.1 2 3 Myeloid-derived suppressor cells (MDSC), tumor associated macrophages (TAMs), as well as collagens, are important contributors of the immune-suppressive tumor microenvironment, and LAIR1 expression is negatively correlated with patient survival in many solid tumors.4 These findings prompt us to investigate LAIR1 as a novel immuno-oncology target in collagen-rich tumors. Utilizing LAIR1 antagonist antibodies, we aim to mobilize anti-tumor immunity by changing the collagen-induced tolerogenic state of the immune cells into proinflammatory.MethodsThe mRNA expression levels of LAIR1, collagen, and C1q in diverse human cancers were analyzed using the TCGA database. LAIR1 protein expression on tumor infiltrated immune cells were measured by flow cytometry. Human tumor samples were obtained from Cooperative Human Tissue Network (CHTN) by the National Cancer Institute (NCI). Purified human T cells from healthy donors were stimulated with immobilized anti-CD3 in the presence of plate-coated human collagen I. Human monocyte-derived macrophages and dendritic cells (DC) were differentiated with M-CSF+IL-4 or GM-CSF+IL-4, respectively. Immune cell phenotypes were assessed by flow cytometry and cytokine secretion by Luminex.ResultsAnalysis of the TCGA database using signature genes specific to macrophages, T cells, DCs, and natural killer (NK) cells demonstrate that LAIR1 is highly expressed in most macrophage-infiltrated tumors and certain T cell-enriched tumors. LAIR1 and collagen are co-expressed at high levels in multiple macrophage-enriched tumors. Flow cytometry analysis of infiltrated immune cells from fresh tumor tissues showed that the highest level of LAIR1 protein expression was detected on TAMs, followed by monocytes, monocytic MDSCs, DCs, and lymphocytes. In vitro, LAIR1 antagonizing antibodies enhanced T-cell activation, proliferation, and IFNγ and TNFα production in comparison to isotype controls in the presence of collagen. Blocking LAIR1 interaction with collagen also decreased the expression of M2 markers such as PD-L1 and CD209 on monocyte-derived M2 macrophages. Additionally, treatment of monocyte-derived DCs by these antibodies increased the expression of the co-stimulatory protein CD86 and promoted the release of IL-12, a crucial cytokine for lymphocyte activation.ConclusionsThese in vitro data suggest that LAIR1 blockade could potentially reverse T-cell and myeloid immunosuppression mediated by collagen, demonstrating the therapeutic potential of anti-LAIR1 antagonistic antibodies.ReferencesMeyaard L. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol 2008;83:799–803.Son M, et al. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. PNAS 2012;109:3160–3167.Keerthivasan S, et al. Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1. Immunity 2021;54:1511–1526.Xu L, et al. Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1. OncoImmunology 2020;9:e17404771–e17404779.
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Rike, Wote Amelo, and Shani Stern. "Proteins and Transcriptional Dysregulation of the Brain Extracellular Matrix in Parkinson’s Disease: A Systematic Review." International Journal of Molecular Sciences 24, no. 8 (April 18, 2023): 7435. http://dx.doi.org/10.3390/ijms24087435.
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The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational, and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect cellular functions and may result in disease. However, most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix in disease pathogenesis. Thus, due to the ECM’s diversified biological roles, increasing interest in its involvement in disease, and the lack of sufficient compiled evidence regarding its relationship with Parkinson’s disease (PD) pathology, we aimed to compile the existing evidence to boost the current knowledge on the area and provide refined guidance for the future research. Here, in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google Scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson’s disease (PD). A literature search was conducted up until 10 February 2023. The overall hits from the database and manual search for proteomic and transcriptome studies were 1243 and 1041 articles, respectively. Following a full-text review, 10 articles from proteomic and 24 from transcriptomic studies were found to be eligible for inclusion. According to proteomic studies, proteins such as collagens, fibronectin, annexins, and tenascins were recognized to be differentially expressed in Parkinson’s disease. Transcriptomic studies displayed dysregulated pathways including ECM–receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson’s disease. A limited number of relevant studies were accessed from our search, indicating that much work remains to be carried out to better understand the roles of the ECM in neurodegeneration and Parkinson’s disease. However, we believe that our review will elicit focused primary studies and thus support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson’s disease.
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Chamson, A., M. F. Bertheas, and J. Frey. "Collagen biosynthesis in cell culture from chorionic villi." Prenatal Diagnosis 15, no. 2 (February 1995): 165–70. http://dx.doi.org/10.1002/pd.1970150210.
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Celada, Lindsay J., Jonathan A. Kropski, Jose D. Herazo-Maya, Weifeng Luo, Amy Creecy, Andrew T. Abad, Ozioma S. Chioma, et al. "PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production." Science Translational Medicine 10, no. 460 (September 26, 2018): eaar8356. http://dx.doi.org/10.1126/scitranslmed.aar8356.
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Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor–β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+ T cells. PD-1+ T helper 17 cells are the predominant CD4+ T cell subset expressing TGF-β. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
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Neugarten, Joel, Ildiko Medve, Jun Lei, and Sharon R. Silbiger. "Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade." American Journal of Physiology-Renal Physiology 277, no. 6 (December 1, 1999): F875—F881. http://dx.doi.org/10.1152/ajprenal.1999.277.6.f875.
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We have previously shown that estradiol suppresses the synthesis of type I collagen by murine mesangial cells grown in the presence of serum via activation of the transcription factor activator protein-1 (AP-1). We hypothesized that estradiol upregulates AP-1 via activation of the mitogen-activated protein (MAP) kinase cascade, a signal transduction pathway that regulates AP-1 activity. Estradiol (10−10 to 10−7 M) upregulated the MAP kinase pathway in murine mesangial cells grown in the presence of serum in a dose-dependent manner. Activation was evident by 1 min, peaked at 10 min, and was completely dissipated by 2 h. In contrast, estradiol had no significant effect on total (phosphorylated + unphosphorylated) p44 extracellular signal-related protein kinase (ERK) or p42 ERK. Nuclear extracts isolated from mesangial cells treated with estradiol showed increased binding to a consensus sequence AP-1 binding oligonucleotide in gel shift assays. In contrast, nuclear extracts from cells exposed to PD-98059, a highly selective inhibitor of MAP kinase-ERK kinase 1 (MEK1) and MEK2, showed reduced binding. In addition, PD-98059 antagonizes the enhanced binding induced by estradiol. Estradiol (10−9M) suppressed mesangial cell type I collagen synthesis (37.8 ± 2.4%, expressed as a percentage of control values, P < 0.001 vs. control). In contrast, PD-98059 increased type I collagen synthesis (344.6 ± 98.8, P < 0.01) and reversed the suppression of type I collagen synthesis induced by estradiol. The effects of estradiol, PD-98059, and PD-98059 plus estradiol on type I collagen protein synthesis were closely paralleled by their effects on steady-state levels of mRNA for the α1 chain of type I collagen. These data suggest that estradiol suppresses type I collagen synthesis via upregulation of the MAP kinase cascade, leading to stimulation of AP-1 activity.
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Wood, Megan Kay, Monica V. Talor, Taejoon Won, and Daniela Cihakova. "PD-L1 on macrophages protects from severe collagen induced arthritis." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 60.12. http://dx.doi.org/10.4049/jimmunol.206.supp.60.12.
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Abstract Immune related adverse events linked to severe inflammatory arthritis have been identified in 10–43% of patients receiving immune checkpoint inhibitor therapy, aCTLA-4, aPD-1 and aPD-L1, indicating the importance of immune inhibitory pathways in maintaining homeostasis in the synovium. We found that immune checkpoint, PD-L1, is primarily expressed in the joint compared to other immune checkpoints. Furthermore, blocking of PD-L1 during collagen induced arthritis (CIA) resulted in more severe arthritis. Mice synovial macrophages have the highest PD-L1 expression level at homeostasis and macrophage PD-L1 expression is further increased during CIA. Similarly, in human synovial fluid, macrophages have the highest frequency of PD-L1 expression. We hypothesize that the expression of PD-L1 by macrophages is essential for synovial homeostasis and regulation of joint inflammation. We selectively deleted PD-L1 in macrophages using the cre/flox system and induced CIA analyzing disease severity using flow cytometry. LyzcrePD-L1fl/fl showed more severe CIA with a greater change in paw thickness, higher disease and histology score and a higher frequency of CD4 and CD8 T cells in the synovium. Interestingly, female LyzcrePD-L1fl/fl mice have higher arthritis severity to LyzcrePD-L1fl/fl males. This indicates the importance of sex specific PD-L1 expression by synovial macrophages during CIA. Our project has high translational potential since joint specific PD-L1 expression could be modulated for therapeutic purposes in humans with rheumatoid arthritis or check point inhibitors induced arthritis.
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Wood, Megan Kay, Monica V. Talor, Taejoon Won, and Daniela Čiháková. "PD-L1 on macrophages protects from severe collagen induced arthritis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 73.12. http://dx.doi.org/10.4049/jimmunol.204.supp.73.12.
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Abstract Immune related adverse events linked to severe inflammatory arthritis have been identified in 10–43% of patients receiving immune checkpoint inhibitor therapy, aCTLA-4, aPD-1 and aPD-L1, indicating the importance of immune inhibitory pathways in maintaining homeostasis in the synovium. We found that immune checkpoint, PD-L1, is primarily expressed in the joint compared to other immune checkpoints. Furthermore, blocking of PD-L1 during collagen induced arthritis (CIA) resulted in more severe arthritis. Mice synovial macrophages have the highest PD-L1 expression level at homeostasis and macrophage PD-L1 expression is further increased during CIA. Similarly, in human synovial fluid, macrophages have the highest frequency of PD-L1 expression. We hypothesize that the expression of PD-L1 by macrophages is essential for synovial homeostasis and regulation of joint inflammation. We selectively deleted PD-L1 in macrophages using the cre/flox system and induced CIA analyzing disease severity using flow cytometry. LyzcrePD-L1fl/fl showed more severe CIA with a greater change in paw thickness, higher disease and histology score and a higher frequency of CD4 and CD8 T cells in the synovium. Interestingly, female LyzcrePD-L1fl/fl mice have higher arthritis severity to LyzcrePD-L1fl/fl males. This indicates the importance of sex specific PD-L1 expression by synovial macrophages during CIA. Our project has high translational potential since joint specific PD-L1 expression could be modulated for therapeutic purposes in humans with rheumatoid arthritis or check point inhibitors induced arthritis.
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Li, Xian-Wei, Jie Du, Gao-Yun Hu, Chang-Ping Hu, Dai Li, Yuan-Jian Li, and Xiao-Hui Li. "Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats." Canadian Journal of Physiology and Pharmacology 92, no. 1 (January 2014): 58–69. http://dx.doi.org/10.1139/cjpp-2013-0056.
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Fluorofenidone (AKF-PD) is a novel pyridone derivate that targets transforming growth factor-β1 (TGF-β1) signaling. Previous studies have proven that AKF-PD functions as an antifibrotic agent in pulmonary fibrosis and renal fibrosis models. Activated TGF-β1 signaling is thought to be a major feature of pulmonary hypertension (PH). TGF-β1 exerts powerful pro-proliferation effects on pulmonary arterial smooth muscle cells (PASMCs), and hence, prompts vascular remodeling. This study is designed to investigate the effect of AKF-PD on vascular remodeling in a rat model of hypoxia-induced PH. PH was induced in rats by 4 weeks of hypoxia. The expression of TGF-β1, collagen I, and collagen III was analyzed by ELISA, immunohistochemistry, real-time PCR, or Western blot. Proliferation of cultured PASMCs was determined by the BrdU incorporation method and flow cytometry. The results showed that AKF-PD treatment (0.5 or 1.0 g·(kg body mass)·d−1) for 4 weeks attenuated pulmonary vascular remodeling and improved homodynamic parameters. TGF-β1 level was significantly down-regulated by AKF-PD both in vivo and in vitro. Furthermore, hypoxia- and TGF-β1-induced PASMC proliferation and collagen expression were both significantly suppressed by AKF-PD. These results suggest that AKF-PD ameliorates the progression of PH induced by hypoxia in rats through its regulation of TGF-β1 expression, PASMC proliferation, and the extracellular matrix.
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Peng, Yu, Huixiang Yang, Nasui Wang, Yan Ouyang, Yanrong Yi, Litao Liao, Hong Shen, Gaoyun Hu, Zhaohe Wang, and Lijian Tao. "Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 306, no. 3 (February 1, 2014): G253—G263. http://dx.doi.org/10.1152/ajpgi.00471.2012.
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Fluorofenidone (AKF-PD) is a novel pyridone agent. The purpose of this study is to investigate the inhibitory effects of AKF-PD on liver fibrosis in rats and the involved molecular mechanism related to hepatic stellate cells (HSCs). Rats treated with dimethylnitrosamine or CCl4 were randomly divided into normal, model, AKF-PD treatment, and pirfenidone (PFD) treatment groups. The isolated primary rat HSCs were treated with AKF-PD and PFD respectively. Cell proliferation and cell cycle distribution were analyzed by bromodeoxyuridine and flow cytometry, respectively. The expression of collagen I and α-smooth muscle actin (α-SMA) were determined by Western blot, immunohistochemical staining, and real-time RT-PCR. The expression of cyclin D1, cyclin E, and p27kip1 and phosphorylation of MEK, ERK, Akt, and 70-kDa ribosomal S6 kinase (p70S6K) were detected by Western blot. AKF-PD significantly inhibited PDGF-BB-induced HSC proliferation and activation by attenuating the expression of collagen I and α-SMA, causing G0/G1 phase cell cycle arrest, reducing expression of cyclin D1 and cyclin E, and promoting expression of p27kip1. AKF-PD also downregulated PDGF-BB-induced MEK, ERK, Akt, and p70S6K phosphorylation in HSCs. In rat liver fibrosis, AKF-PD alleviated hepatic fibrosis by decreasing necroinflammatory score and semiquantitative score, and reducing expression of collagen I and α-SMA. AKF-PD attenuated the progression of hepatic fibrosis by suppressing HSCs proliferation and activation via the ERK/MAPK and PI3K/Akt signaling pathways. AKF-PD may be used as a potential novel therapeutic agent against liver fibrosis.
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Hirahara, Ichiro, Eiji Kusano, Satoru Yanagiba, Yukio Miyata, Yasuhiro Ando, Shigeaki Muto, and Yasushi Asano. "Peritoneal Injury by Methylglyoxal in Peritoneal Dialysis." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 26, no. 3 (May 2006): 380–92. http://dx.doi.org/10.1177/089686080602600317.
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Background Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline, such as ultrafiltration loss. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis, a serious complication of PD. Glucose degradation products contained in PD fluids contribute to the bioincompatibility of conventional PD fluids. Methylglyoxal (MGO) is an extremely toxic glucose degradation product. The present study examined the injurious effect of MGO on peritoneum in vivo. Methods Male Sprague–Dawley rats ( n = 6) were administered PD fluids (pH 5.0) containing 0, 0.66, 2, 6.6, or 20 mmol/L MGO every day for 21 days. On day 22, peritoneal function was estimated by the peritoneal equilibration test. Drained dialysate was analyzed for type IV collagen-7S, matrix metalloproteinase (MMP), and vascular endothelial growth factor (VEGF). Histological analysis was also performed. Results In rats receiving PD fluids containing more than 0.66 mmol/L MGO, peritoneal function decreased significantly and levels of type IV collagen-7S and MMP-2 in drained dialysate increased significantly. In the 20-mmol/L MGO-treated rats, loss of body weight, expression of VEGF, thickening of the peritoneum, and formation of abdominal cocoon were induced. MMP-2 and VEGF were produced by infiltrating cells in the peritoneum. Type IV collagen was detected in basement membrane of microvessels. Conclusion MGO induced not only peritoneal injury but also abdominal cocoon formation in vivo. The decline of peritoneal function may result from reconstitution of microvessel basement membrane or neovascularization.
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Hurkmans, Daan P., Christina Jensen, Stijn L. W. Koolen, Joachim Aerts, Morten Asser Karsdal, Ron H. J. Mathijssen, and Nicholas Willumsen. "Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma." Journal for ImmunoTherapy of Cancer 8, no. 2 (October 2020): e001193. http://dx.doi.org/10.1136/jitc-2020-001193.
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BackgroundImmune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor induce a response in only a subgroup of patients with metastatic melanoma. Previous research suggests that transforming growth factor beta signaling and a collagen-rich peritumoral stroma (tumor fibrosis), may negatively interfere with the interaction between T cells and tumor cells and thereby contribute to resistance mechanisms by immune-exclusion, while increased tumor infiltration of M1-like macrophages enhances T cell activity. Hence, the current study aimed to assess the relationship between blood-based markers of collagen or vimentin turnover (reflecting M1 macrophage activity) and clinical outcome in patients with metastatic melanoma after PD-1 inhibition.MethodsPatients with metastatic melanoma who were treated with anti-PD-1 monotherapy between May 2016 and March 2019 were included in a prospective observational study. N-terminal pro-peptide of type III collagen (PRO-C3) cross-linked N-terminal pro-peptides of type III collagen (PC3X), matrix metalloprotease (MMP)-degraded type III (C3M) and type IV collagen (C4M), granzyme B-degraded type IV collagen and citrullinated and MMP-degraded vimentin (VICM) were measured with immunoassays in serum before (n=107), and 6 weeks after the first administration of immunotherapy (n=94). The association between biomarker levels and overall survival (OS) or progression-free survival (PFS) was assessed.ResultsMultivariate Cox regression analysis identified high baseline PRO-C3 (Q4) and PC3X (Q4) as independent variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06 to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09 to 3.18, p=0.023). High baseline PRO-C3 was also independently related to worse OS (HR=2.08, 95% CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3 ratio was related to improved OS (HR=0.42, 95% CI=0.20 to 0.90, p=0.025). An increase in VICM (p<0.0001; in 56% of the patients) was observed after 6 weeks of treatment, and an increase in VICM was independently associated with improved OS (HR=0.28, 95% CI=0.10 to 0.77, p=0.014).ConclusionsBlood-based biomarkers reflecting excessive type III collagen turnover were associated with worse OS and PFS after PD-1 inhibition in metastatic melanoma. Moreover, an increase in VICM levels after 6 weeks of treatment was associated with improved OS. These findings suggest that type III collagen and vimentin turnover contribute to resistance/response mechanisms of PD-1 inhibitors and hold promise of assessing extracellular matrix-derived and stroma-derived components to predict immunotherapy response.
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Brockington, Martin, Susan C. Brown, Anne Lampe, Yeliz Yuva, Lucy Feng, Cecilia Jimenez-Mallebrera, Caroline A. Sewry, Kevin M. Flanigan, Kate Bushby, and Francesco Muntoni. "Prenatal diagnosis of Ullrich congenital muscular dystrophy using haplotype analysis and collagen VI immunocytochemistry." Prenatal Diagnosis 24, no. 6 (June 2004): 440–44. http://dx.doi.org/10.1002/pd.902.
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Dorj, Odontuya, Wei-Fang Lee, Eisner Salamanca, Yu-Hwa Pan, Yi-Fan Wu, Yung-Szu Hsu, Jerry C. Y. Lin, Yu-De Lin, Cheuk-Sing Choy, and Wei-Jen Chang. "Guided Tissue Regeneration Treatment Yields Better Results in Class II Furcations in the Mandible Than in the Maxilla: A Retrospective Study." International Journal of Environmental Research and Public Health 18, no. 14 (July 13, 2021): 7447. http://dx.doi.org/10.3390/ijerph18147447.
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Absorbable porcine collagen membrane with a bovine bone graft can be considered for regenerative treatment in periodontal class II furcation defects. We evaluated the clinical efficacy of guided tissue regeneration (GTR) treatment with bovine bone xenograft and a porcine collagen membrane in molars with class II furcations. Probing depth (PD), clinical attachment level (CAL), and bone level (BL) were recorded at baseline and at 3, 6, and 9 months postoperatively. Thirty class II furcation defects from the lower and upper molars were assessed. Significant improvements in PD and CAL were observed from baseline to 9 months in all groups (p < 0.01). BL improved in all groups except group A in the upper molars in radiographic assessment (p < 0.05). The lower and upper molars showed PD reduction of 50.5% ± 7.44% and 46.2% ± 11.2%, respectively, at 9 months (p = 0.044). In furcations of 1–3 mm, the lower and upper molars showed PD reductions of 51.2% ± 4.49% and 36.5% ± 16.14%, respectively (p = 0.035). The lower and upper molars showed a CAL gain of 51.1% ± 4.64% and 33.6% ± 18.8%, respectively (p = 0.037). Thus, GTR with bovine bone graft and porcine collagen membrane yielded good results in class II furcations, with better results in the lower than in the upper molars.
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Febriharta, Angga, and Kwartarini Murdiastuti. "The effect of acellular dermal matrix therapy on biphasic calsium sulfate bone graft." Majalah Kedokteran Gigi Indonesia 6, no. 1 (July 15, 2020): 48. http://dx.doi.org/10.22146/majkedgiind.37428.
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Infrabony pocket therapy is needed to eliminate pocket wall, creating easy to clean conditions for new attachment, and bone regeneration. Biphasic calcium sulfate (BCS) bone grafts combined with collagen membranes are known to regenerate bone tissue and have good osteoconductive effects. The addition of collagen membranes promotes migration and proliferation of fibroblast cells, osteoblasts, and homeostasis. However, the collagen membrane is a rapidbioresynthesis and may cause disease transmission from animal. Acellular dermal matrix (ADMA) membrane contains a bioactive matrix that has the ability to support normal revascularization, cell repopulation, and tissue remodeling. Combination of BCS with ADMA membrane are proven to induce bone and tissue regeneration. The objective of this study is to determine the therapeutic effect of BSC and ADMA combination to eradicate pocket, gingival recession, bone recession and attachment loss. The samples were taken from 20 infrabony pocket sites divided into 2 groups. The first was treated by combination of BCS and ADMA, while the second group was treated by the combination of BCS and collagen membrane. After 1 and 3 months of flap surgery, the result was observed by probing depth(PD), relative attachment loss (RAL), gingival recession, alveolar bone height and radiological examination. The result showed the decrease of PD, RAL, gingival recession, and alveolar bone height in both two groups. However, there wereno significant differences between those two groups. In conclusion, the combination of BCS and ADMA or BCS and collagen decreased the PD, RAL, gingival recession and alveolar bone height.
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Odoom-Wubah, Tareque, Saúl Rubio, José L. Tirado, Gregorio F. Ortiz, Bior James Akoi, Jiale Huang, and Qingbiao Li. "Waste Pd/Fish-Collagen as anode for energy storage." Renewable and Sustainable Energy Reviews 131 (October 2020): 109968. http://dx.doi.org/10.1016/j.rser.2020.109968.
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Pinnaduwage, Dilini S., Shiv P. Srivastava, Xiangsheng Yan, Shyam Jani, David G. Brachman, and Stephen P. Sorensen. "Dosimetric Impacts of Source Migration, Radioisotope Type, and Decay with Permanent Implantable Collagen Tile Brachytherapy for Brain Tumors." Technology in Cancer Research & Treatment 21 (January 2022): 153303382211068. http://dx.doi.org/10.1177/15330338221106852.
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Introduction: Brachytherapy using permanently implantable collagen tiles containing cesium-131 (Cs-131) is indicated for treatment of malignant intracranial neoplasms. We quantified Cs-131 source migration and modeled the resulting dosimetric impact for Cs-131, iodine-125 (I-125), and palladium-103 (Pd-103). Methods and Materials: This was a retrospective analysis of a subgroup of patients enrolled in a prospective, single-center, nonrandomized, clinical trial (NCT03088579) of Cs-131 collagen tile brachytherapy. Postimplant Cs-131 plans and hypothetical I-125 and Pd-103 calculations were compared for 20 glioblastoma patients for a set seed geometry. Dosimetric impact of decay and seed migration was calculated for 2 hypothetical scenarios: Scenario 1, assuming seed positions on a given image set were unchanged until acquisition of the subsequent set; Scenario 2, assuming any change in seed positions occurred the day following acquisition of the prior images. Seed migration over time was quantified for a subset of 7 patients who underwent subsequent image-guided radiotherapy. Results: Mean seed migration was 1.7 mm (range: 0.7-3.1); maximum seed migration was 4.3 mm. Mean dose to the 60 Gy volume differed by 0.4 Gy (0.6%, range 0.1-1.0) and 0.9 Gy (1.5%, range 0.2-1.7) for Cs-131, 1.2 Gy (2.0%, range 0.1-2.1) and 1.6 Gy (2.6%, range 1.2-2.6) for I-125, and 0.8 Gy (1.3%, range 0.2-1.5) and 1.4 Gy (2.3%, range 0.3-1.9) for Pd-103, for Scenarios 1 and 2, respectively, compared with the postimplant plan. For a set seed geometry mean implant dose was higher for Pd-103 (1.3 times) and I-125 (1.1 times) versus Cs-131. Dose fall-off was steepest for Pd-103: gradient index 1.88 versus 2.23 (I-125) and 2.40 (Cs-131). Conclusions: Dose differences due to source migration were relatively small, suggesting robust prevention of seed migration from Cs-131-containing collagen tiles. Intratarget heterogeneity was greater with Pd-103 and I-125 than Cs-131. Dose fall-off was fastest with Pd-103 followed by I-125 and then Cs-131.
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Alhamdani, Mohamed-Saiel Saeed, Hasan Fayadh Al-Azzawie, and Fawzi K. H. Abbas. "Decreased Formation of Advanced Glycation End-Products in Peritoneal Fluid by Carnosine and Related Peptides." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 27, no. 1 (January 2007): 86–89. http://dx.doi.org/10.1177/089686080702700118.
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Background Formation of advanced glycation end-products (AGEs) is a major problem in uremic patients treated with peritoneal dialysis (PD). Application of additives with known anti-glycosylation properties to PD fluid may be beneficial in minimizing the formation of AGEs. This study aimed to evaluate the effect of carnosine and its related peptides homocarnosine and anserine against the formation of AGEs in PD fluid. Methods PD solutions (1.5% dextrose) were incubated with human serum albumin (HSA) or collagen (type IV) with or without 10 mmol/L of each of carnosine, anserine, homo-carnosine, histidine, and aminoguanidine. The formation of AGEs was followed by fluorescence spectrophotometry at weekly intervals for 7 weeks. For the determination of the acute effect of carnosine and related compounds, HSA and collagen were incubated with 4.25% dextrose PD solutions for 24 hours, followed by incubation with 20 mmol/L of carnosine and related compounds for another 24 hours. The rate of AGE formation was monitored by fluorescence spectrophotometry. Results Carnosine and related compounds showed effective regression in AGE formation in both types of proteins in both long- and short-term exposure to PD fluids at a rate of effectiveness of the order of carnosine > homocarnosine > anserine, aminoguanidine > histidine in long-term exposure, and homocarnosine > carnosine > aminoguanidine > anserine > histidine in short-term exposure. Conclusion Carnosine and related peptides could suppress the formation of AGEs initiated by PD fluid. This observation may provide a new therapeutic approach for the prevention and treatment of the AGE-related complications in PD patients.
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Giuntini, F., V. M. Chauhan, J. W. Aylott, G. A. Rosser, A. Athanasiadis, A. Beeby, A. J. MacRobert, R. A. Brown, and R. W. Boyle. "Conjugatable water-soluble Pt(ii) and Pd(ii) porphyrin complexes: novel nano- and molecular probes for optical oxygen tension measurement in tissue engineering." Photochem. Photobiol. Sci. 13, no. 7 (2014): 1039–51. http://dx.doi.org/10.1039/c4pp00026a.
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Engels, A. C., M. F. Hoylaerts, M. Endo, S. Loyen, G. Verbist, S. Manodoro, P. DeKoninck, J. Richter, and J. A. Deprest. "In vitro sealing of iatrogenic fetal membrane defects by a collagen plug imbued with fibrinogen and plasma." Prenatal Diagnosis 33, no. 2 (January 7, 2013): 162–67. http://dx.doi.org/10.1002/pd.4032.
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Hu, Qiong-ying, Yun Yuan, Yu-chen Li, Lu-yao Yang, Xiang-yu Zhou, Da-qian Xiong, and Zi-yi Zhao. "Programmed Cell Death Ligand 1-Transfected Mouse Bone Marrow Mesenchymal Stem Cells as Targeted Therapy for Rheumatoid Arthritis." BioMed Research International 2021 (August 30, 2021): 1–11. http://dx.doi.org/10.1155/2021/5574282.
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Programmed cell death 1 ligand (PD-L1) and its receptor (PD-1) are key molecules for immunoregulation and immunotherapy. PD-L1 binding PD-1 is an effective way to regulate T or B cell immunity in autoimmune diseases such as rheumatoid arthritis (RA). In our study, we overexpressed PD-L1 by constructing a recombinant of PD-L1-lentiviral vector, which was subsequently used to transfect mouse bone marrow mesenchymal stem cells (MBMMSCs) and significantly suppressed the development of collagen-induced arthritis (CIA) in DBA/1j mice. In addition, PD-L1-transfected MBMMSCs (PD-L1-MBMMSCs) ameliorated joint damage, reduced proinflammatory cytokine expression, and inhibited T and B cell activation. Furthermore, PD-L1-MBMMSCs decreased the number of dendritic cells and increased the numbers of regulatory T cells and regulatory B cells in joints of CIA mice. In conclusion, our results provided a potential therapeutic strategy for RA treatment with PD-L1-MBMMSC-targeted therapy.
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Kunin, Margarita, Vered Carmon, Pazit Beckerman, and Dganit Dinour. "Effect of Peritoneal Dialysis on Serum Fibrosis Biomarkers in Patients with Refractory Congestive Heart Failure." International Journal of Molecular Sciences 20, no. 11 (May 28, 2019): 2610. http://dx.doi.org/10.3390/ijms20112610.
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Background: Cardiac collagen remodeling is important in the progression of heart failure. Estimation of cardiac collagen turnover by serum levels of serological markers is used for monitoring cardiac tissue repair and fibrosis. Peritoneal dialysis (PD) is used for the long-term management of refractory congestive heart failure (CHF). In this study, we investigated the effect of PD treatment on circulating fibrosis markers levels in patients with refractory CHF and fluid overload. Methods: Twenty-five patients with refractory CHF treated with PD were prospectively enrolled in the study. Circulating fibrosis markers procollagen type III C-peptide (PIIINP), matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of metalloproteinases I (TIMP-1) levels were checked at baseline and after three and six months of treatment. Results: The clinical benefit of PD manifested by improved NYHA functional class and reduced hospitalization rate. Serum brain natriuretic peptide (BNP) levels decreased significantly during the treatment. Serum MMP-2 and TIMP-1 decreased significantly on PD. Circulating PIIINP showed two patterns of change, either decreased or increased following PD treatment. Patients in whom circulating PIIINP decreased had significantly lower baseline serum albumin, lower baseline mean arterial blood pressure, higher serum CRP, and a less significant improvement in hospitalization rate compared to the patients in whom circulating PIIINP increased. Patients in whom all three markers decreased demonstrated a trend to longer survival compared to patients whose markers increased or did not change. Conclusion: In refractory CHF patients PD treatment was associated with a reduction in circulating fibrosis markers.
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Wang, Zhikui, Zhongqi Zhou, Wenjie Ji, Lina Sun, Yulin Man, Jifeng Wang, and Hongjuan Zhang. "Silencing of lncRNA 6030408B16RIK prevents ultrafiltration failure in peritoneal dialysis via microRNA-326-3p-mediated WISP2 down-regulation." Biochemical Journal 477, no. 10 (May 29, 2020): 1907–21. http://dx.doi.org/10.1042/bcj20190877.
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Continuous exposure to peritoneal dialysis (PD) fluid results in peritoneal fibrosis and ultimately causes ultrafiltration failure. Noncoding RNAs, including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), have been reported to participate in ultrafiltration failure in PD. Therefore, our study aimed to investigate the mechanism of lncRNA 6030408B16RIK in association with miR-326-3p in ultrafiltration failure in PD. Peritoneal tissues were collected from uremic patients with or without PD. A uremic rat model with PD was first established by 5/6 nephrectomy. The relationship between lncRNA 6030408B16RIK, miR-326-3p and WISP2 was identified using luciferase reporter, RNA pull-down and RIP assays. After ectopic expression and depletion treatments in cells, expression of α-SMA, phosphorylated β-catenin, FSP1, E-cadherin and Vimentin was evaluated by RT-qPCR and Western blot analyses, and Collagen III and CD31 expression by immunohistochemistry. Ultrafiltration volume and glucose transport capacity were assessed by the peritoneal equilibration test. Expression of lncRNA 6030408B16RIK and WISP2 was up-regulated and miR-326-3p expression was poor in peritoneal tissues of uremic PD patients and model rats. LncRNA 6030408B16RIK competitively bound to miR-326-3p and then elevated WISP2 expression. Silencing of lncRNA 6030408B16RIK and WISP2 or overexpression of miR-326-3p was shown to decrease the expression of α-SMA, phosphorylated β-catenin, FSP1, Vimentin, Collagen III and CD31, while reducing glucose transport capacity and increasing E-cadherin expression and ultrafiltration volume in uremic PD rats. In summary, lncRNA 6030408B16RIK silencing exerts an anti-fibrotic effect on uremic PD rats with ultrafiltration failure by inactivating the WISP2-dependent Wnt/β-catenin pathway via miR-326-3p.
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Coleman, Christopher M., Jordan J. Minor, Laura E. Burt, Barbara A. Thornhill, Michael S. Forbes, and Robert L. Chevalier. "Angiotensin AT1-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat." American Journal of Physiology-Renal Physiology 293, no. 1 (July 2007): F262—F268. http://dx.doi.org/10.1152/ajprenal.00071.2007.
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The renin-angiotensin system is activated in the developing kidney and is necessary for normal renal development, but is further activated by unilateral ureteral obstruction (UUO). During nephrogenesis, there is a switch from a preponderance of angiotensin AT2 to AT1 receptors in the rat. We examined the renal cellular response to angiotensin II receptor inhibition in the neonatal rat subjected to partial UUO under anesthesia within 48 h of birth. Group I (“early”) received saline vehicle, losartan (AT1 inhibitor), or PD-123319 (AT2 inhibitor) during the completion of nephrogenesis in the first 10 days of life. Group II (“late”) received each of the three treatments throughout the subsequent 10 days of life. Kidneys were harvested at 21 days, and the distribution of renin, apoptosis, macrophages, α-smooth muscle actin, and collagen was determined. Losartan and PD-123319 each increased vascular renin distribution in both kidneys. Partial UUO reduced growth and increased apoptosis, macrophages, α-smooth muscle actin, and collagen in the obstructed kidney. Early losartan treatment further increased α-smooth muscle actin and collagen in the obstructed kidney and induced apoptosis, macrophages, and collagen in the contralateral kidney. Late losartan treatment had no effect on any of the parameters in either kidney, and PD-123319 had no effect on either kidney. We conclude that selective inhibition of AT1 receptors during nephrogenesis (but not during subsequent renal maturation) exacerbates injury to the obstructed kidney and also injures the contralateral kidney. These results suggest that angiotensin II receptor blockers should be avoided in the developing hydronephrotic kidney.
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Gokalp, Cenk, Fatma Keklik Karadag, Matthias Christoph Braunisch, Christoph Schmaderer, Emrah Gunay, Hatice Demet Kiper, Mahmut Tobu, Celalettin Ustün, Meltem Sezis Demirci, and Mehmet Ozkahya. "In Vitro Closure Times (PFA-100) Are Different Between Peritoneal Dialysis and Hemodialysis." Hämostaseologie 40, no. 05 (July 27, 2020): 671–78. http://dx.doi.org/10.1055/a-1171-0499.
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Abstract Introduction Platelet dysfunction is not uncommon in patients with end-stage renal disease (ESRD). Type of renal replacement therapy may have an effect on platelet functions, which has not been well investigated. We evaluated in vitro closure time (CT) differences between peritoneal dialysis (PD) and hemodialysis (HD) patients using platelet function analyzer (PFA-100)and observed a significant difference between these renal replacement therapies. Methods Patients with ESRD undergoing PD (n = 24) or HD (n = 23) for more than 6 months were included. Blood samples for collagen/epinephrine (Col/EPI) and collagen/adenosine diphosphate (Col/ADP) measurements were obtained before HD at a mid-week session for HD patients and at an outpatient control time for PD patients. Results Three of 24 (12.5%) PD patients and 16 of 23 (69.5%) HD patients had prolonged PFA-100 Col/EPI, p< 0.001. Likewise, 4.2% of PD patients and 87.0% of HD patients had prolonged PFA-100 Col/ADP, p< 0.001. Moreover, the median times of PFA-Col/EPI and PFA-100 Col/ADP were significantly lower in PD patients compared with those of HD patients (p< 0.001). Multivariate analysis showed that the type of renal replacement was a risk factor for both elevated PFA-100 Col/ADP and PFA-100 Col/EPI after adjusted for platelets, hematocrit, and urea (p< 0.001). Conclusions The type of renal replacement therapy may have an effect on in vitro CTs; therefore, studies including more patients with long-term follow-up are needed to investigate if the difference has any impact on clinical outcomes.
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Kozako, Tomohiro, Makoto Yoshimitsu, Masaki Akimoto, Kakushi Matsushita, Yohann White, Shingo Toji, Shuji Izumo, Shunro Sonoda, and Naomichi Arima. "Immunological Function against Human T-Lymphotrophic Virus Type I in Carriers with Collagen Diseases and HAM/TSP." Blood 112, no. 11 (November 16, 2008): 1470. http://dx.doi.org/10.1182/blood.v112.11.1470.1470.
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Abstract Human T-cell leukemia virus-1 (HTLV-1) is the first human retrovirus that has infected approximately 10–20 million people worldwide and causes adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) after long-term chronic infection. The immune response to HTLV-1 is typically enhanced in HAM/TSP, while impaired cell-mediated immunity has been identified as a causative basis of immunodeficiency in ATLL. The negative immuno-regulatory program death-1 (PD-1) signaling is involved in auto-immunity, allergy, sites of immune privilege, and antitumor immunity. We have previously reported decreased frequency and function of HTLV-1 Tax-specific CD8+ T-cell in ATLL patients due to insufficient cytolytic effector molecules, as well as upregulated PD-1 expression on HTLV-1-specific CTLs from asymptomatic carriers (ACs) and ATLL patients. That PD-1 expression was significantly higher on HTLV-1 specific CD8+ T-cells, as well as CMV− and EBV-specific CTLs in ATLL patients compared to ACs, suggested that PD-1 signaling plays a role in fostering persistent HTLV-1 infections, facilitating immune evasion by ATLL cells, which may further ATLL development (ASH annual meeting 2006, 2007). However, there is no report on the repertoir and PD-1 expression of HTLV-1-specific CTL in carriers with hyper immune states such as collagen disease or HAM/TSP. Therefore, to characterize HTLV-1-specific CTL in asymptomatic HTLV-1 carriers (ACs), carriers with collagen disease (CCs) and HAM/TSP patients, we examined the frequency, diversity and PD-1 expression of HTLV-1-specific CTL in 23 ACs, 33 carrier with collagen vascular disease, 40 HAM/TSP patients and 18 healthy donors (HDs) using 16 distinct HTLV-1 Tax/Env HLA-A*0201 and HLA-A*2402 tetramers. The difference in frequency of HTLV-1 Tax-specific CTL positivity was not statistically significant between CCs, HAM/TSP or ACs. In contrast, HTLV-1 Env-specific CTL were significantly more frequent in autoimmune disorders and HAM/TSP than those in ACs (Table 1). On the other hand, percentages of CD8+ lymphocytes from these carriers expressing PD-1 were significantly higher than that from HDs. Futhermore, the rates of PD-1 expression on CMV- or EBV-specific CTL in CCs, HAM/TSP and ACs were similar although PD-1 expression was significantly down-regulated on HTLV-1-specific CTL in CCs and HAM/TSP compaired to ACs (Figure1, p<0.05 and p<0.01, respectively). Few lymphocytes from these carriers were positive for the PD-L1 ligand, while PD-L1 expression was observed on lymphocytes cultured for 12 hours from ACs (5 of 6), but less from CCs and HAM/TSP (1 of 6 and 0 of 4, respectively). The diversity, frequency and repertoir of HTLV-1-specific CD8+ T cell clones, especially HTLV-1 Env CTLs, may be related to the hyper immune response in CCs and HAM/TSP. The down-regulation of PD-1 on HTLV-1 Tax-specific CTL and loss of PD-L1 expression in CCs and HAM/TSP may explain the apparent hyper immune response against HTLV-1 Tax protein. Table 1. HTLV-1/HLA tetramers positive subjects HLA allele Tetramers AC CC HAM/TSP The number of subjects positive for tetramers; the percentages of HTLV-1/HLA tetramer+ CD8+ T cells in the CD8+ lymphocytes > 0.1% are counted as subjects positives for tetramer, *, P < 0.01, significant differences from AC by χ2 test. A*02 Tax 100% (8/8) 75% (9/12) 90% (9/10) A*02 Env 0% (0/8) 25% (3/12) 10% (1/10) A*24 Tax 94% (17/18) 88% (21/24) 100% (15/15) A*24 Env 6% (1/18) 63% (15/24)* 40% (6/15)* Tax CTL 96% (22/23) 82% (27/33) 100% (18/18) Eav CTL 4% (1/23) 48% (16/33)* 50% (9/18)* Figure 1. PD-1 expression on virus-specific CD8+ T lymphocytes in ACs, carriers with collagen disease (CCs) and HAM/TSP. Percentage of PD-1 expression on CD8+ lymphocytes and HTLV-1-, CMV-, EBV-specific CD8+ lymphocytes in AC, CC, HAM/TSP and healthy donors (HDs). Horizontal bars indicate the mean percentage of PD-1-positive cells. The number below each subject is the mean±SD. *P<0.001; **P<0.01 (Significant differences by Mann-Whitney U test). Figure 1. PD-1 expression on virus-specific CD8+ T lymphocytes in ACs, carriers with collagen disease (CCs) and HAM/TSP. Percentage of PD-1 expression on CD8+ lymphocytes and HTLV-1-, CMV-, EBV-specific CD8+ lymphocytes in AC, CC, HAM/TSP and healthy donors (HDs). Horizontal bars indicate the mean percentage of PD-1-positive cells. The number below each subject is the mean±SD. *P<0.001; **P<0.01 (Significant differences by Mann-Whitney U test).
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Gopal, Srila, Esther J. Cooke, Jenny Y. Zhou, Ilana Levin, Pamela Emery, Tina Manon- Jensen, Morten Karsdal, and Annette von Drygalski. "Systemic Vascular Basement Membrane Markers Linked to Synovial Vascular Remodeling Are Bio-Markers of Hemarthrosis in Patients with Hemophilia." Blood 132, Supplement 1 (November 29, 2018): 380. http://dx.doi.org/10.1182/blood-2018-99-112725.
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Abstract Introduction: Acute painful joint episodes in hemophilia are not always associated with hemarthrosis. Point-of-Care Musculoskeletal Ultrasound with Power Doppler (POC MSKUS/PD) is a fast and sensitive imaging modality to determine the presence of hemarthrosis and direct management. Systemic collagen cleavage products reflecting extracellular matrix, bone and soft tissue turnover may serve as an alternative tool for the detection of hemarthrosis. Based on previous observations of pronounced vascular remodeling within the synovial tissue during hemarthrosis in patients and hemophilic mouse models, we hypothesized that cleavage products of collagen IV, found in the basement membrane of blood vessels may differentiate between bleeding and non-bleeding states. Methods: Joint bleeding was induced in FVIII-/- mice (+/- FVIII-treatment before and shortly after injury). Synovial vascular remodeling was assessed 14 days later by MSKUS/PD and histology including αSmooth Muscle Actin (αSMA)-staining. Murine plasma samples were analyzed for C4M2 and P4NP-7S, which are type IV collagen turnover products. To determine human relevance, 31 adult patients with hemophilia (PWH), ≥ age 21, were studied prospectively for 3 years with MSKUS/PD during pain-free intervals and painful events for bleed status, vascular flow and 11 plasma markers of collagen turnover(C2M, ARGS, C3M, Pro-C3, C5M, Pro C5, C4M2, P4NP-7S, Col18N, DCN- CS, ColNeo10, NIC). Results: Type IV collagen turn-over markers were significantly elevated in plasma of FVIII-/- deficient mice 14 days after joint bleeding when compared to baseline (C4M2: 2.575 ng/mL vs. 1.94 ng/mL, p=0.029 and P4NP-7S: 80.3 ng/mL vs. 67.81 ng/mL, p= 0.0152 respectively ). This increase coincided with a significant increase in vessel number (2.3 fold, p=0.0008), vascular flow by PD (2.3 fold, p= 0.014) and αSMA staining (5.1 fold, p= 0.0007). C4M2 and P4NP7S plasma levels correlated negatively with αSMA staining, suggesting a role for αSMA in vessel stabilization (C4M2 p=0.02, Pearson r= -0.5707; P4NP-7S p= 0.0130, Pearson r= -0.6238). FVIII-treatment reduced plasma C4M2 and P4NP-7S levels to baseline (C4M2 1.98 ng/mL vs. 1.94 ng/mL, P4NP-7S 59.98 ng/mL vs. 67.81 ng/mL), but had no effect on the other vascular parameters. In patients, results from 91 visits were compiled. Twenty five were due to acute painful episodes with 16 confirmed hemarthroses. Of the 11 biomarkers evaluated, only C4M2 and P4NP-7S were transiently but significantly elevated in plasma during joint bleeding compared to pain free intervals or to non-bleeding painful episodes. Plasma C4M2 levels during acute painful bleeding episodes when compared to non-bleeding states were 41.65 vs. 29.69 ng/mL (p=0.0003), and P4NP-7S levels were 418.9 vs 278.1 ng/mL (p=0.0007), respectively. Baseline levels of C4M2 and P4NP-7S in PWH were above the lab reported normal range, indicating ongoing high vascular basement membrane turnover. Additionally, PWH who developed joint bleeding episodes had a higher level of collagen IV biomarkers at baseline when compared to PWH who did not experience joint bleeding (C4M2 33.91 vs 29.07 ng/mL, P4NP7s 320.6 vs 292.8 ng/mL), although this was not statistically significant. Hemarthrosis was accompanied by pronounced abnormal synovial microvascular flow evidenced by PD, while plasma levels of both biomarkers correlated positively with joint PD signal (C4M2, p= 0.0400, Pearson r=0.4409; P4NP7S-p=0.0141, Pearson r=0.5154). Conclusions: Our findings suggest that systemic vascular collagen turn-over products may be novel biomarker candidates to identify patients at high risk for joint bleeding and to diagnose acute hemarthrosis. Hemarthrosis in hemophilia is associated with pronounced synovial vascular remodeling. Cleavage products of type IV collagen, but not of any other collagen, were systemically elevated in PWH and distinguished bleeding from non-bleeding painful episodes. Type IV collagen is found exclusively in basement membranes and in the case of joint bleeding, the presumed source of these turnover markers is newly formed synovial blood vessels. Therefore, our findings support the concept that vascular instability during neovascularization is involved in the dynamics of hemophilic joint bleeding. These findings broaden the scope of potential diagnostic tools substantially, opening new avenues for personalized treatment of PWH. Disclosures von Drygalski: Bioverativ/Sanofi: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria; HemaBiologics: Consultancy; Genentech: Consultancy; Biomarin: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Hematherix: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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Quarello, Edwin, Fabien Guimiot, Jean-Marie Moalic, Michel Simoneau, Yves Ville, and Anne-Lise Delezoide. "Quantitative evaluation of collagen type VI and SOD gene expression in the nuchal skin of human fetuses with trisomy 21." Prenatal Diagnosis 27, no. 10 (2007): 926–31. http://dx.doi.org/10.1002/pd.1803.
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Kuzyk, Yu I. "PATHOLOGICAL DEFORMATION OF CAROTID ARTERY IN PATIENTS OVER 50: CLINICAL AND MORPHOLOGICAL ANALYSIS." Health and Ecology Issues, no. 4 (December 28, 2013): 83–88. http://dx.doi.org/10.51523/2708-6011.2013-10-4-15.
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The aim was to study cases of pathological deformation of the carotid artery (PD CA) and to determine the age and sex distribution, basic pathomorphological and clinical changes, related diseases and risk factors. Material and methods. The medical records of 175 patients having operated on PD CA were analyzed. The pathomorphological study of carotid artery biopsies received from surgery intervention was analyzed. Results. Women from 50 to 60 more often detected PD CA. Transit ischemic attacks, discirculator encephalopathy and ischemic infarctions were its clinical manifestations. Atherosclerosis, fibromuscular dysplasia and toxic influence were the major causes of PD CA. Kinking is the basic type of PD CA. The pathomorphological changes of PD CA include intimal hyperplasia, unreverse changes of elastic fibers, fibrosis and dystrophy of media’s collagen fibers, adventitial sclerosis. Conclusion. Further pathomorphological studies aimed at the definition of distinctive morphogenesis characteristic for each type of PD CA are needed for more accurate definition of its etiology and pathogenesis.
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Kohl, Thomas. "Iatrogenic fetal membrane damage from complex fetoscopic surgery in human fetuses might not be amenable to simple closure by collagen plugs." Prenatal Diagnosis 28, no. 9 (September 2008): 876–77. http://dx.doi.org/10.1002/pd.2046.
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Chen, Yang, Nasui Wang, Qiongjing Yuan, Jiao Qin, Gaoyun Hu, Qianbin Li, Lijian Tao, Yanyun Xie, and Zhangzhe Peng. "The Protective Effect of Fluorofenidone against Cyclosporine A-Induced Nephrotoxicity." Kidney and Blood Pressure Research 44, no. 4 (2019): 656–68. http://dx.doi.org/10.1159/000500924.
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Background/Aims: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. Methods: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-β1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 μmol/L), AKF-PD (400 μg/mL), PFD (400 μg/mL), and GW788388 (5 μmol/L). Results: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-β1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 μg/mL) significantly decreased TGF-β1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. Conclusion: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.
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BÖRSCH-HAUBOLD, Angelika G., Ruth M. KRAMER, and Steve P. WATSON. "Inhibition of mitogen-activated protein kinase kinase does not impair primary activation of human platelets." Biochemical Journal 318, no. 1 (August 15, 1996): 207–12. http://dx.doi.org/10.1042/bj3180207.
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Mitogen-activated protein kinases (MAPKs), a family of protein serine/threonine kinases regulating cell growth and differentiation, are activated by a dual-specificity kinase through phosphorylation at threonine and tyrosine. We used a recently described selective inhibitor of the p42/p44mapk-activating enzyme, PD 98059 [2-(2´-amino-3´-methoxyphenyl)-oxanaphthalen-4-one], to investigate the role of the p42/p44mapk pathway in human platelets. PD 98059 inhibited p42/p44mapk activation in thrombin-, collagen- and phorbol ester-stimulated platelets, as determined from in-gel renaturation kinase assays, with an IC50 of approx. 5 µM (thrombin stimulation). It also prevented activation of MAPK kinase, which was measured in whole-cell lysates with glutathione S-transferase/p42mapk fusion protein (GST–MAPK) as substrate. Inhibition of p42/p44mapk did not affect platelet responses to thrombin or collagen such as aggregation, 5-hydroxytryptamine release and protein kinase C activation. In addition, PD 98059 did not interfere with release of arachidonic acid, a response mediated by cytosolic phospholipase A2 (cPLA2), or with cPLA2 phosphorylation. This suggests that platelet cPLA2 is not regulated by p42/p44mapk after stimulation with physiological agonists. In contrast, phorbol ester-induced phosphorylation of cPLA2 and potentiation of arachidonic acid release stimulated by Ca2+ ionophore A23187 were inhibited by PD 98059, indicating that p42/p44mapk phosphorylates cPLA2 after activation of protein kinase C by the non-physiological tumour promoter.
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Liekens, Daisy, Liesbeth Lewi, Jacques Jani, Liesbeth Heyns, Eline Poliard, Godelieve Verbist, Nicole Ochsenbein-Kölble, Marc Hoylaerts, and Jan Deprest. "Enrichment of collagen plugs with platelets and amniotic fluid cells increases cell proliferation in sealed iatrogenic membrane defects in the foetal rabbit model." Prenatal Diagnosis 28, no. 6 (2008): 503–7. http://dx.doi.org/10.1002/pd.2010.
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Deprest, Jan, Liesbeth Lewi, Roland Devlieger, Luc De Catte, Marc Hoylaerts, Nicole Ochsenbein-Kölble, Grozdana Bilic, Andreas Zisch, and Roland Zimmermann. "Enrichment of collagen plugs with platelets and amniotic fluid cells increases cell proliferation in sealed iatrogenic membrane defects in the fetal rabbit model." Prenatal Diagnosis 28, no. 9 (September 2008): 878–80. http://dx.doi.org/10.1002/pd.2066.
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Cho, Su-Yeon, Chang-Hyun Song, Ji-Eun Lee, Seong Hun Choi, Sae-Kwang Ku, and Soo-Jin Park. "Effects of Platycodin D on Reflux Esophagitis due to Modulation of Antioxidant Defense Systems." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/7918034.
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Aims. The effects of platycodin D (PD) pretreatment were examined in reflux esophagitis (RE) induced rats. Methods. Sham, control, and omeprazole (OMP) group were pretreated with distilled water or OMP as a reference, respectively, and PD pretreated groups were given 3 different PD doses once a day for 7 days. One hour after last pretreatment, RE was induced by ligation of the forestomach and pylorus. At 8 h after operation, all animals were sacrificed. Results. PD showed significant dose-dependent reduction of gastric secretion, myeloperoxidase activity, and RE lesion areas of esophagus and stomach mucosa. There was a reduction of lipid peroxidation in 2 doses of PD groups and elevation of antioxidant enzyme activity in all PD groups. Gastric hexose and sialic acid were significantly increased in PD groups, while collagen was reduced. Plasma histamine levels were significantly reduced in all PD groups, but not in the OMP group. Total invasive lesion sizes of esophagus and gastric fundus were significantly decreased in all PD groups. Thicknesses in esophagus of all PD groups were significantly decreased and thicknesses of funds were significantly increased except lowest PD dose. Conclusions. Therapeutic effects of PD on the esophageal and gastric lesions were shown in RE induced rats dose-dependently. The PD pretreatment had significant antioxidant effects with regulation of histamine levels. This study provides useful information regarding the effectiveness of the drug for RE and further novel drug discovery using natural herbal products.
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Johansson, N., R. Ala-aho, V. Uitto, R. Grenman, N. E. Fusenig, C. Lopez-Otin, and V. M. Kahari. "Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase." Journal of Cell Science 113, no. 2 (January 15, 2000): 227–35. http://dx.doi.org/10.1242/jcs.113.2.227.
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Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by transformed squamous epithelial cells, i.e. squamous cell carcinoma (SCC) cells in culture and in vivo. Here, we have elucidated the signaling pathways regulating MMP-13 expression in transformed human epidermal keratinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-(alpha) (TNF-(alpha) resulted in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines. In addition, transforming growth factor-(beta) (TGF-(beta) activated p38 MAPK in both cell lines, and ERK2 in A-5 cells. Selective inhibition of p38 activity with SB 203580 abolished the enhancement of MMP-13, as well as collagenase-1 (MMP-1) and 92-kDa gelatinase (MMP-9) expression by TNF-(alpha) and TGF-(beta). Blocking the ERK1, 2 pathway by PD 98059 had no effect on the induction of MMP-13 expression by TNF-(alpha) or TGF-(beta), but potently suppressed MMP-1 and MMP-9 production. Inhibition of p38 activity by SB 203580 also suppressed collagenolytic activity produced by both cell lines and inhibited invasion of TNF-(alpha) or TGF-(beta) stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results show that activation of p38 MAPK pathway plays a crucial role in the invasive phenotype of transformed squamous epithelial cells, suggesting p38 MAPK as a target to specifically inhibit their invasion.
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Jung, Mi-Yeon, Jeong-Han Kang, and Edward B. Leof. "Transforming growth factor beta induced PD-L1 expression promotes pro-fibrotic signaling." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 79.8. http://dx.doi.org/10.4049/jimmunol.204.supp.79.8.
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Abstract Immune checkpoint proteins such as programmed death-ligand 1 (PD-L1) retain general immune homeostasis and self-tolerance. PD-L1 binds to programmed cell death protein 1 (PD-1) and inhibits T cell activation or protects tumor cells from T cell-mediated killing. PD-L1 has recently been shown to be up-regulated in invasive lung fibroblasts by p53 and focal adhesion kinase (FAK), any potential role of transforming growth factor-beta (TGFβ) in PD-L1 action is unknown in fibrosis. TGFβ is a mysterious protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, fibrotic disorders, and immune modulation, et al. In the current study, we showed that TGFβ induces the expression of the immunoinhibitory molecule PD-L1 in human and murine fibroblasts in a Smad2/3- and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGFβ-dependent induction of extracellular matrix proteins, including collagen Ia1 (colIa1) and alpha-smooth muscle actin (α-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGFβ signaling, TGFβ stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T-cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases.
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Lin, Yuan-Chuan, Yu-Chen Lin, Wei-Wen Kuo, Chia-Yao Shen, Yi-Chang Cheng, Yueh-Min Lin, Ruey-Lin Chang, Vijaya V. Padma, Chih-Yang Huang, and Chih-Yang Huang. "Platycodin D Reverses Pathological Cardiac Hypertrophy and Fibrosis in Spontaneously Hypertensive Rats." American Journal of Chinese Medicine 46, no. 03 (January 2018): 537–49. http://dx.doi.org/10.1142/s0192415x18500271.
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Platycodin D (PD) is the main active saponin isolated from Platycodon grandiflorum (PG) and is reported to exhibit anticancer, anti-angiogenic, anti-inflammation and anti-obesity biological effects. The current study aims to evaluate the therapeutic efficacy of PD in cardiac fibrosis and for hypertrophy in spontaneous hypertension rats (SHRs) and to verify inhibition of the signaling pathway. Significant increases in the cardiac functional indices of left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end systole (LVIDs); the eccentric hypertrophy marker p-MEK5; concentric hypertrophy markers, such as CaMKII[Formula: see text] and calcineurin; and expression levels of NFATc3, p-GATA4 and BNP were observed in spontaneously hypertensive groups. PD treatment reversed these increases in SHRs. In addition, an increase in the fibrosis markers FGF2, uPA, MMP2, MMP9, TGF[Formula: see text]-1 and CTGF during cardiac hypertrophy was detected by western blotting analyses. These results demonstrated that PD treatment considerably attenuates cardiac fibrosis. Histopathological examination revealed that PD treatment remarkably reduced collagen accumulation in contrast to spontaneously hypertensive groups. This study clearly suggests that PD provides myocardial protection by alleviating two damaging responses to hypertension, fibrosis and hypertrophy, in the heart.
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Jun, Ji Hye, Sohae Park, Jae Yeon Kim, Ja-Yun Lim, Gyu Tae Park, Jae Ho Kim, and Gi Jin Kim. "Combination Therapy of Placenta-Derived Mesenchymal Stem Cells with WKYMVm Promotes Hepatic Function in a Rat Model with Hepatic Disease via Vascular Remodeling." Cells 11, no. 2 (January 11, 2022): 232. http://dx.doi.org/10.3390/cells11020232.
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Changes in the structure and function of blood vessels are important factors that play a primary role in regeneration of injured organs. WKYMVm has been reported as a therapeutic factor that promotes the migration and proliferation of angiogenic cells. Additionally, we previously demonstrated that placenta-derived mesenchymal stem cells (PD-MSCs) induce hepatic regeneration in hepatic failure via antifibrotic effects. Therefore, our objectives were to analyze the combination effect of PD-MSCs and WKYMVm in a rat model with bile duct ligation (BDL) and evaluate their therapeutic mechanism. To analyze the anti-fibrotic and angiogenic effects on liver regeneration, it was analyzed using ELISA, qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry. Collagen accumulation was significantly decreased in PD-MSCs with the WKYMVm combination (Tx+WK) group compared with the nontransplantation (NTx) and PD-MSC-transplanted (Tx) group (p < 0.05). Furthermore, the combination of PD-MSCs with WKYMVm significantly promoted hepatic function by increasing hepatocyte proliferation and albumin as well as angiogenesis by activated FPR2 signaling (p < 0.05). The combination therapy of PD-MSCs with WKYMVm could be an efficient treatment in hepatic diseases via vascular remodeling. Therefore, the combination therapy of PD-MSCs with WKYMVm could be a new therapeutic strategy in degenerative medicine.
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Díaz, Raquel, Pilar Sandoval, Raul R. Rodrigues-Diez, Gloria del Peso, José A. Jiménez-Heffernan, Ricardo Ramos-Ruíz, Carlos Llorens, et al. "Increased miR-7641 Levels in Peritoneal Hyalinizing Vasculopathy in Long-Term Peritoneal Dialysis Patients." International Journal of Molecular Sciences 21, no. 16 (August 13, 2020): 5824. http://dx.doi.org/10.3390/ijms21165824.
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Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. Clinical data were collected and lesions were evaluated by immunohistochemistry. In selected biopsies a microRNA (miRNA)-sequencing analysis was performed. Only fifteen patients (15%) showed PHV at different degrees. PHV prevalence was significantly lower among patients using PD fluids containing low glucose degradation products (GDP) (5.9% vs. 24.5%), angiotensin converting enzyme inhibitors (ACEIs) (7.5% vs. 23.4%), statins (6.5% vs. 22.6%) or presenting residual renal function, suggesting the existence of several PHV protective factors. Peritoneal biopsies from PHV samples showed loss of endothelial markers and induction of mesenchymal proteins, associated with collagen IV accumulation and wide reduplication of the basement membrane. Moreover, co-expression of endothelial and mesenchymal markers, as well as TGF-β1/Smad3 signaling activation were found in PHV biopsies. These findings suggest that an endothelial-to-mesenchymal transition (EndMT) process was taking place. Additionally, significantly higher levels of miR-7641 were observed in severe PHV compared to non-PHV peritoneal biopsies. Peritoneal damage by GDPs induce miRNA deregulation and an EndMT process in submesothelial vessels, which could contribute to collagen IV accumulation and PHV.
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Guo, Runsheng, Guojun Hao, Yi Bao, Jun Xiao, Xiaojiang Zhan, Xintian Shi, Laimin Luo, Jing Zhou, Qinkai Chen, and Xin Wei. "MiR-200a negatively regulates TGF-β1-induced epithelial-mesenchymal transition of peritoneal mesothelial cells by targeting ZEB1/2 expression." American Journal of Physiology-Renal Physiology 314, no. 6 (June 1, 2018): F1087—F1095. http://dx.doi.org/10.1152/ajprenal.00566.2016.
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Although epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells was recognized as the key process of peritoneal fibrosis, which is a major cause of peritoneal failure related to peritoneal dialysis (PD), mechanisms underlying these processes remain largely unknown. In this study, we found that miR-200a was significantly downregulated in peritoneal tissues with fibrosis in a rat model of PD. In vitro, transforming growth factor (TGF)-β1-induced EMT, identified by de novo expression of α-smooth muscle actin and a loss of E-cadherin in human peritoneal mesothelial cells (HPMCs), was associated with downregulation of miR-200a but upregulation of zinc finger E-box-binding homeobox 1/2 (ZEB1/2), suggesting a close link between miR-200a and ZEB1/2 in TGF-β1-induced EMT. It was further demonstrated that miR-200a was able to bind to the 3′UTR of ZEB1/2, and overexpression of miR-200a blocked TGF-β1-induced upregulation of ZEB1/2 and, therefore, inhibited EMT and collagen expression. In contrast, overexpression ZEB1/2 blocked miR-200a inhibition of EMT and collagen expression in HMPCs. In conclusion, miR-200a could negatively regulate TGF-β1-induced EMT by targeting ZEB1/2 in peritoneal mesothelial cells. Blockade of EMT in HPMCS indicates the therapeutic potential of miR-200a as a treatment for peritoneal fibrosis associated with PD.
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Shi, Zhong-Dong, Xin-Ying Ji, Danielle E. Berardi, Henry Qazi, and John M. Tarbell. "Interstitial flow induces MMP-1 expression and vascular SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 1 (January 2010): H127—H135. http://dx.doi.org/10.1152/ajpheart.00732.2009.
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The migration of vascular smooth muscle cells (SMCs) and fibroblasts into the intima after vascular injury is a central process in vascular lesion formation. The elevation of transmural interstitial flow is also observed after damage to the vascular endothelium. We have previously shown that interstitial flow upregulates matrix metalloproteinase-1 (MMP-1) expression, which in turn promotes SMC and fibroblast migration in collagen I gels. In this study, we investigated further the mechanism of flow-induced MMP-1 expression. An ERK1/2 inhibitor PD-98059 completely abolished interstitial flow-induced SMC migration and MMP-1 expression. Interstitial flow promoted ERK1/2 phosphorylation, whereas PD-98059 abolished flow-induced activation. Silencing ERK1/2 completely abolished MMP-1 expression and SMC migration. In addition, interstitial flow increased the expression of activator protein-1 transcription factors (c-Jun and c-Fos), whereas PD-98059 attenuated flow-induced expression. Knocking down c- jun completely abolished flow-induced MMP-1 expression, whereas silencing c- fos did not affect MMP-1 expression. Taken together, our data indicate that interstitial flow induces MMP-1 expression and SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism and suggest that interstitial flow, ERK1/2 MAPK, c-Jun, and MMP-1 may play important roles in SMC migration and neointima formation after vascular injury.
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Lin, Chien-Yu, and Kun Cheng. "Abstract 257: Normalization of tumor stroma improves the anti-tumor activity of anti-PD-L1 peptides in pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 257. http://dx.doi.org/10.1158/1538-7445.am2022-257.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by the abundant fibrotic stroma surrounding malignant epithelial cells. The tumor stroma is composed of extracellular matrix proteins, myofibroblasts, stellate cells, and immune cells, and comprises up to 80% of the tumor mass. The stroma promotes the progression and metastasis of tumors and the development of chemoresistance. However, the strategies of completed depletion of the stroma resulted in a more aggressive tumor and a poor survival rate in clinical trials. We discovered that silencing the RNA binding protein αCP2, which is encoded by the poly(rC)-binding protein 2 (PCBP2) gene, could destabilize the type I collagen mRNA in human pancreatic stellate cells and mouse NIH/3T3 fibroblasts, leading to the normalization of the tumor stroma. We recently discovered an anti-PD-L1 peptide that effectively blocks the PD1/PD-L1 pathway. We hypothesize that silencing αCP2 modulates the PDAC stroma, thus improving the therapeutic efficacy of immunotherapy. Therefore, the objective of this study is to develop a combination therapy strategy to treat PDAC with PCBP2 siRNA nanoparticles and the anti-PD-L1 peptide. A mixture of 1×106 PANC02 tumor cells and NIH/313 fibroblast cells was subcutaneously implanted into C57BL/6 mice to establish the desmoplastic PDAC model. The mice were treated with saline, PCBP2 siRNA nanoparticles, the anti-PD-L1 peptide, and PCBP2 siRNA nanoparticles plus the anti-PD-L1 peptide. The results showed that the combination of PCBP2 siRNA nanoparticles with the anti-PD-L1 peptide reduced tumor growth. PCBP2 siRNA decreased type I collagen expression in the tumor. The normalized stroma showed increased infiltration of effective immune cells. This approach provides a new strategy to improve the therapeutic efficacy of immunotherapy in PDAC by normalizing the tumor stroma with the PCBP2 siRNA nanoparticle. Citation Format: Chien-Yu Lin, Kun Cheng. Normalization of tumor stroma improves the anti-tumor activity of anti-PD-L1 peptides in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 257.
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Eichberger, Jonas, Daniela Schulz, Kristian Pscheidl, Mathias Fiedler, Torsten Eugen Reichert, Richard Josef Bauer, and Tobias Ettl. "PD-L1 Influences Cell Spreading, Migration and Invasion in Head and Neck Cancer Cells." International Journal of Molecular Sciences 21, no. 21 (October 29, 2020): 8089. http://dx.doi.org/10.3390/ijms21218089.
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The programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis blockade has been implemented in advanced-stage tumor therapy for various entities, including head and neck squamous cell carcinoma (HNSCC). Despite a promising tumor response in a subgroup of HNSCC patients, the majority suffer from disease progression. PD-L1 is known to influence several intrinsic mechanisms in cancer cells, such as proliferation, apoptosis, migration and invasion. Here, we modulated PD-L1 expression in three HNSCC cell lines with differential intrinsic PD-L1 expression. In addition to an alteration in the epithelial-to-mesenchymal transition (EMT) marker expression, we observed PD-L1-dependent cell spreading, migration and invasion in a spheroid spreading assay on four different coatings (poly-L-lysine, collagen type I, fibronectin and Matrigel®) and a chemotactic transwell migration/invasion assay. Furthermore, the overexpression of PD-L1 led to increased gene expression and small interfering ribonucleic acid (siRNA) knockdown and decreased gene expression of Rho-GTPases and related proteins in a RT2 Profiler™ PCR Array. Rac1 and Rho-GTPase pulldown assays revealed a change in the activation state concordantly with PD-L1 expression. In summary, our results suggest a major role for PD-L1 in favoring cell motility, including cell spreading, migration and invasion. This is presumably caused by altered N-cadherin expression and changes in the activation states of small Rho-GTPases Rho and Rac1.
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Sanders, Matthew A., and Marc D. Basson. "Collagen IV regulates Caco-2 migration and ERK activation via α1β1- and α2β1-integrin-dependent Src kinase activation." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 4 (April 2004): G547—G557. http://dx.doi.org/10.1152/ajpgi.00262.2003.
Full textAbstract:
Our previous work indicates intestinal epithelial cell ERK activation by collagen IV, a major component of the intestinal epithelial basement membrane, requires focal adhesion kinase (FAK) and suggests FAK and ERK may have important roles in regulating intestinal epithelial cell migration. We therefore sought to identify FAK downstream targets regulating intestinal epithelial cell spreading, migration, and ERK activation on collagen IV and the integrins involved. Both dominant-negative Src and Src inhibitor PP2 strongly inhibited collagen IV ERK activation in Caco-2 intestinal epithelial cells. Collagen IV stimulated Grb2 binding site FAK Y925 phosphorylation, which was inhibited by PP2 and required FAK Y397 autophosphorylation. Additionally, FAK Y925F expression blocked collagen IV ERK activation. α1β1- Or α2β1-integrin blockade with α1- or α2-integrin subunit antibodies indicated that either integrin can mediate adhesion, cell spreading, and FAK, Src, and ERK activation on collagen IV. Both dominant-negative Src and PP2 inhibited Caco-2 spreading on collagen IV. PP2 inhibited p130Cas tyrosine phosphorylation, but dominant-negative p130Cas did not inhibit cell spreading. PP2 inhibited Caco-2 migration on collagen IV much more strongly than the mitogen-activated protein kinase kinase inhibitor PD-98059, which completely inhibited collagen IV ERK activation. These results suggest a pathway for collagen IV ERK activation requiring Src phosphorylation of FAK Y925 not previously described for this matrix protein and suggest either α1β1- or α2β1-integrins can regulate Caco-2 spreading and ERK activation on collagen IV via Src. Additionally, these results suggest Src regulates Caco-2 migration on collagen IV primarily through ERK-independent pathways.