Journal articles on the topic 'Anti-integrins therapies'
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Tabatabai, Ghazaleh, Jorg-Christian Tonn, Roger Stupp, and Michael Weller. "The Role of Integrins in Glioma Biology and Anti-Glioma Therapies." Current Pharmaceutical Design 17, no. 23 (August 1, 2011): 2402–10. http://dx.doi.org/10.2174/138161211797249189.
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Khanna, Reena, Mahmoud H. Mosli, and Brian G. Feagan. "Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?" Digestive Diseases 34, no. 1-2 (2016): 153–59. http://dx.doi.org/10.1159/000443132.
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Background: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. Key Messages: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4β7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. Conclusions: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.
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Yerramothu, Praveen. "New Therapies of Neovascular AMD—Beyond Anti-VEGFs." Vision 2, no. 3 (July 30, 2018): 31. http://dx.doi.org/10.3390/vision2030031.
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Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30–40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.
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Garlatti, Valentina, Sara Lovisa, Silvio Danese, and Stefania Vetrano. "The Multiple Faces of Integrin–ECM Interactions in Inflammatory Bowel Disease." International Journal of Molecular Sciences 22, no. 19 (September 28, 2021): 10439. http://dx.doi.org/10.3390/ijms221910439.
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Inflammatory Bowel Disease (IBD) comprises a series of chronic and relapsing intestinal diseases, with Crohn’s disease and ulcerative colitis being the most common. The abundant and uncontrolled deposition of extracellular matrix, namely fibrosis, is one of the major hallmarks of IBD and is responsible for the progressive narrowing and closure of the intestine, defined as stenosis. Although fibrosis is usually considered the product of chronic inflammation, the substantial failure of anti-inflammatory therapies to target and reduce fibrosis in IBD suggests that fibrosis might be sustained in an inflammation-independent manner. Pharmacological therapies targeting integrins have recently shown great promise in the treatment of IBD. The efficacy of these therapies mainly relies on their capacity to target the integrin-mediated recruitment and functionality of the immune cells at the damage site. However, by nature, integrins also act as mechanosensitive molecules involved in the intracellular transduction of signals and modifications originating from the extracellular matrix. Therefore, understanding integrin signaling in the context of IBD may offer important insights into mechanisms of matrix remodeling, which are uncoupled from inflammation and could underlie the onset and persistency of intestinal fibrosis. In this review, we present the currently available knowledge on the role of integrins in the etiopathogenesis of IBD, highlighting their role in the context of immune-dependent and independent mechanisms.
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Yoo, Jun Hwan, Stefan Holubar, and Florian Rieder. "Fibrostenotic strictures in Crohn’s disease." Intestinal Research 18, no. 4 (October 31, 2020): 379–401. http://dx.doi.org/10.5217/ir.2019.09148.
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The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn’s disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.
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Łasiñska, Izabela, and Jacek Mackiewicz. "Integrins as A New Target for Cancer Treatment." Anti-Cancer Agents in Medicinal Chemistry 19, no. 5 (June 27, 2019): 580–86. http://dx.doi.org/10.2174/1871520618666181119103413.
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:Despite the great progress in the development of targeted therapies for different types of cancer utilizing monoclonal antibodies (e.g., cetuximab for colorectal cancer and head and neck cancer therapy), kinase inhibitors (e.g., sorafenib for kidney cancer and gastrointestinal stromal tumours therapy), and immunomodulatory treatments (e.g., nivolumab and pembrolizumab for melanoma therapy and lung cancer therapy), there is still a need to search for new, more effective treatments.:Integrins are responsible for intercellular adhesion and interaction with the cellular matrix. The function of integrins is related to the transduction of intracellular signals associated with adhesion, migration, cell proliferation, differentiation, and apoptosis. Molecules targeting integrins that lead to cancer cell death have been developed. The most advanced molecules studied in clinical trials are abituzumab, intetumumab and cilengitide. There are different groups of anti-integrin drugs: monoclonal antibodies (e.g., abituzumab) and other such as cilengitide, E7820 and MK-0429. These drugs have been evaluated in various cancer types. However, they have shown modest efficacy, and none of them have yet been approved for cancer treatment. Studies have shown that patient selection using biomarkers might improve the efficacy of anti-integrin cancer treatment. Many preclinical models have demonstrated promising results using integrin visualization for cancer detection and treatment efficacy monitoring; however, these strategies require further evaluation in humans.
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Dotan, Iris, Matthieu Allez, Silvio Danese, Mary Keir, Swati Tole, and Jacqueline McBride. "The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies." Medicinal Research Reviews 40, no. 1 (June 19, 2019): 245–62. http://dx.doi.org/10.1002/med.21601.
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Sawada, Kenjiro, Chifumi Ohyagi-Hara, Tadashi Kimura, and Ken-ichirou Morishige. "Integrin Inhibitors as a Therapeutic Agent for Ovarian Cancer." Journal of Oncology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/915140.
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Ovarian cancer is a deadly disease, with a cure rate of only 30%. Despite aggressive treatments, relapse remains almost inevitable in patients with advanced-stage disease. In recent years, great progress has been made towards targeting integrins in cancer treatment, and clinical studies with various integrin inhibitors have demonstrated their effectiveness in blocking cancer progression. Given that the initial critical step of ovarian cancer metastasis is the attachment of cancer cells onto the peritoneum or omentum, in addition to the proven positive clinical results of anti-angiogenic therapy, targeting integrins is likely to be one of the most feasible approaches. This paper summarizes the current understanding of the integrin biology in ovarian cancer metastasis and the various therapeutic approaches attempted with integrin inhibitors. Although no integrin inhibitors have shown favorable results so far, integrin-targeted therapies continue to be a promising approach to be explored for further clinical investigation.
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Kustiati, Ulayatul, Suleyman Ergün, Srikanth Karnati, Dwi Aris Agung Nugrahaningsih, Dwi Liliek Kusindarta, and Hevi Wihadmadyatami. "Ethanolic Extract of Ocimum sanctum Linn. Inhibits Cell Migration of Human Lung Adenocarcinoma Cells (A549) by Downregulation of Integrin αvβ3, α5β1, and VEGF." Scientia Pharmaceutica 90, no. 4 (October 31, 2022): 69. http://dx.doi.org/10.3390/scipharm90040069.
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Adenocarcinoma lung cancer is a type of non-small cell lung carcinoma (NSCLC), which accounts for 85% of lung cancer incidence globally. The therapies that are being applied, both conventional therapies and antibody-based treatments, are still found to have side effects. Several previous studies have demonstrated the ability of the ethanolic extract of Ocimum sanctum Linn. (EEOS) as an ethnomedicine with anti-tumor properties. The aim of this study was to determine the effect of Ocimum sanctum Linn. ethanolic extract in inhibiting the proliferation, angiogenesis, and migration of A549 cells (NSCLC). The adhesion as well as the migration assay was performed. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to measure the expression of αvβ3 integrins, α5β1 integrins, and VEGF. The cells were divided into the following treatment groups: control (non-treated/NT), positive control (AP3/inhibitor β3 80 µg/mL), cisplatin (9 µg/mL), and EEOS at concentrations of 50, 70, 100, and 200 µg/mL. The results showed that EEOS inhibits the adhesion ability and migration of A549 cells, with an optimal concentration of 200 µg/mL. ELISA testing showed that the group of A549 cells given EEOS 200 µg/mL presented a decrease in the optimal expression of integrin α5β1, integrin αvβ3, and VEGF.
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Wehkamp, Jan, and Eduard F. Stange. "Recent advances and emerging therapies in the non-surgical management of ulcerative colitis." F1000Research 7 (August 7, 2018): 1207. http://dx.doi.org/10.12688/f1000research.15159.1.
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The so-called “biologicals” (monoclonal antibodies to various inflammatory targets like tumor necrosis factor or integrins) have revolutionized the treatment of inflammatory bowel diseases. In ulcerative colitis, they have an established role in inducing remission in steroid-refractory disease and, thereafter, maintaining remission with or without azathioprine. Nevertheless, their limitations are also obvious: lack of primary response or loss of response during maintenance as well as various, in part severe, side effects. The latter are less frequent in anti-integrin treatment, but efficacy, especially during induction, is delayed. New antibodies as well as small molecules have also demonstrated clinical efficacy and are soon to be licensed for ulcerative colitis. None of these novel drugs seems to be much more effective overall than the competition, but they provide new options in otherwise refractory patients. This increasing complexity requires new algorithms, but it is still premature to outline each drug’s role in future treatment paradigms.
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Dormond, Olivier, and Curzio Rüegg. "Regulation of endothelial cell integrin function and angiogenesis by COX-2, cAMP and Protein Kinase A." Thrombosis and Haemostasis 90, no. 10 (2003): 577–85. http://dx.doi.org/10.1160/th03-03-0196.
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SummaryAngiogenesis, the development of new blood vessels from preexisting vessels, is a key step in tumor growth, invasion and metastasis formation. Inhibition of tumor angiogenesis is considered as an attractive approach to suppress cancer progression and spreading. Adhesion receptors of the integrin family promote tumor angiogenesis by mediating cell migration, proliferation and survival of angiogenic endothelial cells. Integrins up regulated and highly expressed on neovascular endothelial cells, such as αVβ3 and α5β1, have been considered as relevant targets for anti-angiogenic therapies. Small molecular integrin antagonists or blocking antibodies suppress angiogenesis and tumor progression in many animal models, and some of them are currently being tested in cancer clinical trials as anti-angiogenic agents. COX-2 inhibitors exert anti-cancer effects, at least in part, by inhibiting tumor angiogenesis. We have recently shown that COX-2 inhibitors suppress endothelial cell migration and angiogenesis by preventing αVβ3-mediated and cAMP/PKA-dependent activation of the small GTPases Rac and Cdc42. Here we will review the evidence for the involvement of vascular integrins in mediating angiogenesis and the role of COX-2 metabolites in modulating the cAMP/Protein Kinase A pathway and αVβ3-dependent Rac activation in endothelial cells.The pulication was partially financed by Serono Foundation for the Advancement of Medical Sience.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6–9, 2003 in Geneva, Switzerland.
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Furfaro, Federica, Ludovico Alfarone, Daniela Gilardi, Carmen Correale, Mariangela Allocca, Gionata Fiorino, Marjorie Argollo, et al. "TL1A: A New Potential Target in the Treatment of Inflammatory Bowel Disease." Current Drug Targets 22, no. 7 (April 26, 2021): 760–69. http://dx.doi.org/10.2174/1389450122999210120205607.
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Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. In the last few years, the development of biological agents targeting cytokines and receptors involved in IBD pathogenesis has led to better outcomes and has improved the course of the disease. Despite their effectiveness, drugs such as tumor necrosis factor (TNF) inhibitors, anti-Interleukin-12/23 and anti-integrins, do not induce a response in about one-third of patients, and 40% of patients lose response over time. Therefore, more efficient therapies are required. Recent studies showed that TL1A (Tumor necrosis factor-like cytokine 1A) acts as a regulator of mucosal immunity and participates in immunological pathways involved in the IBD pathogenesis. In this review article, we analyze the role of TL1A as a new potential target therapy in IBD patients.
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Mitsdoerffer, Meike, Giovanni Di Liberto, Sarah Dötsch, Christopher Sie, Ingrid Wagner, Monika Pfaller, Mario Kreutzfeldt, et al. "Formation and immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity." Brain 144, no. 6 (March 9, 2021): 1697–710. http://dx.doi.org/10.1093/brain/awab093.
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Abstract Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic multiple sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of multiple sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T-cell and B-cell receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20% of B cells in organized meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in multiple sclerosis.
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Yang, Edward, Ann M. Arvin, and Stefan L. Oliver. "Role for the αV Integrin Subunit in Varicella-Zoster Virus-Mediated Fusion and Infection." Journal of Virology 90, no. 16 (June 8, 2016): 7567–78. http://dx.doi.org/10.1128/jvi.00792-16.
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ABSTRACTVaricella-zoster virus (VZV) is an alphaherpesvirus that causes varicella and herpes zoster. Membrane fusion is essential for VZV entry and the distinctive syncytium formation in VZV-infected skin and neuronal tissue. Herpesvirus fusion is mediated by a complex of glycoproteins gB and gH-gL, which are necessary and sufficient for VZV to induce membrane fusion. However, the cellular requirements of fusion are poorly understood. Integrins have been implicated to facilitate entry of several human herpesviruses, but their role in VZV entry has not yet been explored. To determine the involvement of integrins in VZV fusion, a quantitative cell-cell fusion assay was developed using a VZV-permissive melanoma cell line. The cells constitutively expressed a reporter protein and short hairpin RNAs (shRNAs) to knock down the expression of integrin subunits shown to be expressed in these cells by RNA sequencing. The αV integrin subunit was identified as mediating VZV gB/gH-gL fusion, as its knockdown by shRNAs reduced fusion levels to 60% of that of control cells. A comparable reduction in fusion levels was observed when an anti-αV antibody specific to its extracellular domain was tested in the fusion assay, confirming that the domain was important for VZV fusion. In addition, reduced spread was observed in αV knockdown cells infected with the VZV pOka strain relative to that of the control cells. This was demonstrated by reductions in plaque size, replication kinetics, and virion entry in the αV subunit knockdown cells. Thus, the αV integrin subunit is important for VZV gB/gH-gL fusion and infection.IMPORTANCEVaricella-zoster virus (VZV) is a highly infectious pathogen that causes chickenpox and shingles. A common complication of shingles is the excruciating condition called postherpetic neuralgia, which has proven difficult to treat. While a vaccine is now available, it is not recommended for immunocompromised individuals and its efficacy decreases with the recipient's age. These limitations highlight the need for new therapies. This study examines the role of integrins in membrane fusion mediated by VZV glycoproteins gB and gH-gL, a required process for VZV infection. This knowledge will further the understanding of VZV entry and provide insight into the development of better therapies.
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Ager, Ann, H. Angharad Watson, Sophie C. Wehenkel, and Rebar N. Mohammed. "Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 377–85. http://dx.doi.org/10.1042/bst20150254.
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The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8+ T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8+ T-cell infiltration of tumours and increase the efficacy of adoptive CD8+ T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy ‘normalizes’ (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients.
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Mair, Devin B., Heather M. Ames, and Rong Li. "Mechanisms of invasion and motility of high-grade gliomas in the brain." Molecular Biology of the Cell 29, no. 21 (October 15, 2018): 2509–15. http://dx.doi.org/10.1091/mbc.e18-02-0123.
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High-grade gliomas are especially difficult tumors to treat due to their invasive behavior. This has led to extensive research focusing on arresting glioma cell migration. Cell migration involves the sensing of a migratory cue, followed by polarization in the direction of the cue, and reorganization of the actin cytoskeleton to allow for a protrusive leading edge and a contractile trailing edge. Transmission of these forces to produce motility also requires adhesive interactions of the cell with the extracellular microenvironment. In glioma cells, transmembrane receptors such as CD44 and integrins bind the cell to the surrounding extracellular matrix that provides a substrate on which the cell can exert the requisite forces for cell motility. These various essential parts of the migratory machinery are potential targets to halt glioma cell invasion. In this review, we discuss the mechanisms of glioma cell migration and how they may be targeted in anti-invasion therapies.
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Wang, Shizhen Emily. "The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-β Signaling in Breast Cancer Malignancy." Journal of Signal Transduction 2011 (February 24, 2011): 1–8. http://dx.doi.org/10.1155/2011/804236.
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Accumulating evidence indicates a functional crosstalk between the HER2 (ErbB2) tyrosine kinase and the TGF-β signaling mediated by its serine/threonine kinase receptors. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated cancer progression and metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. The transformed cellular context with constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, converts TGF-β from a tumor suppressor to a malignancy-promoting factor. TGF-β, in turn, potentiates oncogenic HER2 signaling by inducing shedding of the ErbB ligands and clustering of HER2 with integrins. In addition, TGF-β is associated with resistance to trastuzumab, an anti-HER2 therapeutic antibody. Recent mechanistic studies indicate that TGF-β and HER2 cooperate through both Smad-dependent and independent mechanisms. Blockade of HER2:TGF-β crosstalk may significantly enhance the efficiency of conventional therapies in breast cancer patients with HER2 overexpression.
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Morris, Kenise, and Anne-Laure Papa. "Abstract A004: The role of calcium in metastatic progression." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A004. http://dx.doi.org/10.1158/1538-7445.metastasis22-a004.
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Abstract Calcium is essential to the structural stability of integrin proteins implicated in platelet–cancer cell interactions, namely integrins GPIIb/IIIa and avb3, which share a common beta subunit (Pelletier et al., J Biol Chem, 1996), (Zhang and Chen, Cell Adh Migr, 2012). Additionally, calcium is essential for ligand binding to these integrins (e.g., fibrinogen) that bridge platelets and cancer cells (Raborn et al., Biochemistry, 2011) and for the downstream signaling following mechanical and chemical stimulation in the integrin microenvironment (Michelson, Platelets, 2013). Platelet-cancer cell interactions are key players in cancer progression as platelets support metastatic dissemination (Morris et al., Biochim. Biophys. Acta BBA - Rev. Cancer, 2022). Despite previous studies recognizing calcium’s role in integrin stability and function, calcium’s importance for platelet support in cancer progression is not well understood. Therefore, we aim to (1) characterize the receptor expression and ligand binding ability of GPIIb/IIIa and avb3 on respective cells via anti-CD41a (for platelets and breast cancer MDA-MB-231 cells) and anti-avb3 antibody (for lung cancer A549 cells), (2) characterize platelet function by assessing platelet aggregation using light transmission aggregometry and platelet adhesion on a thrombogenic surface, (3) characterize platelet-cancer cell interaction via flow cytometry, and (4) assess cancer cell invasion in the presence of platelets via transwell assay; all in the presence of an environment with calcium chelation and hypercalcemic conditions. Our results demonstrate that platelet GPIIb/IIIa, cancer cell GPIIb/IIIa (MDA-MB-231) and cancer cell integrin avb3 (A549) are modulated with calcium chelation. Additionally, platelet function, specifically aggregation is significantly decreased with calcium chelation and significantly increased with hypercalcemia. We also observed that the interaction between platelets and cancer cells is reduced with calcium chelation, platelet-MDA-MB-231 interaction specifically being significantly reduced in the presence of sodium citrate. Our overall hypothesis is that the observed effect of calcium levels of platelet and cancer cell integrins could have a significant influence on platelet-cancer cell interactions and cancer cell migration in hypercalcemia, often seen in patients with malignancy. A greater understanding of these interactions could have impact for the design of specific inhibitors with anti-metastatic effects and potentially lead to novel targeted therapies to combat metastatic dissemination. Citation Format: Kenise Morris, Anne-Laure Papa. The role of calcium in metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A004.
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Vetter, Marcel, and Markus F. Neurath. "Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges." Therapeutic Advances in Gastroenterology 10, no. 10 (September 5, 2017): 773–90. http://dx.doi.org/10.1177/1756283x17727388.
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To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn’s disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn’s disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn’s disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn’s disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn’s disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.
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Van Assche, Gert, and Paul Rutgeerts. "Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 2 (February 2005): G169—G174. http://dx.doi.org/10.1152/ajpgi.00423.2004.
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Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.
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Walsh, Garry M., Alexander J. Robinson, and Ping Wu. "Recent Developments in Targeting Eosinophil Accumulation as a Novel Therapeutic Approach for Asthma." Open Allergy Journal 1, no. 1 (July 22, 2008): 35–41. http://dx.doi.org/10.2174/1874838400801010035.
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Current therapies for asthma are aimed at controlling disease symptoms and for the majority of patients inhaled glucocorticoid anti-inflammatory therapy is both effective and well-tolerated. However, concerns remain about the adverse effects of glucocorticoids while a subset of asthmatic patients remains symptomatic despite optimal treatment thereby creating a clear unmet medical need. There is considerable evidence that implicates eosinophils as important effector cells and immunomodulators in the inflammation characteristic of asthma. Numerous in vitro and animal studies have demonstrated essential roles for cell adhesion molecules in eosinophil adhesion and transendothelial migration including the selectins, ICAM-1, VCAM-1 together with many of the μ1 and μ2 integrins. A large body of evidence has also implicated several cytokines and chemokines in the selective recruitment of eosinophils to sites of asthmatic inflammation. Biopharmaceutical approaches have been used to identify inhibitory molecules that target key elements in the processes controlling eosinophil accumulation in asthma. This review will summarise the problems and successes regarding recent developments in therapeutic strategies aimed at reducing eosinophil-mediated inflammation in the asthmatic lung.
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Khamessi, Oussema, Hazem Ben Mabrouk, Selim Kamoun, Chaima Hkimi, Kais Ghedira, and Riadh Kharrat. "The First Snake Venom KTS/Disintegrins-Integrin Interactions Using Bioinformatics Approaches." Molecules 28, no. 1 (December 31, 2022): 325. http://dx.doi.org/10.3390/molecules28010325.
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Snake venom contains a number of active molecules that have been shown to possess high anti-tumor activities; disintegrins are an excellent example among these. Their ability to interact and bind with integrins suggests that they could be very valuable molecules for the development of new cancer therapeutic approaches. However, in the absence of a clear Lysine-Threonine-Serine (KTS) Disintegrins Integrin interaction model, the exact compound features behind it are still unknown. In this study, we investigated the structural characteristics of three KTS-disintegrins and the interaction mechanisms with the α1β1 integrin receptor using in silico bioinformatics approaches. Normal mode analysis showed that the flexibility of the KTSR motif and the C-terminal region play a key role and influence the KTS-Disintegrin-integrin interaction. Protein-protein docking also suggested that the interaction involving the KTSR motif is highly dependent on the residue following K21, S23 and R24. These findings contribute to a better understanding of the KTS-Disintegrin-Integrin structural differences and their interactions with α1β1 receptors, which could improve the selection process of the best active molecules for antitumor therapies.
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Kawamoto, Eiji, Nodoka Nago, Takayuki Okamoto, Arong Gaowa, Asami Masui-Ito, Yuichi Akama, Samuel Darkwah, et al. "The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin." Biomedicines 9, no. 2 (February 7, 2021): 162. http://dx.doi.org/10.3390/biomedicines9020162.
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Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca2+ and Mg2+ but not under strong integrin-activation conditions in the presence of Mg2+ without Ca2+. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of β1 integrin of breast cancer cell lines to fibronectin.
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Johnston, B., T. B. Issekutz, and P. Kubes. "The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo." Journal of Experimental Medicine 183, no. 5 (May 1, 1996): 1995–2006. http://dx.doi.org/10.1084/jem.183.5.1995.
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A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the alpha 4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the alpha 4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for approximately 50% of the leukocyte rolling whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti-alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the alpha 4-integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the alpha 4-integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and beta 2-integrins.
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Scanlon, C. S., E. A. Van Tubergen, R. C. Inglehart, and N. J. D’Silva. "Biomarkers of Epithelial-Mesenchymal Transition in Squamous Cell Carcinoma." Journal of Dental Research 92, no. 2 (November 5, 2012): 114–21. http://dx.doi.org/10.1177/0022034512467352.
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An understanding of the process by which tumor cells destroy the basement membrane of the surface epithelium, invade, and metastasize is essential to the development of novel treatment of head and neck squamous cell carcinoma (HNSCC). In recent years, there has been increased interest in the role of epithelial-mesenchymal transition (EMT) in invasion. EMT is a process that describes the development of motile, mesenchymal-like cells from non-motile parent epithelial cells. There are 3 known types of EMT that mediate development, wound healing, and carcinogenesis. This review summarizes studies of known EMT biomarkers in the context of HNSCC progression. The biomarkers discussed come from a wide range of proteins, including cell-surface proteins (E-cadherin, N-cadherin, and Integrins), cytoskeletal proteins (α-Smooth Muscle Actin, Vimentin, and β-catenin), extracellular matrix proteins (Collagens, Fibronectin, and Laminin), and transcription factors (SNAIL1, SNAIL2, TWIST, and LEF-1). Overall, the findings of these studies suggest that EMT mediates HNSCC progression. The mechanistic role of the EMT markers that have been associated with HNSCC should be more clearly defined if new anti-HNSCC therapies to block EMT progression are to be developed.
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Huang, Jianmei, Jianming Huang, and Guonan Zhang. "Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity." Cancers 14, no. 23 (November 26, 2022): 5840. http://dx.doi.org/10.3390/cancers14235840.
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Sialylation is an enzymatic process that covalently attaches sialic acids to glycoproteins and glycolipids and terminates them by creating sialic acid-containing glycans (sialoglycans). Sialoglycans, usually located in the outmost layers of cells, play crucial biological roles, notably in tumor transformation, growth, metastasis, and immune evasion. Thus, a deeper comprehension of sialylation in cancer will help to facilitate the development of innovative cancer therapies. Cancer sialylation-related articles have consistently increased over the last four years. The primary subjects of these studies are sialylation, cancer, immunotherapy, and metastasis. Tumor cells activate endothelial cells and metastasize to distant organs in part by the interactions of abnormally sialylated integrins with selectins. Furthermore, cancer sialylation masks tumor antigenic epitopes and induces an immunosuppressive environment, allowing cancer cells to escape immune monitoring. Cytotoxic T lymphocytes develop different recognition epitopes for glycosylated and nonglycosylated peptides. Therefore, targeting tumor-derived sialoglycans is a promising approach to cancer treatments for limiting the dissemination of tumor cells, revealing immunogenic tumor antigens, and boosting anti-cancer immunity. Exploring the exact tumor sialoglycans may facilitate the identification of new glycan targets, paving the way for the development of customized cancer treatments.
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Monasterio, Carmen, Annette Schmitt-Gräff, Matthias Pohl, Thomas Truschel, Klaus Warnatz, Wolfgang Kreisel, Robert Thimme, and Peter Hasselblatt. "Fatal ulcerative enteritis of the small intestine in a patient with ulcerative colitis treated with vedolizumab." Zeitschrift für Gastroenterologie 55, no. 10 (June 27, 2017): 1014–20. http://dx.doi.org/10.1055/s-0043-111805.
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AbstractVedolizumab (VDZ) inhibits α4β7 integrins and is used to target intestinal immune responses in patients with inflammatory bowel disease, which is considered to be relatively safe. Here we report on a fatal complication following VDZ administration. A 64-year-old female patient with ulcerative colitis (UC) refractory to tumor necrosis factor inhibitors was treated with VDZ. One week after the second VDZ infusion, she was admitted to hospital with severe diarrhea and systemic inflammatory response syndrome (SIRS). Blood stream infections were ruled out, and endoscopy revealed extensive ulcerations of the small intestine covered with pseudomembranes, reminiscent of invasive candidiasis or mesenteric ischemia. Histology confirmed subtotal destruction of small intestinal epithelia and colonization with Candida. Moreover, small mesenteric vessels were occluded by hyaline thrombi, likely as a result of SIRS, while perfusion of large mesenteric vessels was not compromised. Beta-D-glucan concentrations were highly elevated, and antimycotic therapy was initiated for suspected invasive candidiasis but did not result in any clinical benefit. Given the non-responsiveness to anti-infective therapies, an autoimmune phenomenon was suspected and immunosuppressive therapy was escalated. However, the patient eventually died from multi-organ failure. This case should raise the awareness for rare but severe complications related to immunosuppressive therapy, particularly in high risk patients.
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Eddy, Allison. "Serine proteases, inhibitors and receptors in renal fibrosis." Thrombosis and Haemostasis 101, no. 04 (2009): 656–64. http://dx.doi.org/10.1160/th08-12-0779.
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SummaryChronic kidney disease (CKD) is estimated to affect one in eight adults. Their kidney function progressively deteriorates as inflammatory and fibrotic processes damage nephrons. New therapies to prevent renal functional decline must build on basic research studies that identify critical cellular and molecular mediators. Plasminogen activator inhibitor-1 (PAI-1), a potent fibrosis-promoting glycoprotein, is one promising candidate. Absent from normal kidneys, PAI-1 is frequently expressed in injured kidneys. Studies in genetically engineered mice have demonstrated its potency as a pro-fibrotic molecule. Somewhat surprising, its ability to inhibit serine protease activity does not appear to be its primary pro-fibrotic effect in CKD. Both tissue-type plasminogen activator and plasminogen deficiency significantly reduced renal fibrosis severity after ureteral obstruction, while genetic urokinase (uPA) deficiency had no effect. PAI-1 expression is associated with enhanced recruitment of key cellular effectors of renal fibrosis – interstitial macrophages and myofibroblasts. The ability of PAI-1 to promote cell migration involves interactions with the low-density lipoprotein receptor-associate protein-1 and also complex interactions with uPA bound to its receptor (uPAR) and several leukocyte and matrix integrins that associate with uPAR as co-receptors. uPAR is expressed by several cell types in damaged kidneys, and studies in uPAR-deficient mice have shown that its serves a protective role. uPAR mediates additional anti-fibrotic effects – it interacts with specific co-receptors to degrade PAI-1 and extracellular collagens, and soluble uPAR has leukocyte chemoattractant properties. Molecular pathways activated by serine proteases and their inhibitor, PAI-1, are promising targets for future anti-fibrotic therapeutic agents.
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Stuve, Olaf, Geert R. A. M. D'Haens, Walter Reinisch, Severine Vermeire, Harald Vogelsang, Matthieu Allez, Pierre Desreumaux, et al. "Anti-MAdCAM-1 therapy does not affect immune surveillance in the central nervous system." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 139.6. http://dx.doi.org/10.4049/jimmunol.196.supp.139.6.
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Abstract Background Blocking integrins can be associated with an increased risk of progressive multifocal encephalopathy (PML). MAdCAM-1 is an adhesion molecule that is not constitutively expressed in healthy CNS and considered mostly gut-selective. However, MAdCAM-1 is upregulated in choroid plexus epithelium during experimental autoimmune encephalomyelitis (EAE. PF-00547659 is a fully human mAb that is highly selective for MAdCAM-1. The purpose of this study was to investigate its effect on cellular elements of immune surveillance in the CNS and blood of patients with Crohn’s disease (CD). Methods All methods were tested in a control cohort of volunteers with CD (Cohort 1). Study patients (Cohort 2) had CD and prior treatment with anti-TNF and immunosuppressant therapies. Patients underwent a lumbar puncture (LP1) followed by 3 monthly injections of 225 mg PF-00547659. After the last dose, a LP2 was performed. CSF was analyzed within 24h by multi-parameter flow cytometry. Results In Cohort 1, the lymphocyte subset percentages were the same at both time points. Cohort 2 consisted of 30 patients in whom 2 LPs were performed. Their pre-treatment lymphocyte numbers were lower than those of subjects who had stopped immunosuppressants, but otherwise results were the same. CSF lymphocytes (cells per mL) shown as geometric means (CV%). LP1: 37 patients, total lymphocytes 391 (140%), CD3+/CD4+ cells 246 (152%), CD3+/CD8+ cells 100 (126%), CD4:CD8 ratio 2.46 (57%). LP2: 30 patients, total lymphocytes 513 (137%), CD3+/CD4+ cells 332 (143%), CD3+/CD8+ cells 123 (125%), CD4:CD8 ratio 2.69 (56%). Conclusion This is the first evidence that a therapeutic dose of anti-MAdCAM-1 mAb does not affect the number and composition of leukocytes in the CNS.
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Li, Yi, Jianping Chen, Andrew A. Bolinger, Haiying Chen, Zhiqing Liu, Yingzi Cong, Allan R. Brasier, Irina V. Pinchuk, Bing Tian, and Jia Zhou. "Target-Based Small Molecule Drug Discovery Towards Novel Therapeutics for Inflammatory Bowel Diseases." Inflammatory Bowel Diseases 27, Supplement_2 (November 15, 2021): S38—S62. http://dx.doi.org/10.1093/ibd/izab190.
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Abstract Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a class of severe and chronic diseases of the gastrointestinal (GI) tract with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is a major contributing factor to neoplastic transformation and the development of colitis-associated colorectal cancer. Conversely, persistence of transmural inflammation in CD is associated with formation of fibrosing strictures, resulting in substantial morbidity. The recent introduction of biological response modifiers as IBD therapies, such as antibodies neutralizing tumor necrosis factor (TNF)-α, have replaced nonselective anti-inflammatory corticosteroids in disease management. However, a large proportion (~40%) of patients with the treatment of anti-TNF-α antibodies are discontinued or withdrawn from therapy because of (1) primary nonresponse, (2) secondary loss of response, (3) opportunistic infection, or (4) onset of cancer. Therefore, the development of novel and effective therapeutics targeting specific signaling pathways in the pathogenesis of IBD is urgently needed. In this comprehensive review, we summarize the recent advances in drug discovery of new small molecules in preclinical or clinical development for treating IBD that target biologically relevant pathways in mucosal inflammation. These include intracellular enzymes (Janus kinases, receptor interacting protein, phosphodiesterase 4, IκB kinase), integrins, G protein-coupled receptors (S1P, CCR9, CXCR4, CB2) and inflammasome mediators (NLRP3), etc. We will also discuss emerging evidence of a distinct mechanism of action, bromodomain-containing protein 4, an epigenetic regulator of pathways involved in the activation, communication, and trafficking of immune cells. We highlight their chemotypes, mode of actions, structure-activity relationships, characterizations, and their in vitro/in vivo activities and therapeutic potential. The perspectives on the relevant challenges, new opportunities, and future directions in this field are also discussed.
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Carlos, TM, and JM Harlan. "Leukocyte-endothelial adhesion molecules." Blood 84, no. 7 (October 1, 1994): 2068–101. http://dx.doi.org/10.1182/blood.v84.7.2068.2068.
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Abstract In the 9 years since the last review on leukocyte and endothelial interactions was published in this journal many of the critical structures involved in leukocyte adherence to and migration across endothelium have been elucidated. With the advent of cell and molecular biology approaches, investigations have progressed from the early descriptions by intravital microscopy and histology, to functional and immunologic characterization of adhesion molecules, and now to the development of genetically deficient animals and the first phase I trial of “anti-adhesion” therapy in humans. The molecular cloning and definition of the adhesive functions of the leukocyte integrins, endothelial members of the Ig gene superfamily, and the selectins has already provided sufficient information to construct an operative paradigm of the molecular basis of leukocyte emigration. The regulation of these adhesion molecules by chemoattractants, cytokines, or chemokines, and the interrelationships of adhesion pathways need to be examined in vitro and, particularly, in vivo. Additional studies are required to dissect the contribution of the individual adhesion molecules to leukocyte emigration in various models of inflammation or immune reaction. Certainly, new adhesion structures will be identified, and the current paradigm of leukocyte emigration will be refined. The promise of new insights into the biology and pathology of the inflammatory and immune response, and the potential for new therapies for a wide variety of diseases assures that this will continue to be an exciting area of investigation.
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Carlos, TM, and JM Harlan. "Leukocyte-endothelial adhesion molecules." Blood 84, no. 7 (October 1, 1994): 2068–101. http://dx.doi.org/10.1182/blood.v84.7.2068.bloodjournal8472068.
Full textAbstract:
In the 9 years since the last review on leukocyte and endothelial interactions was published in this journal many of the critical structures involved in leukocyte adherence to and migration across endothelium have been elucidated. With the advent of cell and molecular biology approaches, investigations have progressed from the early descriptions by intravital microscopy and histology, to functional and immunologic characterization of adhesion molecules, and now to the development of genetically deficient animals and the first phase I trial of “anti-adhesion” therapy in humans. The molecular cloning and definition of the adhesive functions of the leukocyte integrins, endothelial members of the Ig gene superfamily, and the selectins has already provided sufficient information to construct an operative paradigm of the molecular basis of leukocyte emigration. The regulation of these adhesion molecules by chemoattractants, cytokines, or chemokines, and the interrelationships of adhesion pathways need to be examined in vitro and, particularly, in vivo. Additional studies are required to dissect the contribution of the individual adhesion molecules to leukocyte emigration in various models of inflammation or immune reaction. Certainly, new adhesion structures will be identified, and the current paradigm of leukocyte emigration will be refined. The promise of new insights into the biology and pathology of the inflammatory and immune response, and the potential for new therapies for a wide variety of diseases assures that this will continue to be an exciting area of investigation.
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Tabe, Yoko, Linhua Jin, Gordon B. Mills, Yuko Tsutsumi-Ishii, Michael Andreeff, and Marina Konopleva. "Mesenchymal Stem Cells Promote Survival of Leukemic Cells Via Integrin-Linked Kinase (ILK)-Dependent Akt and STAT3 Activation: Implications for Leukemia Therapy." Blood 104, no. 11 (November 16, 2004): 3377. http://dx.doi.org/10.1182/blood.v104.11.3377.3377.
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Abstract The β integrins play an important role in the cell-to-cell interactions, which trigger intracellular signal transduction pathways. Integrin-linked kinase (ILK) has been shown to directly interact with β integrins and phosphorylate Akt, which promotes cell survival. On the other hand, PI3K/Akt and JAK/STAT signaling pathways are also recognized as potent anti-apoptotic mediators activated by ligation of growth factor receptors. We have previously demonstrated that stroma cells protect acute promyelocytic leukemic (APL) cells from apoptosis (Tabe, Blood103:1815–1822, 2004). Here, we investigate the ability of bone marrow stroma cells to activate Akt, STAT3, and ILK signaling in leukemic cells co-cultured with stroma in low-serum conditions (0.5% FCS). Human mesenchymal stem cells (MSC), co-cultivated with APL-derived NB4 cells in direct cell-to-cell contact, partially inhibited spontaneous apoptosis and enhanced viability of NB4, while separation from stromal cells by transwell insert abrogated this supporting effect of MSC. Western blot analysis using phosphospecific antibodies demonstrated that direct cell-to-cell contact with MSC caused strong activation of Akt and STAT3 signaling in NB4 cells, which have low baseline phosphorylation of these proteins. Treatment with PI3K inhibitor LY294002 or JAK/STAT3 inhibitor (AG480) decreased both, Akt and STAT3 activation in NB4 cells, however, in cells co-cultured in direct contact with MSC the Akt and STAT3 phosphorylation levels were still significantly higher than in suspension cultures and in cells separated by transwell. These observations indicate cross-talk between PI3K/Akt and JAK/STAT pathways, and that Akt is activated independent from PI3K in NB4 cells through direct interaction with MSC. Both, LY294002 and AG480 induced apoptosis and decreased viability of suspension NB4 cells, but this effect was partially abrogated by MSC co-culture. Next, we examined the effects of these signal transduction inhibitors on MSC. MSC expressed both, phospho-Akt and phospho-Stat3, which was inhibited by LY294002 and AG480. LY294002 but not AG480 induced moderate apoptosis in MSC (annexin V positivity; MSC alone19.7 %; LY294002, 30.8%; AG480, 20.1% at 72 hours). Finally, we investigated Akt and STAT3 activation associated with ILK in NB4 cells. Treatment with ILK inhibitor KP004 (QLT Inc., Vancouver, Canada) decreased phosphorylation of Akt and STAT3 only in NB4 cells co-cultured with MSC and not in suspension cultures. The specific abrogation of MSC-mediated signaling resulted in higher induction of apoptosis in stroma co-cultured cells compared to suspension cells (annexin V positivity; KP004 treated suspension cultures 47.4±4.3%; MSC co-cultures 64.9±10.3%). These results indicate that bone marrow stroma cells support survival of leukemic cells through β integrin linked ILK, which activates Akt in a PI3K-independent manner and also stimulates STAT3. We propose that abrogation of ILK/Akt and STAT3 signaling may overcome protective effects of the bone marrow microenvironment on APL cells and thereby greatly enhance anti-leukemic therapies.
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Lee, J., G. Kim, J. C. Kim, J. H. Park, C. Han, and M. Kim. "P098 Novel drug candidate for the treatment of Inflammatory Bowel Disease with unique mechanisms of action." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i261. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0228.
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Abstract Background Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation and severe dysfunction of the gastrointestinal tract. Despite significant improvements in therapeutic agents targeting IBD, many subjects with IBD fail to achieve recovery or do not respond to current medication. Moreover, current therapy has been limited to the management of inflammation, while almost no progress has been made in the development of anti-fibrotic therapies for IBD. NEXEL's novel protein NP-011, targeting αVβ3 and αVβ5 integrins and phosphatidylserine, has shown anti-inflammatory and anti-fibrotic effects in various in vivo models with fibrosis. This study was designed to evaluate the therapeutic potential of NP-011 for the treatment of IBD using mice models. Methods Acute ulcerative colitis was induced by exposure to 2% dextran sodium sulfate (DSS)-treated drinking water from Day 1 to Day 7; Normal control animals did not receive DSS. Animals were then dosed with vehicle (NP-011 storage buffer, n=10), comparative protein, MFG-E8 (n=10), or NP-011 (n=10) daily for five days (IV) from Day 7 to Day 11. All animals were sacrificed on Day 14. The chronic colitis model was induced by exposure to 2% DSS-treated drinking water (initial three consecutive days of each week) and recovered by providing normal water (four days each from Day 3 and Day 10). Animals were dosed with the vehicle, three commercial drugs (n=10, 1.03 mg/kg, on Day 3), and NP-011 (n=10, 320, and 640 ug/kg, on Day 3 and Day 10) by intravenous injection. All animals were sacrificed on Day 18. Colon length and histological changes (inflammation and crypt damage) were analyzed. Results The induction of colitis was characterized by weight loss. Treatment with comparative protein or NP-011 improved body weight gain during recovery. Both proteins suppressed the shortening of the colon and reduced histological score, including intestinal inflammation and crypt damage. Notably, the administration of NP-011 showed higher efficiency than the same dose of the comparative protein in improving these pathologic parameters. NP-011 was also effective in the chronic model of colitis. Colon shortening, inflammation reactions, and crypt damage were markedly attenuated in NP-011-administered mice with comparable efficacy to commercial drugs. Conclusion Treatment with NP-011 demonstrated substantial improvement in histological characteristics of bowel pathology and suppression of colon shortening in the IBD mice model. Taken together, this novel protein, NP-011, could be a promising drug candidate for the treatment of IBD with unique mechanisms of action, including anti-inflammation and anti-fibrosis *JL, GK, and JCK have equally contributed to this study.
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Berghoff, Anna Sophie, Orsolya Rajky, Frank Winkler, Michael Weller, Christoph Zielinski, Jens Schittenhelm, and Matthias Preusser. "Evaluation of invasion patterns and their correlation with integrin alphavbeta expression in brain metastases of solid cancers." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2059. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2059.
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2059 Background: Understanding the pathobiology of brain metastases (BM) could guide the establishment of new targeted therapies. Methods: We collected 57 autopsy specimens of BM (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 1 kidney cancer, 2 colorectal cancer, 13 other) and histologically evaluated the patterns of invasion into the surrounding brain parenchyma. Expression of the following integrins was evaluated using immunohistochemistry: with novel antibodies for αv subunit, αvβ3, αvβ5, αvβ6 and αvβ8 integrin. Results: We observed three main invasion patterns: well-demarcated (29/57, 51%), vascular co-option (10/57, 18%) and diffuse infiltration (18/57, 32%). There was no association of invasion pattern with primary tumor type, although vascular co-option was most common in melanomas (4/10, 40%). αv subunit expression was lowest in the vascular co-option group (p = 0.05, t-test). αvβ6 levels were higher in the well-demarcated group than in the vascular co-option group (p = 0.025; t-test) and were higher in lung cancer BM than in melanoma BM (0.01, t-test). αvβ3 and αvβ5 were frequently expressed in tumoral (αvβ3: 30/57, 53%; αvβ5: 55/57, 97%) and peritumoral (αvβ3: 29/57, 51%, αvβ5: 54/57 (95%) vascular structures and 27/57 (47%) specimens showed avb5 and 6/57 (11%) αvβ3 expression on tumor cells. Prior radio- or chemotherapy did not correlate with invasion pattern or integrin expression. Conclusions: We delineate three distinct invasion patterns of BM into the brain parenchyma: well-demarcated growth, vascular co-option and diffuse infiltration. Integrin expression is frequent on tumor and vascular cells in BM and associated with distinct invasion patterns. Anti-integrin therapy could be a valid treatment option in patients with BM.
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Hsieh, Yao-Te, Eun Ji Gang, Halvard Bonig, Ronald J. Biediger, Peter Vanderslice, and Yong-Mi Kim. "The Small Molecule Inhibitor of VLA4 TBC3486 Sensitizes Resistant ALL to Chemotherapy." Blood 120, no. 21 (November 16, 2012): 1500. http://dx.doi.org/10.1182/blood.v120.21.1500.1500.
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Abstract Abstract 1500 Significant progress notwithstanding, drug resistant acute lymphoblastic leukemia (ALL) remains a therapeutic challenge, as well as acute and long-term off-target toxicity of anti-ALL therapies can be dose-limiting or debilitating. Therefore, the development of more targeted therapies is desirable. We recently provided evidence that chemotherapy resistance of ALL cells can be partly overcome by interfering with the function of VLA4, the alpha4beta1 integrin, in vivo. In those studies, we used the anti-functional antibody Natalizumab. We extended our studies to an alternative VLA4 inhibitor, the novel non-peptidic small molecule TBC3486. Previous in vitro assays and molecular modeling studies indicate that TBC3486 behaves as a ligand mimetic, competing with VCAM-1 for the MIDAS site of VLA-4. As such, the compound has been shown to be efficacious in VLA-4 dependent models of inflammatory and autoimmune disease. The potential usefulness of this novel inhibitor in leukemia treatment was tested in our established in vitro and in vivo assays. LAX7R cells, primary pre-B-ALL with a normal karyotype from a patient with an early relapse, were used throughout for the studies reported here. LAX7R cells were treated with 25μM TBC3486 or THI0012 control, the inactive enantiomer of TBC3486, and seeded onto plates coated with human VCAM-1. Adhesion, scored after 2 days, was significantly inhibited by TBC3486 compared to control treated cells (7.9%±4.0 vs 95.4%±8.0; p=0.003). Proliferation rate and cell viability were unaffected by the treatments. In a co-culture system of LAX7R cells with OP9 stroma cells, which we use as an in vitro model of stroma-mediated chemotherapy resistance, we assessed differential effects of VDL (Vincristine, Dexamethasone, L-Asparaginase) on leukemia cell survival in the presence or absence of TBC3486. Stromal adhesion significantly protected LAX7R cells against VDL chemotherapy; this effect was significantly attenuated by TBC3486 compared to the control as determined by Trypan blue exclusion of dead cells (Cell viability of 39.9%±5.1 vs. 57.2±1.8; p=0.02). After these encouraging observations, we next evaluated the benefit of TBC3486 on leukemia progression in a xenotransplant assay. LAX7R cells were lentivirally labelled with luciferase for in vivo tracking and injected into NOD/SCID hosts. Three days after leukemia cell transfer, mice received either TBC3486 or THI0012 (control) (10mg/kg/d) daily for 2 weeks (intraperitoneally), with or without VDL chemotherapy. This experiment is in progress, but already survival of leukemia-bearing mice was significantly prolonged, from a median survival time (MST) for control mice of 33 days post-leukemia injection to a MST of 47 days post-leukemia injection for TBC3486 treated mice (p=0.02). Similarly, bioluminescence imaging revealed a marked delay of leukemia cell dissemination (p<0.0001). Taken together, our data demonstrate that small molecule inhibition of VLA4 using the novel TBC3486 is a suitable approach for targeting of chemotherapy-resistant leukemia. Further studies are warranted to understand and evaluate preclinically adjuvant small molecule inhibition of integrins to overcome relapse of ALL. Disclosures: No relevant conflicts of interest to declare.
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De Lorenzo, Emanuele, Serena Pillozzi, Marika Masselli, Olivia Crociani, Andrea Becchetti, and Annarosa Arcangeli. "Potassium Channels as Novel Pharmacological Targets in Acute Myeloid Leukemia." Blood 112, no. 11 (November 16, 2008): 4034. http://dx.doi.org/10.1182/blood.v112.11.4034.4034.
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Abstract Targeted therapies are considerably changing the treatment and prognosis of hematologic malignancies. The progressive elucidation of the molecular mechanisms that regulate establishment and progression of tumours is leading to more specific and efficacious pharmacological approaches. In this picture, ion channels represent a relatively unexpected, but very promising players. In particular hERG1 channel expression is altered in many primary leukemias and frequently turn out to exert pleiotropic effects on cancer cell physiology, interaction with the external matrix and stimulation of angiogenesis. hERG1 channels can also trigger intracellular signaling cascades by forming protein complexes with integrins as well as other membrane proteins. These results convey the hypothesis that drugs acting on ion channels could have therapeutic value in the treatment of cancers. Recent evidence suggests that, in certain tumours, application of channel inhibitors does in fact impair cell growth both in vitro and in vivo. A major objection to such a pharmacological approach is the presence of serious side effects, particularly cardiac arrhythmias, especially in the case of hERG1 blockers. This flaw is now being overcome by different approaches, ie the identification of non-arrhythmogenic compounds or calibration of treatment by exploitation of drug selectivity for specific channel states. We tested this possibility in a preclinical model represented by NOD-SCID mice injected with acute leukemia cells and treated with hERG1 blockers. Previous experiments, using NOD/SCID mice injected with AML cells, had shown that herg1 over-expression confers a greater malignancy (Pillozzi S et al, Blood110:1238–50, 2007). The treatment of mice injected with AML cells with specific hERG1 blockers as well as with anti-hERG1 mAb, led to a significant decrease of AML engraftment into the BM and migration into the PB and peripheral organs (Pillozzi S et al, Blood ASH110: 877, 2007). We recently extended our work to an AML cell line stably transfected with the herg1 cDNA (HL60-hERG1), as well as to a ALL cell line (697), which endogenously shows a high herg1 expression. Three groups of treatment were established: control group, E4031-treated group (i.p. starting 1 week after inoculum, 20 mg/kg, daily for 2 weeks) and E4031-treated group (as above, daily until the end of experiment). Various morphometric characteristics of microvessels (density, total vascular area, several size- and shape-related parameters), highlighted through anti-CD34 staining, were quantitated in the BM. Overall, the group of mice treated with hERG1 inhibitors had decreased number of microvessels, decreased total vascular area and size-related parameters. Moreover, E4031 treated mice showed a longer survival compared to the untreated ones. Finally, we evaluated cardiac toxicity in vivo of E4031: no significant variation in ECG parameters were detected, nor gross morphological alterations. Nevertheless, we are also testing different pharmacological categories of hERG1 blockers, such the anti-psychotic drug sertindole, proven to be avoid of any cardiac side effect, despite a strong block of hERG1.
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Nimmanapalli, Ramadevi, Elvira Gerbino, William S. Dalton, and Melissa Alsina. "Adhesion of 8226 Myeloma Cell Lines Induces over Expression of HSP70 and its Inhibition Reverses CAM-DR and Acquired Drug Resistance in Multiple Myeloma." Blood 104, no. 11 (November 16, 2004): 636. http://dx.doi.org/10.1182/blood.v104.11.636.636.
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Abstract Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma cells that accumulate preferentially in the bone marrow. In spite of high-dose chemotherapy and novel targeted therapies, myeloma remains to be an incurable disease due to emergence of drug resistance. Therefore, identification of mechanisms involved in drug resistance are essential to develop new and more effective targeted therapies. Heat shock proteins (HSPs) are a super family of highly conserved proteins, which are induced in plant, yeast, bacterial and mammalian cells in response to an array of physiological and environmental stress cues. Among heat shock protein families, HSP70 is one of the most highly conserved and is the only protein expressed in response to cellular stress. HSPs have been implicated in multidrug resistance, as they have been repeatedly demonstrated to inhibit apoptosis induced by a number of chemotherapeutic agents (Chant et al., 1996). We have shown that adhesion of myeloma cells to either bone marrow stromal cells or FN enhances HSP70 expression and secretion as determined by real-time RT-PCR and ELISA, respectively. Inhibition of the HSP70 expression using either KNK437 (HSF-1 inhibitor) or RNAi to HSP70, decreased 8226 cell adhesion to stromal cells as well as to FN as early as two hours, and this adhesion was mediated through α4β1 and α5β1 integrins. Treatment of 8226 cells with KNK437 or RNAi HSP70, induce apoptosis at 24 hours in a dose dependent manner. Interestingly, this effect was independent of adhesion (FN 55% apoptosis vs suspension 42% apoptosis) and is mediated by caspase-3 and PARP cleavage. Further more, treatment of 8226 cells with HSP70 inhibitors reversed CAM-DR to melphalan. To investigate whether HSP70 inhibition can cause apoptosis in Melphalan-resistant myeloma cells, we treated 8226/S and 8226/LR5 cells with either KNK437 alone or in combination with Melphalan. Our results show that KNK437 not only caused more apoptosis in 8226/LR5 (55% with 100 μM) cells than in the sensitive parental cells (42%), but also sensitized 8226/LR5 cells to Melphalan (64%), even though intracellular protein and RNA expression of heat shock protein 27, 70 and 90 was not affected in either Melphalan-sensitive or -resistant cells. These results suggest that 8226/LR5 cells depend on HSP70 for survival more than parental 8226 cells Similarly, pretreatment of 8226 cells with either KNK437, or RNAi against HSP70, enhanced the proteasome inhibitor, Bortezomib- induced apoptosis (Bortezomib 10 nM 8 %, KNK437 25 μM 14 % Combination, 30 %). This apoptosis was mediated by Caspase 3 and was correlated with reduced HSP70 expression. 8226 myeloma cells treated with Bortezomib (10 nM) caused increased RNA and protein expression of HSP70, HSP27 and HSP90 as early as 4 and 8 hrs, respectively. Further studies elucidating the mechanism/s by which HSP70 inhibition sensitizes Melphalan or bortezomib induced apoptosis are currently under investigation. Our preclinical studies provide the basis for potential need for the development of anti HSP70 inhibitors for clinical studies in myeloma.
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Weidow, Brandy L., Jacqueline Vidosh, and John P. Biggerstaff. "The Role of Soluble Fibrin and Fibrin Inhibitory Peptides in Cancer Metastasis." Blood 108, no. 11 (November 16, 2006): 5200. http://dx.doi.org/10.1182/blood.v108.11.5200.5200.
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Abstract Circulating soluble fibrin (sFn) is a marker for ongoing disseminated intravascular coagulation and may have prognostic significance, especially in metastatic cancers. Anti-coagulant therapies have been effective in reducing metastasis in several cancers, but with increased risk of bleeding. The authors have previously demonstrated that soluble fibrin (sFn), which is elevated in many cancer patients, enhances metastasis in an experimental model, and increases platelet/tumor cell adherence by cross-linking platelet aIIbb3 to tumor cell CD54 (a receptor for two of the leukocyte b2 integrins aLb2 and aMb2). sFn also binds to monocyte aMb2 (Mac1), and the peptide sequences of the fibrin(ogen) binding sites for aMb2 and CD54 have recently been identified. It was, therefore, hypothesized that sFn binding to these receptors would result in inhibition of monocyte/tumor cell adherence, and consequently cytotoxicity, which may be reversed by inclusion of blocking peptides. To test this, monocyte adherence to A375 melanoma cells was quantified at physiologically relevant shear rates (35–560 s−1) using a laminar flow perfusion chamber mounted on a Leica DMIRB inverted microscope equipped with a computer controlled digital imaging camera. Effector and target cells were untreated, or incubated with sFn (fibrinogen (Fg), 0.5 mg/ml; fibrin polymerization inhibitor Gly-Pro-Arg-Pro amide (GPRPa), 4 mM; and human thrombin (0.125 U/ml)) in the presence or absence of specific single or combined blocking peptides directed against the sFn binding sites on CD54 (P1) and aMb2 (P2), or the sFn g-chain binding sites for CD54 (P3) and aMb2 (P4). The effect of peptides on thrombin (0.125 U/ml) induced clotting of purified Fg (0.5 mg/ml) was assessed visually. The effect of sFn on monocyte cytotoxicity (effector: target 20:1) against green fluorescent protein (GFP) transfected A375 melanoma cells was measured by GFP release from lysed cells using a Perkin-Elmer Victor-3 96-well fluorescence plate reader. Pre-treatment of tumor cells with sFn significantly (P<0.01) increased monocyte adherence to 68.5 + 0.7% compared to the untreated control (32.9 +1.3%), whereas monocyte pre-treatment had no significant effect (P>0.05) on adherence. However, pre-incubation of both cells with sFn resulted in a significant (P<0.01) inhibition of adherence to 15.95 ± 1.0% (62% inhibition). sFn mediated inhibition of adherence was significantly reduced by pre-treatment of cells with a combination of P1 + P2 (to 22.3 ± 13.8% inhibition; P<0.01), and by pre-incubation of sFn with P3 + P4 (to 9.9 ± 3.6% inhibition; P<0.01). Single peptides blocked to an intermediate level, and controls performed appropriately. Furthermore, blocking peptides did not inhibit thrombin induced clotting of Fg. Pretreatment of both monocytes and A375 cells significantly inhibited specific cytotoxicity by 40% (P < 0.01 compared to untreated cytotoxicity − 28.6 ± 0.7%), and intermediate killing was observed when only one cell type was sFn treated. These results show that sFn incubation with both effector and target cells inhibits both cellular adherence and cytotoxicity by a mechanism involving monocyte aMb2 and tumor cell CD54. Adherence was restored by inclusion of sFn blocking peptides, which did not affect clotting. Clinically, these peptides may be effective therapeutically in reducing sFn mediated immunosuppression and may enhance the immune response to metastasizing cancer cells, without the risk of bleeding problems associated with other therapies.
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Greenfield, Katharine, Saloomeh Mokhtari, Melissa Haug, Christopher D. Porada, and Graca Almeida-Porada. "Identification and Phenotypic Characterization of a Subpopulation of Acute Myelogenous Leukemia (AML) Cells with Increased Plastic Adherence." Blood 120, no. 21 (November 16, 2012): 2556. http://dx.doi.org/10.1182/blood.v120.21.2556.2556.
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Abstract Abstract 2556 The high incidence of relapse in acute myelogenous leukemia (AML) patients has been attributed to the existence of a small population of leukemic stem cells (LSC) that current therapies are unable to eradicate. LSC, in similarity to normal hematopoietic stem cells (HSC), are able to engraft, self-renew, and interact with cells within the bone marrow (BM) niche. During leukemogenesis, changes within the BM microenvironment promote LSC survival and expansion, and shelter leukemic cells from chemotherapy. Therefore, displacing these cells from the BM niches prior to chemotherapy may decrease drug resistance and prevent relapse of the disease. The binding of α4β1 integrins (VLA-4 or CD49d/CD29) to the stromal extracellular matrix and cell surface ligands is a key component in homing and trafficking, specifically in the migration of HSC beneath marrow stromal cells, and VLA-4 has been shown to be crucial for the persistence of minimal residual disease in AML. KG1a is a differentiation-resistant AML cell line containing a very primitive population of CD34+CD38- cells. Upon culture, the majority of KG1a cells remain in suspension, while a small percentage adheres to the tissue culture plastic (Adh-KG1a). Here, we hypothesized that characterization of adhesion molecules that were either unique or significantly altered in this subset could lead to identification of putative therapeutic targets for dislodging AML cells from microenvironmental niches. KG1a and Adh-KG1a populations were evaluated by flow-cytometry for the presence of CD49d and CD29.The FACSort results were then analyzed using FlowJo7.6 software. No statistically significant (p>0.05) differences were found in the percentage of Adh-KG1a and KG1a that expressed CD49d (91.6±3% vs. 86.2±5%) or CD29 (95.0±2% vs. 91.8±1.8%). However, we found that there is a small and unique population of adherent CD29+ cells, with lower fluorescent intensity (MFI=326), that is not present in the non-adherent population (MFI=435), suggesting that this low level of surface expression is unique to the adherent fraction. Analysis of CD11a, CD44, CD18, CD106, CD105, CD34, CD107 and CD38 showed that none of these molecules were expressed at significantly different levels between KG1a and the Adh-KG1a fraction. Addition of anti-CD44 or anti-CD29 antibodies to the cells in culture did not result in decreased numbers of Adh-KG1a cells/flask, but resulted in induction of heterotypic aggregation of Adh-KG1a. Cell cycle analysis did not show significant differences between the 2 populations. However, analysis of CD54 expression demonstrated that 12.2% more of the Adh-KG1a were positive for CD54 than the non-adherent cells. Furthermore, characterization of gangliosides on KG1a and Adh-KG1a showed that the non-adherent fraction contained significantly more GM3 than the Adh-KG1a. Given prior reports showing that: 1) high levels of VLA-4 (CD49d/CD29) are associated with better prognosis in AML; 2) high levels of CD54 correlate with low relapse-free survival probability in AML; and 3) ganglioside composition has been shown to exert a pronounced effect on drug-resistance/sensitivity in AML, our findings of an adherent population of primitive hematopoietic stem/progenitor cells within KG1a that are CD29dim, express high levels of CD54, and contain lower levels of GM3, suggest that this unique subpopulation may play an important role in relapse in AML, and could represent a target for novel therapeutics that could better eradicate the elusive LSC and promise an improved disease-free survival rate in AML. Disclosures: No relevant conflicts of interest to declare.
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Blaess, J., J. Walther, J. E. Gottenberg, J. Sibilia, L. Arnaud, and R. Felten. "AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1464.1–1465. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1124.
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Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared
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McQueen, Teresa, Yoko Tabe, Marina Konopleva, and Michael Andreeff. "Inhibition of PI3K or Integrin-Linked Kinase (ILK) Target Primary AML Cells within the Bone Marrow Microenvironment in the In Vitro Co-Culture System." Blood 108, no. 11 (November 16, 2006): 1903. http://dx.doi.org/10.1182/blood.v108.11.1903.1903.
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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow microenvironment such as marrow stromal cells (MSC). It is proposed that specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death, and we indeed demonstrated that MSC protect primary AML cells from Ara-C induced apoptosis in vitro (Konopleva, Leukemia 2002). Integrin-linked kinase (ILK) has been shown to directly interact with β integrins and phosphorylate AKT in a PI3-kinase(PI3K)-dependent manner to promote cell survival and proliferation. In this study, we tested the hypothesis that selective inhibition of ILK signaling will provide a novel approach for targeting both leukemic cells and cells in their surrounding microenvironment. Direct co-culture of human MSC and leukemic NB4 cells results in activation of PI3K/ILK/AKT signaling as evidenced by enhanced ILK kinase activity, elevated phospho(p)-Akt, p-GSK3β and nuclear translocation of β-catenin. Both, PI3K inhibitor LY294002 (10μM) and specific ILK inhibitor QLT0267 (10μM) inhibited stroma-induced activation of AKT and suppressed GSK phosphorylation. This resulted in massive induction of apoptosis which was not abrogated by stromal co-culture (AnnexinV positivity %, MSC(−) vs MSC(+); 51.4+2.5 vs 55.8+3.5 p=0.26, LY 47.0+8.1 vs 47.9+6.1 p=0.85, 48hrs). In contrast, MSC co-culture effectively blocked apoptosis induced by MEK inhibitor PD98059 despite activation of pERK (62.5+3.2% vs 45.6+2.3%, p=0.02). We next examined anti-leukemia effects of PI3K and ILK inhibitors in the co-culture system of primary AML and human MSC. AML blasts from 7 primary AML samples with high (>54%) blast count were co-cultured with MSC for 24 hours, after which they were exposed to 10μM LY294002 or QLT0267 for 4–8 days. After this period, induction of apoptosis was analyzed in non-adherent AML cells by Annexin V flow cytometry after gating on the CD90-negative (non-MSC) population. To control for differences in spontaneous apoptosis, we calculated % specific apoptosis as (test - control) x 100 / (100 - control). MSCs protected leukemic blasts from spontaneous apoptosis in all 7 samples studied (mean annexin V positivity, 49.5±7.2% vs 25.3±4.8%, p<0.001). In contrast, inhibition of PI3K/ILK signaling induced unopposed apoptosis even in MSC co-cultures (% specific apoptosis, LY294002, 30.3±4.8%; LY+MSC, 28.3±7.7%; QLT0267, 26.9±9.8%; QLT+MSC, 33.1±9.3%, p>0.3 comparing cell death in the presence or absence of MSC). This resulted in corresponding loss of viability (% of control, LY294002, 66.0±11.0%; LY+MSC, 57.6±11.2%; QLT0267, 66.4±7.28%; QLT+MSC, 50.4±11.3%, p>0.1 comparing viability in the presence or absence of MSC). These observations indicate that disruption of leukemia/stroma interactions by specific PI3K/ILK inhibitors represents a novel therapeutic approach to eradicate leukemia in the bone marrow microenvironment. Further studies are aimed at the elucidation of the role of the BM microenvironment and its ability to activate specific signaling pathways in the pathogenesis of leukemias. Focus on this stroma-leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies.
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Blunt, Matthew D., Jack Parnell, Marta Larrayoz, Lindsay Smith, Rachel Dobson, Jonathan C. Strefford, Freda K. Stevenson, et al. "The Syk\Jak Inhibitor Cerdulatinib (PRT062070) Shows Promising Preclinical Activity in Chronic Lymphocytic Leukemia By Antagonising B Cell Receptor and Microenvironmental Signalling." Blood 126, no. 23 (December 3, 2015): 1716. http://dx.doi.org/10.1182/blood.v126.23.1716.1716.
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Abstract The emergence of B cell receptor (BCR) kinase inhibitors has proved effective for the treatment of a number of B-cell malignancies including chronic lymphocytic leukemia (CLL). BTK and PI3K inhibitors have clear efficacy in suppressing tumor progression but have not been curative. A number of patients have developed resistance to these drugs following mutation of the BTK or PLCγ2 gene. Whilst, other patients are unable to tolerate these drugs due to adverse events or progress whilst on therapy for unknown reasons. Thus the development of novel drugs which are still effective once other BCR-kinases inhibitors become ineffective is of paramount importance. Spleen tyrosine kinase (Syk) is essential for B cell receptor signalling pathways as well as a variety of other surface receptors such as MHCII, FC receptors and integrins, all of which have been shown to play a role in CLL biology. Importantly, Syk inhibition has been shown to overcome resistance to ibrutinib, identifying Syk inhibition as a promising strategy to treat these patients. Furthermore, we have previously shown that IL-4 is found in CLL lymph nodes and can promote resistance to ibrutinib and idelalisib by restoring αIgM induced calcium flux and phosphorylated ERK (ASH 2014, abstract #3299). IL-4 signalling is mediated through the JAK/STAT signalling pathways via JAK1 and JAK3, therefore simultaneous inhibition of both Syk and JAK1/3 may be therapeutically beneficial over BCR kinase inhibitors alone. Cerdulatinib (PRT062070) is a dual JAK/Syk inhibitor in a phase I open label dose escalation study and is currently demonstrating clinical activity in patients with relapsed/refractory B cell malignancies including CLL. Our group has now demonstrated in vitro that cerdulatinib, at plasma concentrations achievable in patients, can induce apoptosis of CLL cells in a concentration and time dependent manner with a mean IC50 of 3µM and 1µM at 48 and 72h respectively, defined by annexin V/PI and cleavage of caspase 3 and poly ADP ribose polymerase (PARP). Apoptosis was caspase dependent since treatment with the pan caspase inhibitor ZVAD.fmk significantly inhibited cerdulatinib induced cell death at 24h. Cerdulatinib induced apoptosis coincided with an increase in pro-apoptotic proteins Noxa and Puma and a decrease in the anti-apoptotic protein Mcl-1. Cerdulatinib significantly inhibited IL-4 induced phosphorylation of STAT6 at 300nM (p=.005), BCR induced phosphorylation of AKTS473 with soluble (p=.008) and bead immobilised (BI) (p=.025) αIgM at 30nM and phosphorylation of AKTT308 with BI αIgM at 300nM (p=.008). Furthermore, in patients with CLL, it is thought that CD40L and IL-4 are key factors, which promote survival of CLL cells in proliferation centres within the lymph node microenvironment. Therefore, we cultured CLL cells with a vehicle control or IL-4\CD40L, prior to treatment with cerdulatinib. Cerdulatinib alone induced similar levels of apoptosis irrespective of IL-4/CD40L treatment, suggesting cerdulatinib may be able to overcome microenvironmental signals and target cells within the lymph node. Next we explored the possibility of augmenting cerdulatinib induced apoptosis by simultaneous inhibition with the Bcl-2\Bcl-XL inhibitor ABT-199. In vitro in the presence of IL-4/CD40L, ABT-199 synergised with cerdulatinib to induce significantly greater cell death than with either agent alone. Therefore these data provide in vitro evidence for the use of cerdulatinib in clinical trials for the treatment of CLL as either a single agent or in combination with other therapies such as ABT-199. Disclosures Strefford: Roche: Research Funding. Davies:Seattle Genetics: Research Funding; Takeda: Honoraria. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Steele:Portola Pharmaceuticals: Other: Travel bursary to ASH 2015; Janssen: Other: Travel bursary to EHA 2015.
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Roth, Patrick. "The role of integrins in glioma biology and anti-glioma therapies." SpringerPlus 4, S1 (June 12, 2015). http://dx.doi.org/10.1186/2193-1801-4-s1-l12.
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Al-Bawardy, Badr, Raina Shivashankar, and Deborah D. Proctor. "Novel and Emerging Therapies for Inflammatory Bowel Disease." Frontiers in Pharmacology 12 (April 14, 2021). http://dx.doi.org/10.3389/fphar.2021.651415.
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Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease are chronic, relapsing and remitting disorders of intestinal inflammation with potential systemic manifestations. Despite the availability of current biologics, such as anti-tumor necrosis factor (anti-TNF), anti-integrins, anti-interleukins and small molecules such as tofacitinib, the rates of primary and secondary treatment failure remain high in IBD. This highlights the importance of continued development of new therapeutic targets and modifications of existing ones to improve the treatment response rates and to also improve the safety profile and tolerability of these medications. In this review we will discuss novel treatment target agents including selective janus kinase (JAK) inhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.
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Leal, Raquel F., and Azucena Salas. "Adhesion Molecules as a Therapeutic Target in IBD." EMJ Gastroenterology, December 16, 2013, 62–73. http://dx.doi.org/10.33590/emjgastroenterol/10314457.
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Recruitment of circulating leukocytes to areas of inflammation is a key process in the pathophysiology of inflammatory bowel diseases, including ulcerative colitis (UC). This is a finely regulated multistep process in which specialised adhesion and signalling molecules mediate a series of sequential steps. Following activation, integrins expressed on the surface of leukocytes become the key mediators of firm adhesion and emigration through interaction with immunoglobulin superfamily molecules expressed on the vascular endothelium. The anti α4 antibody natalizumab has shown efficacy in inducing and maintaining response and remission in patients with moderate and severe Crohn’s disease. However, a major safety setback involving the onset of progressive multifocal leukoencephalopathy (PML) in 1/1000 treated cases led to limitations on its clinical use and application in UC. The more selective anti α4β7 antibody vedolizumab has proven efficacious for inducing clinical and endoscopic remission in UC. Selective expression of the α4β7 receptor MAdCAM-1, which occurs predominantly in the intestine, may avoid the risk of those central nervous system infectious complications associated with the nonselective blockade of all α4 integrins. Moreover, treatment with anti-MAdCAM-1 or anti-α7 antibody (etrolizumab) showed promising results for inducing remission in UC. In conclusion, the development of safe and effective drugs that target these molecular components of the inflammatory response may yield novel, improved therapies for inflammatory bowel disease (IBD) that address as yet unmet needs.
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Reddy, Emily C., Guangheng Zhu, Pingguo Chen, Adili Reheman, Xi Lei, June Li, Xiaohong Xu, John Freedman, and Heyu Ni. "Abstract 54: PSI Domain of ß3 Integrin Has Endogenous Thiol Isomerase Function and is a Novel Antithrombotic Therapeutic Target." Arteriosclerosis, Thrombosis, and Vascular Biology 34, suppl_1 (May 2014). http://dx.doi.org/10.1161/atvb.34.suppl_1.54.
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Integrin αIIbβ3 plays a critical role in platelet aggregation and adhesion, key events in hemostasis and thrombosis. Integrin activation involves complex signalling events that lead to conformational changes exposing ligand-binding sites; however, mechanisms underlying integrin activation remain poorly understood. The β subunit contains a PSI domain that is highly conserved across integrins and species, though its function is unknown. Integrin β subunits are cysteine-rich and endogenous thiol isomerase activity in integrin β3 has been reported. The PSI domain contains two CXXC sequences, the active site motif of protein disulfide isomerase (PDI). Based on this observation and the location of this domain at the knee region of the integrin, we hypothesized that integrin PSI domain has endogenous thiol isomerase function, which plays a key regulatory role in integrin conformation and function. Targeting the PSI domain may have therapeutic potential. Using reduced, denatured RNase, a recombinant murine integrin β3 PSI domain demonstrated endogenous PDI-like activity. This PDI-like activity was dose-dependently inhibited by the PDI inhibitor, bacitracin. Mutation of either CXXC motif within the integrin β3 PSI domain reduced PDI-like activity, while removal of both CXXC motifs completely abolished this activity. We developed unique mouse anti-mouse/anti-human β3 PSI domain monoclonal antibodies (anti-PSI mAbs) that inhibited the PDI-like activity of both the murine recombinant integrin β3 PSI domain and purified human platelet β3 integrin, in a dose-dependent manner. Interestingly, the anti-PSI mAbs blocked fibrinogen to human platelet β3 integrin in a cell free system. Furthermore, anti-PSI mAbs inhibited murine and human platelet aggregation in vitro and ex vivo and inhibited murine thrombus formation in vivo without significantly changing bleeding time or platelet count. In conclusion, we identified that the PSI domain has PDI function, is a fundamental regulator of platelet β3 integrin activation, and is a potential novel target for anti-thrombotic therapies. Since PSI domain is conserved in all integrin β subunits, our discovery may have broad implications for the role of integrins in cell biology of many human diseases.
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Lightner, Amy L., Zeji Du, Timothy E. Peterson, Ao Shi, Mark Li, Sinibaldo Rafael Romero Arocha, and Atta Behfar. "Commonly Used Immunosuppressives Affect Mesenchymal Stem Cell Viability and Function: Should We Rethinking Clinical Trial Inclusion and Exclusion Criteria?" Crohn's & Colitis 360 1, no. 3 (August 19, 2019). http://dx.doi.org/10.1093/crocol/otz025.
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Abstract Background Clinical trials utilizing mesenchymal stem cells (MCSs) for the treatment of perianal Crohn disease are expanding. Most enrolled Crohn patients are being actively treated with corticosteroids, immunomodulators, and biologic therapy for their luminal and perianal disease at the time of enrollment and treatment. Aim We sought to broaden the understanding of the effect of corticosteroids, immunomodulators, and biologic therapy on the viability and function of MCSs. This information is important for tailoring inclusion and exclusion criteria of clinical trials. Methods Human adipose–derived mesenchymal stem cells (hAMCSs) were harvested and isolated from healthy patient donors. At Passage 3, hAMCSs were treated with 7 commonly used immunosuppressive therapies used to treat Crohn disease at increasing concentrations: dexamethasone, methotrexate, azathioprine, 6-mercaptopurine, infliximab, vedolizumab, and ustekinumab. Cell proliferation, migration, and cytokine secretion were analyzed at Day 4. Results Dexamethasone and azathioprine and 6-mercaptopurien affected cell proliferation and migration. Dexamethasone even resulted in cell death at high physiologic concentrations. The same drugs also had the most profound impacts on IL-6, IL-8, and monocyte chemoattractant protein-1 secretion profiles. Biologic therapies, including anti-tumor necrosis factor, anti-interleukin, and anti-integrins, had the smallest impact on hAMSC proliferation, migration, and cytokine secretion profile. Conclusions In clinical trials with MCSs, a washout period may be recommended for corticosteroids and immunomodulators to minimize any effect of systemic immunosuppression on MSC function and efficacy.
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Caron, Bénédicte, William J. Sandborn, Remo Panaccione, Stefan Schreiber, Ailsa Hart, Virginia Solitano, Silvio Danese, and Laurent Peyrin-Biroulet. "Efficacy of Pharmacological Agents for Ulcerative Proctitis: A Systematic Literature Review." Journal of Crohn's and Colitis, November 30, 2021. http://dx.doi.org/10.1093/ecco-jcc/jjab218.
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Abstract Background Ulcerative proctitis is a common and often highly symptomatic form of inflammatory bowel disease. We performed a systematic review to assess the efficacy of different therapies in the management of patients with ulcerative proctitis. Methods We identified randomized controlled trials in adults with ulcerative proctitis treated with oral or topical therapies for induction of response or remission, or prevention of relapse. Results A total of 32 randomized controlled trials were included [27 induction/2839 participants, five maintenance/334 participants]. Follow-up varied from 3 to 8 weeks for induction, and from 6 to 24 months for maintenance of remission. 5-Aminosalicylic acid [5-ASA] suppository was the most frequently evaluated treatment [14/32, 43.7%], followed by steroid enema [7/32, 21.9%]. Topical 5-ASA demonstrated effectiveness for induction of clinical response or remission and prevention of relapse in several studies. Combined topical steroids and 5-ASA was more effective than topical 5-ASA or topical steroids alone to induce response [100% of patients for combination vs 70% for beclomethasone alone and 76% for 5-ASA alone]. One observational study suggested azathioprine may be effective in patients with ulcerative proctitis. Only two cohort studies evaluated the efficacy of tumour necrosis factor inhibitors in ulcerative proctitis. Small molecules, anti-integrins and anti-interleukin therapies have not been evaluated in isolated ulcerative proctitis. Conclusion The role of topical 5-ASA as a treatment for ulcerative proctitis has been confirmed in this systematic literature review, for induction and maintenance of remission. Future trials are needed to investigate the efficacy of more recent and upcoming drug classes in patients with ulcerative proctitis.
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Kruk, Linus, Attila Braun, Erika Cosset, Thomas Gudermann, and Elmina Mammadova-Bach. "Galectin functions in cancer-associated inflammation and thrombosis." Frontiers in Cardiovascular Medicine 10 (February 17, 2023). http://dx.doi.org/10.3389/fcvm.2023.1052959.
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Galectins are carbohydrate-binding proteins that regulate many cellular functions including proliferation, adhesion, migration, and phagocytosis. Increasing experimental and clinical evidence indicates that galectins influence many steps of cancer development by inducing the recruitment of immune cells to the inflammatory sites and modulating the effector function of neutrophils, monocytes, and lymphocytes. Recent studies described that different isoforms of galectins can induce platelet adhesion, aggregation, and granule release through the interaction with platelet-specific glycoproteins and integrins. Patients with cancer and/or deep-venous thrombosis have increased levels of galectins in the vasculature, suggesting that these proteins could be important contributors to cancer-associated inflammation and thrombosis. In this review, we summarize the pathological role of galectins in inflammatory and thrombotic events, influencing tumor progression and metastasis. We also discuss the potential of anti-cancer therapies targeting galectins in the pathological context of cancer-associated inflammation and thrombosis.