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941.
Michiel Kroesen Paul Gielen Ingrid C. Brok Inna Armandari Peter M. Hoogerbrugge Gosse J. Adema 《Oncotarget》2014,5(16):6558-6572
Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer. 相似文献
942.
943.
944.
Anna Duarri PhD Justyna Jezierska MSc Michiel Fokkens BSc Michel Meijer BSc Helenius J. Schelhaas MD PhD Wilfred F. A. den Dunnen MD PhD Freerk van Dijk BSc Corien Verschuuren‐Bemelmans MD Gerard Hageman MD Pieter van de Vlies BSc Benno Küsters MD PhD Bart P. van de Warrenburg MD PhD Berry Kremer MD PhD Cisca Wijmenga PhD Richard J. Sinke PhD Morris A. Swertz PhD Harm H. Kampinga PhD Erik Boddeke PhD Dineke S. Verbeek PhD 《Annals of neurology》2012,72(6):870-880
945.
PC Rummel KN Arfelt L Baumann TJ Jenkins S Thiele HR Lüttichau A Johnsen J Pease S Ghosh R Kolbeck MM Rosenkilde 《British journal of pharmacology》2012,167(6):1206-1217
BACKGROUND AND PURPOSE
Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes.EXPERIMENTAL APPROACH
The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gαi signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148.KEY RESULTS
All compounds were highly potent inverse agonists with EC50 values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC50 values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [125I]-CCL1 (Ki 3.4–842 nM), whereas the affinities measured against [125I]-MC148 were less widely spread (Ki 0.37–27 nM), and matched the inverse agonist potencies.CONCLUSION AND IMPLICATIONS
Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties. 相似文献946.
947.
HM Den Ruijter SA Peters TJ Anderson AR Britton JM Dekker MJ Eijkemans G Engström GW Evans J de Graaf DE Grobbee B Hedblad A Hofman S Holewijn A Ikeda M Kavousi K Kitagawa A Kitamura H Koffijberg EM Lonn MW Lorenz EB Mathiesen G Nijpels S Okazaki DH O'Leary JF Polak JF Price C Robertson CM Rembold M Rosvall T Rundek JT Salonen M Sitzer CD Stehouwer JC Witteman KG Moons ML Bots 《JAMA : the journal of the American Medical Association》2012,308(8):796-803
948.
949.
van der Vlist M de Witte L de Vries RD Litjens M de Jong MA Fluitsma D de Swart RL Geijtenbeek TB 《European journal of immunology》2011,41(9):2619-2631
Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4(+) T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8(+) T cells. Notably, neither immature nor mature LCs were able to cross-present exogenous UV-inactivated MV or MV-infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to cross-present MV antigens, suggest that human LCs may not be directly involved in priming MV-specific CD8(+) T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8(+) T-cell priming via the endogenous antigen presentation pathway. 相似文献
950.