Articles de revues : « Polyfunctional ligand »

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Sarma, P., P. Mahanta, D. Basumatary et C. Medhi. « Manganese(IV) Complexes Derived from Polyfunctional Dihydrazone : Structural, Electrochemical and Antimicrobial Studies ». Asian Journal of Chemistry 33, n^o 5 (2021) : 1144–52. http://dx.doi.org/10.14233/ajchem.2021.23162.

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Manganese(IV) complexes viz. [MnIV(nagh)(A)2]·2H2O and [MnIV(nagh)(NN)] have been synthesized from ligand bis(2-hydroxy-1-naphthaldehyde)glutaryldihydrazone (naghH4) and auxiliary ligands, A = H2O (1)/pyridine (2)/2-picoline (3)/3-picoline (4)/ 4-picoline (5) or NN = 2,2′-bipyridine (6)/1,10-phenanthroline (7). The elemental analysis, mass spectral and thermal studies supported the composition of all the manganese(IV) complexes. Structural aspects were determined from magnetic susceptibility, molar conductivity and spectral studies i.e. electronic, electron spin resonance and infrared. Their non-electrolytic nature were determined from molar conductances. Results from studies of magnetic moment, electronic and ESR suggested Mn(IV) ion in six-coordinate octahedral stereochemistry. The ligand coordinated to the metal in enolic form as a tetradentate in an anti-cis configuration as was correlated from IR data. Redox activities and antimicrobial potential against few Gram-positive and Gram-negative bacteria have been investigated for the dihydrazone and some manganese(IV) complexes.

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Pellei, Maura, Carlo Santini, Marilena Mancini, Simone Alidori, Mercedes Camalli et Riccardo Spagna. « New triorganotin(IV) complexes of a polyfunctional S,N,O-ligand ». Polyhedron 24, n^o 9 (juin 2005) : 995–1001. http://dx.doi.org/10.1016/j.poly.2005.04.001.

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Cantwell, Mark J., Andreas N. Saltos, Hong Zheng, Dana Foresman et Amer A. Beg. « Abstract 6655 : Oncolytic adenovirus dually expressing interferon beta and membrane-stable CD40 ligand increases polyfunctional CD8+T cells associated with antitumor activity ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 6655. http://dx.doi.org/10.1158/1538-7445.am2024-6655.

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Abstract MEM-288 is a dual-transgene armed oncolytic adenovirus in phase 1 clinical development as a standalone agent and in combination with immune checkpoint inhibitors (ICI). It encodes two potent immune agonists: IFNβ and a recombinant membrane-stable chimeric form of CD40L (MEM40). We previously demonstrated this agonist combination is better than either agonist individually to activate conventional dendritic cells type 1 (cDC1) crucial for CD8+ T cell cross-priming, and to increase tumor-antigen reactive CD8+ T cells. Furthermore, first-in-human Phase 1 clinical trial (NCT05076760) results of MEM-288 for advanced non-small cell lung cancer (NSCLC) and other solid tumors showed MEM-288 tumor shrinkage was associated with systemic antitumor T cell immunity as demonstrated by cytokine, T cell clonotype, and tumor neoantigen analysis. Here, we investigated the precise nature of the localized and systemic T cell response induced by MEM40 + IFNβ in preclinical tumor models. Single-cell RNA sequencing of tumor infiltrating T lymphocytes (TILs) revealed that MEM40 + IFNβ elicited a strong increase in T cells expressing Granzyme B and PRF1, key effector cytokines and cytotoxicity mediators. We tracked the CD8+ T cell response in CD45.1 C57BL/6 mice implanted with syngeneic B16 tumor expressing the model antigen OVA. Interestingly, intratumoral treatment with adenovirus encoding MEM40 + IFNβ did not cause an appreciable increase in absolute numbers of antigen-reactive CD8+ T cells, despite tumor growth inhibition. However, MEM40 + IFNβ compared to control unarmed adenovirus induced a significant (p < 0.005) 5-fold increase in polyfunctional IFNγ+TNFα+PRF1+ and IFNγ+TNFα+Granzyme B+ CD8+ T cells. Polyfunctional CD8+ T cells have the capacity to simultaneously produce effector cytokines and cytotoxicity mediators and are known to be strongly associated with antitumor T cell activity. The robust polyfunctional CD8+ T cell response in these studies is consistent with T cell-driven antitumor activity found in both our preclinical tumor experiments and our clinical studies in advanced NSCLC patients responding to MEM-288. Overall, our findings suggest MEM40 + IFNβ generates a strong polyfunctional CD8+ T cell response in the TME that warrants continued evaluation to understand the pleiotropic mechanisms of this cancer immunotherapy. Citation Format: Mark J. Cantwell, Andreas N. Saltos, Hong Zheng, Dana Foresman, Amer A. Beg. Oncolytic adenovirus dually expressing interferon beta and membrane-stable CD40 ligand increases polyfunctional CD8+T cells associated with antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6655.

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Mahanta, P., P. Sarma, D. Basumatary et C. Medhi. « Mononuclear Manganese(IV) Complexes Derived from Polyfunctional Fumaryldihydrazone ». Asian Journal of Chemistry 34, n^o 4 (2022) : 959–66. http://dx.doi.org/10.14233/ajchem.2022.23625.

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A series of mononuclear manganese(IV) complexes of disalicylaldehyde fumaroyldihydrazone (slfhH4) were synthesized by reacting manganese acetate tetrahydrate with dihydrazone in absence and presence of various pyridine bases in methanol medium. Pyridine (py) and its derivatives like 2-picoline (2-pic), 3-picoline (3-pic), 4-picoline (4-pic), 2,2′-bipyridine (bpy) and 1,10-phenanthroline (phen) were added to the reaction mixture of metal salt and dihydrazone to explore the binding possibilities of these molecules to manganese center. The elemental analysis, mass spectral and thermal studies were used to derive their composition. Study of magnetic moment, molar conductances, electronic, EPR and infrared spectroscopy have led to interpretation of their tentative structures. Magnetic moment and EPR studies correspond to their Mn(IV) oxidation state. The dihydrazone functions as tetradentate ligand chelating the manganese(IV) ion present in octahedral geometry with anti-cis configuration in enol form. Electrochemical and antimicrobial studies were also performed.

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Kwissa, Marcin, Rama R. Amara, Harriet L. Robinson, Bernard Moss, Sefik Alkan, Abdul Jabbar, Francois Villinger et Bali Pulendran. « Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus ». Journal of Experimental Medicine 204, n^o 11 (22 octobre 2007) : 2733–46. http://dx.doi.org/10.1084/jem.20071211.

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DNA vaccines offer promising strategies for immunization against infections. However, their clinical use requires improvements in immunogenicity. We explored the efficacy of Toll-like receptor (TLR) ligands (TLR-Ls) on augmenting the immunogenicity of a DNA prime–modified vaccinia virus Ankara (MVA) boost vaccine against SIV. Rhesus macaques were injected with Fms-like tyrosine kinase 3 (Flt3)–ligand (FL) to expand dendritic cells (DCs) and were primed with a DNA vaccine encoding immunodeficiency virus antigens mixed with ligands for TLR9 or TLR7/8. Subsequently, the animals were boosted with DNA and twice with recombinant MVA expressing the same antigens. TLR9-L (CpG DNA) mediated activation of DCs in vivo and enhanced the magnitude of antigen-specific CD8+ interferon (IFN) γ+ T cells and polyfunctional CD8+ T cells producing IFN-γ, tumor necrosis factor α, and interleukin 2. Although this trial was designed primarily as an immunogenicity study, we challenged the animals with pathogenic SIVmac251 and observed a reduction in peak viremia and cumulative viral loads in the TLR9-L plus FL-adjuvanted group relative to the unvaccinated group; however, the study design precluded comparisons between the adjuvanted groups and the group vaccinated with DNA/MVA alone. Viral loads were inversely correlated with the magnitude and quality of the immune response. Thus, the immunogenicity of DNA vaccines can be augmented with TLR9-L plus FL.

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Sarma, P., P. Mahanta, D. Basumatary et C. Medhi. « Synthesis, Characterization, Electrochemical and Anitmicrobial Studies of Manganese(IV) Complexes Derived from Polyfunctional Glutaryldihydrazone ». Asian Journal of Chemistry 34, n^o 6 (2022) : 1383–90. http://dx.doi.org/10.14233/ajchem.2022.23626.

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The synthesis and structure elucidation of a new series of manganese(IV) complexes from disalicylaldehyde glutaryldihydrazone (slghH4) of the composition [MnIV(slgh)](A)2]·H2O and [MnIV(slgh)(NN)] (where A= H2O, (1); pyridine, (2); 2-picoline, (3); 3-picoline, (4); 4-picoline, (5) and NN = 2,2′-bipyridine, (6); 1,10-phenanthroline, (7)) were carried out. The composition and structures of all the complexes of Mn(IV) have been evaluated by elemental analysis, thermal studies, molar conductance, mass spectral data, magnetic moment, electronic, electron paramagnetic resonance and infrared spectral studies. Molar conductances of these Mn(IV) complexes suggest their non-electrolytic nature. Magnetic moment and EPR studies suggested that the Mn(IV) ions are six-coordinated octahedral geometry around the metal ions. The IR spectral studies confirmed that the ligand coordinates to the Mn(IV) ion in enolic form and behave as a tetradentate ligand in anti-cis configuration chelating Mn(IV) ion with NNOO coordination sites. The electrochemical and antimicrobial studies of the Mn(IV) complexes have also been carried out.

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БЕЛОБЕЛЕЦКАЯ, М. В., Н. И. СТЕБЛЕВСКАЯ et М. А. МЕДКОВ. « Complex formation of REEs with polydentate organic ligands ». Вестник ДВО РАН, n^o 6(214) (24 décembre 2020) : 7–16. http://dx.doi.org/10.37102/08697698.2020.214.6.001.

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Исследовано комплексообразование европия и тербия с полифункциональными органическими соединениями – β-дикетонами, органическими кислотами. Состав комплексов изучен экстракционным методом, ИК и люминесцентной спектроскопией. Установлено, что при экстракции РЗЭ смешанными экстрагентами идет эффективное комплексообразование РЗЭ в органической фазе. Показана возможность синтеза из насыщенных экстрактов разнолигандных координационных соединений РЗЭ, выделены индивидуальные кристаллические комплексы. The complex formation of europium and terbium with polyfunctional organic compounds: β-diketones, organic acids were investigated. The composition of the complexes was studied by extractive method, infrared and luminescent spectroscopy. It was established that during the extraction of REE by mixed extractants there is an effective complex formation of REE in the organic phase. The possibility of synthesis of different ligand coordination compounds of REE from saturated extracts was shown and individual crystalline complexes were isolated.

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Wade, Casey R., et François P. Gabbaï. « Cyanide and Azide Anion Complexation by a Bidentate Stibonium-Borane Lewis Acid ». Zeitschrift für Naturforschung B 69, n^o 11-12 (1 décembre 2014) : 1199–205. http://dx.doi.org/10.5560/znb.2014-4168.

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Abstract Our ongoing interest in the chemistry of polyfunctional Lewis acids has led us to investigate the reaction of the stibonium-borane [o-(Ph2MeSb)(Mes2B)C6H4]+ (1+) with cyanide and azide, two toxic anions. Both anions react with 1+ to afford the corresponding neutral complexes 1-CN and 1-N3. Structural and computational studies show that the coordinated anion interacts with both the boron and antimony atoms of the bidentate Lewis acid. While the azide complex features a typical κ2N1 : N1 bridging azide ligand, the cyanide complex possesses a cyanoborate moiety whose cyanide interacts side-on with the stibonium center. The Lewis acid-anion interactions observed in these complexes have also been studied computationally using the Natural Bond Orbital method

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Lamy, Isabelle, Michel Seywert, Monique Cromer et Jean-Pierre Scharff. « simple and mixed ligand complexes of copper(II) with polyfunctional phenolic compounds as models of natural substances ». Analytica Chimica Acta 176 (1985) : 201–12. http://dx.doi.org/10.1016/s0003-2670(00)81647-5.

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Sarraj, Bara, Junsheng Ye, Zheng Zhang, Stephen Miller, Geoffrey Kansas et M. Javeed Ansari. « Impaired selectin-dependent leukocyte trafficking induces T cell exhaustion and prevents chronic allograft vasculopathy and rejection (P2140) ». Journal of Immunology 190, n^o 1_Supplement (1 mai 2013) : 69.7. http://dx.doi.org/10.4049/jimmunol.190.supp.69.7.

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Abstract Selectin-selectin ligand interactions mediate the initial steps in leukocyte emigration, an integral part of immune response. Fucosyltransferase-VII (FucT-VII) enzyme, encoded by Fut7 gene, is essential for post-translational modification and function of selectin ligands. In an established model of cardiac allograft vasculopathy and chronic rejection, Fut7-/- recipients, with impaired selectin-dependent leukocyte trafficking, enjoyed long-term graft survival with minimal vasculopathy. This was associated with T cell exhaustion in the periphery characterized by impaired effector cytokine production, proliferative defect, increased expression of inhibitory receptors PD-1 and Tim-3 and low levels of IL-7Ra on CD4 T cells and reduced trafficking of polyfunctional CD4 memory T cells to the allograft. Blocking PD-1, triggered rejection only in Fut7-/- recipients, whereas depleting regulatory T cells triggered rejection in WT recipients. Adoptive transfer experiments confirmed that the exhausted phenotype is seen primarily in CD4 T cells with impaired trafficking ability. In summary, these data suggest that impaired leukocyte trafficking is a novel mechanism of CD4 T cell exhaustion and our experimental system serves as an excellent model to study CD4 T cell exhaustion as a dominant mechanism of transplant tolerance. Further, targeting FucT-VII may serve as a promising strategy to prevent chronic allograft rejection and promote tolerance.

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Frazao, Alexandra, Louise Rethacker, Géraldine Jeudy, Marina Colombo, Eric Pasmant, Marie-Françoise Avril, Antoine Toubert et al. « BRAF inhibitor resistance of melanoma cells triggers increased susceptibility to natural killer cell-mediated lysis ». Journal for ImmunoTherapy of Cancer 8, n^o 2 (septembre 2020) : e000275. http://dx.doi.org/10.1136/jitc-2019-000275.

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BackgroundTargeted therapies and immunotherapies are first-line treatments for patients with advanced melanoma. Serine–threonine protein kinase B-RAF (BRAF) and mitogen-activated protein kinase (MEK) inhibition leads to a 70% response rate in patients with advanced melanoma with a BRAFV600E/K mutation. However, acquired resistance occurs in the majority of patients, leading to relapse. Immunotherapies that activate immune cytotoxic effectors induce long-lasting responses in 30% of patients. In that context, combination of targeted therapies with immunotherapy (IT) is a promising approach. We considered boosting natural killer (NK) cell tumor immunosurveillance, as melanoma cells express stress-induced molecules and activate NK cell lysis.MethodsHere we have generated vemurafenib (a BRAF inihibitor)-resistant (R) cells from BRAFV600E SK28 and M14-sensitive (S) melanoma cell lines and investigated how resistance interferes with immunogenicity to NK cells. We determined the levels of several soluble molecules including NK ligands in 61 melanoma patients at baseline and 6 months M post-treatment with targeted therapies or immunotherapies.ResultsVemurafenib resistance involved activation of p-AKT in SK28R and of p-MEK/p-ERK in M14R cells and was accompanied by modulation of NK ligands. Compared with S cells, SK28R displayed an increased expression of natural killer group 2 D (NKG2D) receptor ligands (major histocompatibility complex class (MHC) I chain-related protein A (MICA) and UL16-binding protein 2 (ULBP2)) whereas M14R exhibited decreased ULBP2 . SK28R and M14R cells induced higher NK degranulation and interferon gamma secretion and were more efficiently lysed by donor and patient NK cells. SK28R showed increased tumor necrosis factor-related apoptosis-inducing ligand receptor II (TRAIL-RII) expression and TRAIL-induced apoptosis, and TRAIL-induced apoptosis of M14R was decreased. Combined BRAF/MEK inhibitors abrogated the growth of SK28S, M14S, and M14R cells, while growth of SK28R was maintained. BRAF/MEK inhibition attenuated NK activity but R cell lines activated polyfunctional NK cells and were lysed with high efficiency. We investigated the relationship of soluble NK ligands and response to treatment in a series of melanoma patients. Soluble NKG2D ligands known to regulate the receptor function have been associated to cancer progression. Serum analysis of patients treated with target therapies or IT indicates that soluble forms of NK ligands (MICA, B7H6, programmed cell death ligand 1, and carcinoembryonic antigen cell adhesion molecule 1) may correlate with clinical response.ConclusionThese results support strategies combining targeted therapies and NK-based immunotherapies.

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Carreno, Roberto. « Autocrine function of CD8+ T cells by modulation of CCR5 expression (112.3) ». Journal of Immunology 186, n^o 1_Supplement (1 avril 2011) : 112.3. http://dx.doi.org/10.4049/jimmunol.186.supp.112.3.

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Abstract Although we have shown CCR5+ T cells are known to play a role in the pathogenesis of graft-versus-host disease (GVHD), the detailed biofunction of CCR5 remains uncertain. Recently we have shown that CCR5+CD8+ T cells exhibit an effector function due to the secretion of cytolytic cytokines TNF-α and INF-γ. In addition, CCR5+CD8+ T cells have been shown to proliferate upon DC stimulation and also secrete the proliferative cytokine IL-2. Thus CCR5+CD8+ T cells maintain a polyfunctional state including both effector and memory. Moreover, in effector CD8+ T cells (CD45RA+CD27- [M3]) there is an upregulation of MIP1-β, the ligand for CCR5. These works indicate that CCR5 plays a role in memory/effector phenotype and function. Here we use CCR5 to further define memory and effector CD8+ T cells, and correlate this to their function. Using FACs we characterized central (CD45RA-CD27+ [M1]) and effector (CD45RA-CD27- [M2]) memory CD8+ T cells have high CCR5 expression. We also observed a decline in CCR5 expression in M3 CD8+ T cells. As a result, we propose that CD8+ T cells utilize autocrine signaling by promoting lymphocyte migration and infiltration to sites of inflammation by modulating the expression of CCR5 and its ligands. Further understanding of this autocrine type signal may help understand the role of CCR5 in GVHD pathogenesis.

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KAROW, Julia, Keith R. HUDSON, Mark A. HALL, Ann B. VERNALLIS, Jacky A. TAYLOR, Achim GOSSLER et John K. HEATH. « Mediation of interleukin-11-dependent biological responses by a soluble form of the interleukin-11 receptor ». Biochemical Journal 318, n^o 2 (1 septembre 1996) : 489–95. http://dx.doi.org/10.1042/bj3180489.

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Interleukin-11 (IL-11) is a polyfunctional cytokine whose biological actions require a specific IL-11 receptor (IL-11R) and the transmembrane transducer gp130. Here we report the production of a soluble form of the murine IL-11R and demonstrate that it interacts with IL-11 ligand with high affinity. The affinity of IL-11 alone for gp130 is below the level of detection, but a complex of IL-11 and soluble IL-11R interacts with gp130 with high affinity. The addition of soluble IL-11R potentiates the effects of exogenous IL-11 in cells that are normally responsive to IL-11. A biological response to IL-11 can be reconstituted in BAF cells transfected with gp130 by addition of IL-11 and soluble IL-11R. These findings show that the cytoplasmic domain of the IL-11R is not required for the biological effects of IL-11 and that a complex of IL-11 and IL-11R mediates signalling by association with gp130.

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Song, Woogil, Kijong Yi, Sungsin Jo, Seyoung Jung, Eun Young Lee, Tae-Jong Kim et Jeong Seok Lee. « Characterization and Neutralization of Pathologic Memory CD4 +T Cells in Spondyloarthritis Synovial Fluid ». Journal of Immunology 210, n^o 1_Supplement (1 mai 2023) : 238.02. http://dx.doi.org/10.4049/jimmunol.210.supp.238.02.

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Abstract Spondyloarthritis (SpA), which has increased T helper 17 (Th17) cell activity, and neutralizing antibodies targeting IL-17 are effective in patients with SpA. However, not all Th17 cells are pathologic; most Th17 cells have physiological roles. Here, we characterize the immune landscape of blood and synovial cells in SpA through single cell to demonstrate the molecular characteristics of pathologic memory CD4 +T cells with Th17 characters. We identified pathologic Th17 (pTh17) cells as polyfunctional IL-17A and IFN-γ-producing memory CD4 +T cells, with clinically supporting evidence for their pathogenic roles at the inflammatory site of SpA. Transcriptome and flow cytometric analysis found that the co-expression of TNFRSF4 and TNFRSF18 is increased in pTh17 cells. Suppression of ligand-receptor interactions via TNFRSF4 and TNFRSF18 effectively decreased clinical arthritis and decreased pTh17 cells in the curdlan-injected SKG mouse model. Our results provide understanding pTh17 cells in SpA and suggest potential therapeutic targets.

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BRAUNSTEIN, P., R. HASSELBRING, A. DECIAN et J. FISCHER. « ChemInform Abstract : Polyfunctional Ligands : Carbon-Carbon Oxidative Coupling of (HC(PPh2)2) - and Crystal Structure of the New Tetraphosphine Ligand (Ph2P)2CH-CH( PPh2)2. » ChemInform 27, n^o 5 (12 août 2010) : no. http://dx.doi.org/10.1002/chin.199605201.

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Lu, Yao, Qiong Xue, Markus R. Eisele, Endah S. Sulistijo, Kara Brower, Lin Han, El-ad David Amir, Dana Pe’er, Kathryn Miller-Jensen et Rong Fan. « Highly multiplexed profiling of single-cell effector functions reveals deep functional heterogeneity in response to pathogenic ligands ». Proceedings of the National Academy of Sciences 112, n^o 7 (2 février 2015) : E607—E615. http://dx.doi.org/10.1073/pnas.1416756112.

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Despite recent advances in single-cell genomic, transcriptional, and mass-cytometric profiling, it remains a challenge to collect highly multiplexed measurements of secreted proteins from single cells for comprehensive analysis of functional states. Herein, we combine spatial and spectral encoding with polydimethylsiloxane (PDMS) microchambers for codetection of 42 immune effector proteins secreted from single cells, representing the highest multiplexing recorded to date for a single-cell secretion assay. Using this platform to profile differentiated macrophages stimulated with lipopolysaccharide (LPS), the ligand of Toll-like receptor 4 (TLR4), reveals previously unobserved deep functional heterogeneity and varying levels of pathogenic activation. Uniquely protein profiling on the same single cells before and after LPS stimulation identified a role for macrophage inhibitory factor (MIF) to potentiate the activation of LPS-induced cytokine production. Advanced clustering analysis identified functional subsets including quiescent, polyfunctional fully activated, partially activated populations with different cytokine profiles. This population architecture is conserved throughout the cell activation process and prevails as it is extended to other TLR ligands and to primary macrophages derived from a healthy donor. This work demonstrates that the phenotypically similar cell population still exhibits a large degree of intrinsic heterogeneity at the functional and cell behavior level. This technology enables full-spectrum dissection of immune functional states in response to pathogenic or environmental stimulation, and opens opportunities to quantify deep functional heterogeneity for more comprehensive and accurate immune monitoring.

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Milaeva, Elena R., et Vladimir Yu Tyurin. « Hybrid metal complexes with opposed biological modes of action – promising selective drug candidates ». Pure and Applied Chemistry 89, n^o 8 (26 juillet 2017) : 1065–88. http://dx.doi.org/10.1515/pac-2016-1130.

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AbstractThe oxidative stress is considered to be involved in the pathogenesis of many diseases. The antioxidative defense system in the living organism regulates the toxic impact of ROS and there is strong evidence that the antioxidants prevent some pathologies including cancer. The specific chemical properties of metal-based drugs impart innovative pharmacological profiles to this type of therapeutic agents, most likely in relation to novel biomolecular mechanisms. This review will focus on a novel approach to design polyfunctional metal-based physiollogically active compounds with opposed modes of action – prooxidant metal center and antioxidant 2,6-dialkylphenol group. The synthesis and anti/prooxidant activity and cytotoxicity studies of novel organometallic/coordination compounds (ferrocenes, complexes with di-(2-picolyl)amine ligand, porphyrins, pyridines, thiols, carboxylates) based on either biogenic metals (Fe, Mn, Co, Cu, Zn, Ni) or exogenic metals (Sn, Au, Rh) are presented and discussed. The results allow us to conclude that combining in one molecule a redox active metal center and cytoprotective functional organic moiety with antioxidative function is a promising way to rational metallodrug design in modern medicinal chemistry.

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Ma, Chunlin, Qingfeng Wang et Rufen Zhang. « Solvothermal Synthesis and Crystal Structure of a Novel 3D Triorganotin Polymer Containing Polyfunctional Ligand 5-mercapto-1(H)-tetrazoleacetic acid ». Journal of Inorganic and Organometallic Polymers and Materials 19, n^o 2 (17 décembre 2008) : 152–56. http://dx.doi.org/10.1007/s10904-008-9238-4.

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Rupa, Sharmin Akther, Md Rassel Moni, Md Abdul Majed Patwary, Md Mayez Mahmud, Md Aminul Haque, Jamal Uddin et S. M. Tareque Abedin. « Synthesis of Novel Tritopic Hydrazone Ligands : Spectroscopy, Biological Activity, DFT, and Molecular Docking Studies ». Molecules 27, n^o 5 (2 mars 2022) : 1656. http://dx.doi.org/10.3390/molecules27051656.

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Polytopic organic ligands with hydrazone moiety are at the forefront of new drug research among many others due to their unique and versatile functionality and ease of strategic ligand design. Quantum chemical calculations of these polyfunctional ligands can be carried out in silico to determine the thermodynamic parameters. In this study two new tritopic dihydrazide ligands, N’2, N’6-bis[(1E)-1-(thiophen-2-yl) ethylidene] pyridine-2,6-dicarbohydrazide (L1) and N’2, N’6-bis[(1E)-1-(1H-pyrrol-2-yl) ethylidene] pyridine-2,6-dicarbohydrazide (L2) were successfully prepared by the condensation reaction of pyridine-2,6-dicarboxylic hydrazide with 2-acetylthiophene and 2-acetylpyrrole. The FT-IR, 1H, and 13C NMR, as well as mass spectra of both L1 and L2, were recorded and analyzed. Quantum chemical calculations were performed at the DFT/B3LYP/cc-pvdz/6-311G+(d,p) level of theory to study the molecular geometry, vibrational frequencies, and thermodynamic properties including changes of ∆H, ∆S, and ∆G for both the ligands. The optimized vibrational frequency and (1H and 13C) NMR obtained by B3LYP/cc-pvdz/6-311G+(d,p) showed good agreement with experimental FT-IR and NMR data. Frontier molecular orbital (FMO) calculations were also conducted to find the HOMO, LUMO, and HOMO–LUMO gaps of the two synthesized compounds. To investigate the biological activities of the ligands, L1 and L2 were tested using in vitro bioassays against some Gram-negative and Gram-positive bacteria and fungus strains. In addition, molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium. The outcomes revealed that both L1 and L2 can suppress microbial growth of bacteria and fungi with variable potency. The antibacterial activity results demonstrated the compound L2 to be potentially effective against Bacillus megaterium with inhibition zones of 12 mm while the molecular docking study showed the binding energies for L1 and L2 to be −7.7 and −8.8 kcal mol−1, respectively, with tyrosinase from Bacillus megaterium.

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Smolyaninov, Ivan V., Andrey I. Poddel’sky, Susanna A. Smolyaninova, Maxim V. Arsenyev, Georgy K. Fukin et Nadezhda T. Berberova. « Polyfunctional Sterically Hindered Catechols with Additional Phenolic Group and Their Triphenylantimony(V) Catecholates : Synthesis, Structure, and Redox Properties ». Molecules 25, n^o 8 (12 avril 2020) : 1770. http://dx.doi.org/10.3390/molecules25081770.

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New polyfunctional sterically hindered 3,5-di-tert-butylcatechols with an additional phenolic group in the sixth position connected by a bridging sulfur atom—(6-(CH2-S-tBu2Phenol)-3,5-DBCat)H2 (L1), (6-(S-tBu2Phenol)-3,5-DBCat)H2 (L2), and (6-(S-Phenol)-3,5-DBCat)H2 (L3) (3,5-DBCat is dianion 3,5-di-tert-butylcatecolate)—were synthesized and characterized in detail. The exchange reaction between catechols L1 and L3 with triphenylantimony(V) dibromide in the presence of triethylamine leads to the corresponding triphenylantimony(V) catecholates (6-(CH2-S-tBu2Phenol)-3,5-DBCat)SbPh3 (1) and (6-(S-Phenol)-3,5-DBCat)SbPh3 (2). The electrochemical properties of catechols L1–L3 and catecholates 1 and 2 were investigated using cyclic voltammetry. The electrochemical oxidation of L1–L3 at the first stage proceeds with the formation of the corresponding o-benzoquinones. The second process is the oxidation of the phenolic moiety. Complexes 1 and 2 significantly expand their redox capabilities, owing to the fact that they can act as the electron donors due to the catecholate metallocycle capable of sequential oxidations, and as donors of the hydrogen atoms, thus forming a stable phenoxyl radical. The molecular structures of the free ligand L1 and complex 1 in the crystal state were determined by single-crystal X-ray analysis.

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Lo Schiavo, Sandra, Maria Grassi, Giovanni De Munno, Francesco Nicolò et Giuseppe Tresoldi. « Polyfunctional phosphine ligands II. Iridium(I) complexes of the 7-diphenylphosphino-2,4-dimethyl-1,8-naphthyridine (dpnapy) ligand. X-ray crystal structure of [{Ir(cod)Cl}2(μ-dpnapy)] ». Inorganica Chimica Acta 216, n^o 1-2 (février 1994) : 209–16. http://dx.doi.org/10.1016/0020-1693(93)03730-x.

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Gütlich, Philipp, Ana B. Gaspar et Yann Garcia. « Spin state switching in iron coordination compounds ». Beilstein Journal of Organic Chemistry 9 (15 février 2013) : 342–91. http://dx.doi.org/10.3762/bjoc.9.39.

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The article deals with coordination compounds of iron(II) that may exhibit thermally induced spin transition, known as spin crossover, depending on the nature of the coordinating ligand sphere. Spin transition in such compounds also occurs under pressure and irradiation with light. The spin states involved have different magnetic and optical properties suitable for their detection and characterization. Spin crossover compounds, though known for more than eight decades, have become most attractive in recent years and are extensively studied by chemists and physicists. The switching properties make such materials potential candidates for practical applications in thermal and pressure sensors as well as optical devices. The article begins with a brief description of the principle of molecular spin state switching using simple concepts of ligand field theory. Conditions to be fulfilled in order to observe spin crossover will be explained and general remarks regarding the chemical nature that is important for the occurrence of spin crossover will be made. A subsequent section describes the molecular consequences of spin crossover and the variety of physical techniques usually applied for their characterization. The effects of light irradiation (LIESST) and application of pressure are subjects of two separate sections. The major part of this account concentrates on selected spin crossover compounds of iron(II), with particular emphasis on the chemical and physical influences on the spin crossover behavior. The vast variety of compounds exhibiting this fascinating switching phenomenon encompasses mono-, oligo- and polynuclear iron(II) complexes and cages, polymeric 1D, 2D and 3D systems, nanomaterials, and polyfunctional materials that combine spin crossover with another physical or chemical property.

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Scharf, Lydia, Johanna Tauriainen, Juliet Frederiksen, Ali Naji, Hans-Gustaf Ljunggren, Anders Sönnerborg, Ole Lund et al. « HIV-induced modifications of TIGIT expression impair CD8 T cell polyfunctionality ». Journal of Immunology 198, n^o 1_Supplement (1 mai 2017) : 78.25. http://dx.doi.org/10.4049/jimmunol.198.supp.78.25.

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Abstract HIV-specific CD8 T cells display an accumulation of inhibitory receptors that are associated with poor effector functions. Expression of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), its co-stimulatory receptor CD226 and their ligand poliovirus receptor (PVR) are altered during chronic viral infections and cancer. Here we show that the TIGIT/CD226/PVR axis is dysregulated during HIV infection and linked to poor polyfunctional activity, increased expression of inhibitory receptors and an altered effector transcriptional programming. We report that TIGIT expression is increased on CD8 T cells in untreated HIV infection. Additionally, a longitudinal increase in TIGIT expression was demonstrated despite early initiation of antiretroviral therapy during acute HIV infection. The HIV-specific TIGIT+ CD8 T cells co-expressed PD-1, CD160 and 2B4 and had an inverse expression profile of the T-box transcription factors T-bet and Eomes. The HIV-specific CD8 T cells were almost exclusively TIGIThiCD226neg/dim and the frequency of TIGIThi cells was inversely correlated with polyfunctionality. Furthermore, the TIGIT/CD226 ligand PVR was increased on CD4 T cells, especially T follicular helper (Tfh) cells in HIV-infected lymph nodes. These results demonstrate a preferential skewing of the TIGIT/CD226 axis towards the inhibitory receptor TIGIT on CD8 T cells during HIV-1 infection, which is linked to severe T cell dysfunction. The findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that potentially could hinder future therapeutic “cure” strategies that require potent HIV-specific CD8 T cells and/or the clearance of HIV-1 infected Tfh cells.

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Falvello, Larry R., Julio Gomez, Isabel Pascual, Milagros Tomás, Esteban P. Urriolabeitia et Arthur J. Schultz. « Saccharinate as a Versatile Polyfunctional Ligand. Four Distinct Coordination Modes, Misdirected Valence, and a Dominant Aggregate Structure from a Single Reaction System ». Inorganic Chemistry 40, n^o 17 (août 2001) : 4455–63. http://dx.doi.org/10.1021/ic010300x.

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Belletti, Daniele, Mauro Carcelli, Corrado Pelizzi et Giancarlo Pelizzi. « Crystal structure of a seven-coordinate cobalt(II) complex with a new polyfunctional hydrazonic ligand, [Co(H4dapis)(OH2)2]Cl2�9/2H2O ». Journal of Crystallographic and Spectroscopic Research 22, n^o 2 (avril 1992) : 185–91. http://dx.doi.org/10.1007/bf01186255.

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Frantz, Stéphanie, Wolfgang Kaim, Jan Fiedler et Carole Duboc. « Complexes of [Re(CO)3Cl] with different oxidation states of the polyfunctional bmtz/H2bmtz ligand system (bmtz=3,6-bis(2-pyrimidyl)-1,2,4,5-tetrazine) ». Inorganica Chimica Acta 357, n^o 12 (septembre 2004) : 3657–65. http://dx.doi.org/10.1016/j.ica.2004.03.056.

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Friedrich, Stefan, Lutz H. Gade, Andrew J. Edwards et Mary McPartlin. « A new class of five-co-ordinate titanium complexes containing a polyfunctional amido ligand. Crystal structure of [TiBr2{CH(2-C5H4N)(CH2NSiMe3)2}] ». Journal of the Chemical Society, Dalton Transactions, n^o 18 (1993) : 2861. http://dx.doi.org/10.1039/dt9930002861.

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Lichterfeld, Mathias, Danlei Mou, Thai Duong Hong Cung, Katie L. Williams, Michael T. Waring, Jinghe Huang, Florencia Pereyra et al. « Telomerase activity of HIV-1–specific CD8+ T cells : constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors ». Blood 112, n^o 9 (1 novembre 2008) : 3679–87. http://dx.doi.org/10.1182/blood-2008-01-135442.

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Abstract Exhaustion of virus-specific T cells may play an important role in the pathophysiology of chronic viral infections. Here, we analyzed telomere length and telomerase activity in HIV-1–specific CD8+ T cells from progressors or controllers to determine underlying molecular pathways of T-cell exhaustion and senescence. Telomere lengths of HIV-1–specific CD8+ T cells from progressors were significantly shorter compared with autologous cytomegalovirus (CMV)/Epstein-Barr virus (EBV)–specific CD8+ T cells or bulk CD8+ T cells, while telomere lengths from controllers significantly exceeded those of autologous bulk CD8+ T cells and reached a similar level as HIV-1–specific CD8+ T cells collected during primary HIV-1 infection. Telomere length stabilization in controllers corresponded to high levels of constitutive telomerase activity, which was associated with preservation of cytotoxic and proliferative properties. Conversely, limited constitutive telomerase activity was observed in HIV-1–specific CD8+ T cells from progressors, although an increase in both telomere length and telomerase activity was achieved in antigenic-peptide–stimulated cells from progressors after blocking the PD-1/PD ligand 1 (PD-L1) pathway. Collectively, these data suggest a causal role of telomere shortening for the functional deficiencies of HIV-1–specific CD8+ T cells in chronic progressive infection, while high constitutive telomerase activities appears to contribute to maintenance of polyfunctional HIV-1–specific CD8+ T cells from HIV-1 controllers.

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Ellermann, Jochen, Falk A. Knoch et Klaus J. Meier. « Chemie polyfunktioneller Moleküle, 108 Tetraedrische Kupfer(I)-Chelatkomplexe der Liganden Bis(diphenylphosphino)amin und Bis(diphenylphosphino)methan / Chemistry of Polyfunctional Molecules, 108 [1] Tetrahedral Copper(I) Chelate Complexes with the Ligands Bis(diphenylphosphino)amine and Bis(diphenylphosphino)methane ». Zeitschrift für Naturforschung B 46, n^o 12 (1 décembre 1991) : 1699–705. http://dx.doi.org/10.1515/znb-1991-1220.

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Reaction of [Cu(PPh3)2(NO3)] (1) in acetone with bis(diphenylphosphino)amine (dppa, 2) yields [Cu(dppa)(PPh3)2]+NO3- (3a). [Cu(dppa)(PPh3)2]+PF6- (3b) has been synthesized by metatheses of 3a with NH4PF6. The salt [Cu(dppm)(PPh3)2]+PF6- (5b) has been prepared by an one batch reaction of [Cu(PPh3)2(NO3)] (1), bis(diphenylphosphino)methane (dppm, 4) and NH4PF6 in methanol, because [Cu(dppm)(PPh3)2]+NO3- (5a) could not be isolated by the direct reaction of 1 with 4. The IR, Raman, 31P{1H} NMR, 1H{31Ρ} NMR as well as the conductivity data are reported and discussed together with the X-ray crystal structure of 3a · 1.8 (CH3)2CO. The structure consists of copper atoms coordinated tetrahedrally by two PPh3 ligands and the chelating dppa ligand and features a highly strained four-membered ring. The distorted tetrahedral cations are hydrogen bridged to the nitrate anions. The colourless needles of 3a· 1.8 (CH3)2CO crystallize in the monoclinic space group C 2/c, with the lattice constants a = 4189.2(27); b = 1223.7(8); c = 2717.8(15) pm;β = 113.16(4)°.

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Kamya, P., S. Boulet, C. M. Tsoukas, J. P. Routy, R. Thomas, P. Cote, M. R. Boulassel et al. « Receptor-Ligand Requirements for Increased NK Cell Polyfunctional Potential in Slow Progressors Infected with HIV-1 Coexpressing KIR3DL1*h/*y and HLA-B*57 ». Journal of Virology 85, n^o 12 (6 avril 2011) : 5949–60. http://dx.doi.org/10.1128/jvi.02652-10.

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Mahmoudi, Ghodrat, Marjan Abedi, Simon E. Lawrence, Ennio Zangrando, Maria G. Babashkina, Axel Klein, Antonio Frontera et Damir A. Safin. « Tetrel Bonding and Other Non-Covalent Interactions Assisted Supramolecular Aggregation in a New Pb(II) Complex of an Isonicotinohydrazide ». Molecules 25, n^o 18 (4 septembre 2020) : 4056. http://dx.doi.org/10.3390/molecules25184056.

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A new supramolecular Pb(II) complex [PbL(NO2)]n was synthesized from Pb(NO3)2, N’-(1-(pyridin-2-yl)ethylidene)isonicotinohydrazide (HL) and NaNO2. [PbL(NO2)]n is constructed from discrete [PbL(NO2)] units with an almost ideal N2O3 square pyramidal coordination environment around Pb(II). The ligand L− is coordinated through the 2-pyridyl N-atom, one aza N-atom, and the carbonyl O-atom. The nitrite ligand binds in a κ2-O,O coordination mode through both O-atoms. The Pb(II) center exhibits a hemidirected coordination geometry with a pronounced coordination gap, which allows a close approach of two additional N-atoms arising from the N=C(O) N-atom of an adjacent molecule and from the 4-pyridyl N-atom from the another adjacent molecule, yielding a N4O3 coordination, constructed from two Pb–N and three Pb–O covalent bonds, and two Pb⋯N tetrel bonds. Dimeric units in the structure of [PbL(NO2)]n are formed by the Pb⋯N=C(O) tetrel bonds and intermolecular electrostatically enforced π+⋯π− stacking interactions between the 2- and 4-pyridyl rings and further stabilized by C–H⋯π intermolecular interactions, formed by one of the methyl H-atoms and the 4-pyridyl ring. These dimers are embedded in a 2D network representing a simplified uninodal 3-connected fes (Shubnikov plane net) topology defined by the point symbol (4∙82). The Hirshfeld surface analysis of [PbL(NO2)] revealed that the intermolecular H⋯X (X = H, C, N, O) contacts occupy an overwhelming majority of the molecular surface of the [PbL(NO2)] coordination unit. Furthermore, the structure is characterized by intermolecular C⋯C and C⋯N interactions, corresponding to the intermolecular π⋯π stacking interactions. Notably, intermolecular Pb⋯N and, most interestingly, Pb⋯H interactions are remarkable contributors to the molecular surface of [PbL(NO2)]. While the former contacts are due to the Pb⋯N tetrel bonds, the latter contacts are mainly due to the interaction with the methyl H-atoms in the π⋯π stacked [PbL(NO2)] molecules. Molecular electrostatic potential (MEP) surface calculations showed marked electrostatic contributions to both the Pb⋯N tetrel bonds and the dimer forming π+⋯π− stacking interactions. Quantum theory of atoms in molecules (QTAIM) analyses underlined the tetrel bonding character of the Pb⋯N interactions. The manifold non-covalent interactions found in this supramolecular assembly are the result of the proper combination of the polyfunctional multidentate pyridine-hydrazide ligand and the small nitrito auxiliary ligand.

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Ma, Chunlin, Guangru Tian et Rufen Zhang. « Solvothermal synthesis and structural characterization of a novel one-dimensional organotin polymer involving high centrosymmetric units containing polyfunctional ligand 4-hydroxy-2-mercapto-6-methylpyrimidine ». Inorganic Chemistry Communications 9, n^o 9 (septembre 2006) : 882–86. http://dx.doi.org/10.1016/j.inoche.2006.05.029.

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Mohsen, Mona O., Matthew Heath, Matthias F. Kramer, Thalia Carreno Velazquez, Alan Bullimore, Murray A. Skinner, Daniel E. Speiser et Martin F. Bachmann. « In situ delivery of nanoparticles formulated with micron-sized crystals protects from murine melanoma ». Journal for ImmunoTherapy of Cancer 10, n^o 9 (septembre 2022) : e004643. http://dx.doi.org/10.1136/jitc-2022-004643.

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IntroductionIntratumoral injections of novel therapeutics can activate tumor antigen-specific T cells for locoregional tumor control and may even induce durable systemic protection (against distant metastases) via recirculating T cells. Here we explored the possibility of a universal immunotherapy that promotes T-cell responses in situ and beyond, upon intratumoral injection of nanoparticles formulated with micron-sized crystals.MethodsCucumber mosaic virus-like particles containing a tetanus toxin peptide (CuMVTT) were formulated with microcrystalline tyrosine (MCT) adjuvant and injected directly in B16F10 melanoma tumors. To further enhance immunogenicity, we loaded the nanoparticles with a TLR7/8 ligand and incorporated a universal tetanus toxin T-helper cell peptide. We assessed therapeutic efficacy and induction of local and systemic immune responses, including RNA sequencing, providing broad insight into the tumor microenvironment and correlates of protection.ResultsMCT crystals were successfully decorated with CuMVTT nanoparticles. This ‘immune-enhancer’ formed immunogenic depots in injected tumors, enhanced polyfunctional CD8+ and CD4+ T cells, and inhibited B16F10 tumor growth locally and systemically. Local inflammation and immune responses were associated with upregulation of genes involved in complement activation and collagen formation.ConclusionsOur new immune-enhancer turned immunologically cold tumors into hot ones and inhibited local and distant tumor growth. This type of immunotherapy does not require the identification of (patient–individual) relevant tumor antigens. It is well tolerated, non-infectious, and affordable, and can readily be upscaled for future clinical testing and broad application in melanoma and likely other solid tumors.

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Matveev, E. Yu, S. S. Akimov, A. S. Kubasov, V. M. Retivov, K. Yu Zhizhin et N. T. Kuznetsov. « THE METHOD FOR OBTAINING A DERIVATIVE CLOSO-DECABORATE ANION WITH PENDANTE DTPA-GROUP ». Fine Chemical Technologies 14, n^o 1 (28 février 2019) : 59–65. http://dx.doi.org/10.32362/2410-6593-2019-14-1-59-65.

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This paper describes the method for obtaining a new derivative of the closo-decaborate anion with diethylenetriaminepentaacetic acid (DTPA) as a pendant group attached to the boron cluster through an alkoxyl spacer chain. This derivative is formed by the interaction of 1,4-dioxane derivative of the anion [B10H10]2- with DTPA potassium salt in an aqueous medium. As a result of the reaction, an exo-polyhedral cyclic substituent is opened, and then the addition of a polyfunctional group through an oxygen atom occurs. The synthesized compound is in fact an effective polydentate ligand capable of coordinating to the complexing agent both due to the donor atoms of the attached DTPA fragment and through the formation of three-center two-electron bonds. The obtained compound interacts with gadolinium(III) carbonate forming a complex of the composition [Gd2B10H9O2C4H8(dtpa)]·3H2O. The synthesized substances were studied by IR spectroscopy, polynuclear (11B, 13C and 1H) NMR spectroscopy, ESI mass spectrometry, elemental and thermographic analysis. closo-Decaborate with the pendant DTPA group is of interest in 10B neutron capture therapy of malignant tumors due to the high content of boron atoms and a convenient way of their transport to the affected cells. The obtained boron-containing derivatives of gadolinium(III) can act as drugs of combined action, because they can perform, in addition to the above described therapeutic function, the diagnostic function due to the presence of gadolinium atoms int hem.

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Perry, Joseph Allan, Jonathan Delong, Joseph Clark, Jeongho Park, Jodi Gullicksrud, Lindsey Shallberg, Christoph Konradt, David Christian et Christopher Hunter. « PD-1 signaling impacts T cell function during the early phase of infection with Toxoplasma gondii ». Journal of Immunology 202, n^o 1_Supplement (1 mai 2019) : 122.5. http://dx.doi.org/10.4049/jimmunol.202.supp.122.5.

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Abstract Long term resistance to T. gondii is mediated via T cell production of IFN-γ, but during chronic infection CD8+ T cells show signs of reduced capacity to secrete IFN-γ associated with increased expression of multiple inhibitory receptors. Blockade of the inhibitory receptor ligand PD-L1 during the chronic phase of infection has been reported to increase the functionality of CD8+ T cell responses and result in reduced parasite burden. However, the impact of PD-1 signaling on the immune response to T. gondii during the early phase of infection is unknown. PD-L1 blockade during the acute phase of toxoplasmosis resulted in an increased proportion of activated CD8+ T cells (CD69+, LFA-1hi) accompanied by an increased proportion of polyfunctional CD8+ T cells (IFN-γ+, Granzyme B+). This effect did not result in increased immune pathology or reduce parasite burden. Unexpectedly, this intervention resulted in a significant increase in the expression of inhibitory receptors such as PD-1, TIM3, and CTLA-4 on the long-lived T-intermediate (Tint, CXCR3+/KLRG1+) CD8+ T cell population, while increasing the proportion of terminally differentiated T cells in specific sites of infection. These datasets suggest PD-1 signaling in the early phase of T. gondii infection constrains CD8+ T cell effector differentiation and may act to preserve pathogen specific Tint subsets that are needed for long term resistance to this persistent infection.

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Camviel, Nicolas, Benita Wolf, Giancarlo Croce, David Gfeller, Vincent Zoete et Caroline Arber. « Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization ». Journal for ImmunoTherapy of Cancer 10, n^o 11 (novembre 2022) : e005091. http://dx.doi.org/10.1136/jitc-2022-005091.

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BackgroundChimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only).MethodsThree new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell–target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo.ResultsAPRIL-CAR T cells in a trimeric ligand binding conformation conferred fast but not sustained antitumor responses in vivo in mouse xenograft models. In vitro trimer-BBζ CAR T cells were more polyfunctional and formed stronger immune synapses than monomer-BBζ CAR T cells. After CAR T cell–myeloma cell contact, BCMA was rapidly downmodulated on target cells with all evaluated binding moieties. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during progression and persisting CAR T cells may not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell–MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo.ConclusionAntitumor responses with APRIL-CAR T cells were fast but not sustained. Rapid BCMA downmodulation occurred independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM when targeting BCMA and can inform the development of improved treatment strategies.

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Granifo, J., M. E. Vargas, J. Costamagna et M. A. Francois. « Coordination of a polyfunctional cyclic ligand containing a PP bond to the fragment [Mo(CO)3(NN)] (NN = 2,2′-bipyridine, 1,10-phenanthroline). Spectroscopic and electrochemical characterization ». Polyhedron 7, n^o 6 (janvier 1988) : 489–94. http://dx.doi.org/10.1016/s0277-5387(00)81196-1.

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De Keersmaecker, Brenda, Sofie Claerhout, Javier Carrasco, Isabelle Bar, Jurgen Corthals, Sofie Wilgenhof, Bart Neyns et Kris Thielemans. « TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab : link between T-cell activation and clinical responses in advanced melanoma ». Journal for ImmunoTherapy of Cancer 8, n^o 1 (février 2020) : e000329. http://dx.doi.org/10.1136/jitc-2019-000329.

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BackgroundWe previously reported that dendritic cell-based mRNA vaccination plus ipilimumab (TriMixDC-MEL IPI) results in an encouraging rate of tumor responses in patients with pretreated advanced melanoma. Here, we report the TriMixDC-MEL IPI-induced T-cell responses detected in the peripheral blood.MethodsMonocyte-derived dendritic cells electroporated with mRNA encoding CD70, CD40 ligand, and constitutively active TLR4 (TriMix) as well as the tumor-associated antigens tyrosinase, gp100, MAGE-A3, or MAGE-C2 were administered together with IPI for four cycles. For 18/39 patients, an additional vaccine was administered before the first IPI administration. We evaluated tumor-associated antigen specific T-cell responses in previously collected peripheral blood mononuclear cells, available from 15 patients.ResultsVaccine-induced enzyme-linked immunospot assay responses detected after in vitro T-cell stimulation were shown in 12/15 patients. Immune responses detected in patients with a complete or partial response were significantly stronger and broader, and exhibited a higher degree of multifunctionality compared with responses in patients with stable or progressive disease. CD8+ T-cell responses from patients with an ongoing clinical response, either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, exhibited the highest degree of multifunctionality.ConclusionsTriMixDC-MEL IPI treatment results in robust CD8+ T-cell responses in a meaningful portion of stage III or IV melanoma patients, and obviously in patients with a clinical response. The levels of polyfunctional and multiantigen T-cell responses measured in patients with a complete response, particularly in patients evidently cured after 5+ years of follow-up, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission.Trial registration numberNCT01302496.

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Gigley, Jason P., Daria L. Ivanova et Stephen L. Denton. « NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronic Toxoplasma gondii infection ». Journal of Immunology 202, n^o 1_Supplement (1 mai 2019) : 190.52. http://dx.doi.org/10.4049/jimmunol.202.supp.190.52.

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Abstract Previous studies demonstrate CD8 T cell immune exhaustion is a major factor in promoting chronic Toxoplasma gondii (T. gondii) infection. How other immune cells are impacted by chronic T. gondii infection to promote CD8 T cell exhaustion and chronic parasite infection are not known. We investigated natural killer cells (NK cells) and how they contribute to chronic Toxoplasmosis. We find NK cells are not exhausted because NK cell numbers do not decrease during late stage infection and do not up regulate PD-1 or LAG3. NK cells in chronic parasite infection have reduced IFNγ, do not produce IL-10 or increase their expression of PD-L1, however, they expressed elevated CD107a. We also find NK cells become more highly mature (KLRG1+) during chronic T. gondii infection. We conclude that they do not become exhausted as do CD8 T cells, but alter their function during chronic T. gondii infection. Importantly, we demonstrate NK cell depletion with anti-NK1.1 is therapeutic and rescues mice from death normally caused by CD8 T cell exhaustion and parasite reactivation. This treatment reduced CD8 T cell apoptosis, increased parasite specific polyfunctional CD8 T cell responses and prevented parasite reactivation. NKp46+ NK cells were enriched for expression of CD94 and NKG2A. NKp46 ligand and Qa-1b expression were altered to promote enrichment of this specific NK cell population. Blockade with anti-NKp46 also rescued the mice from death associated with exhausted CD8 T cells and parasite reactivation. We hypothesize NK cells via NKp46 significantly contribute to promoting chronic T. gondii infection. Understanding how NK cells develop this response will improve therapies for individuals at risk for reactivation of chronic infections.

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Linette, Gerald P., Michelle Becker-Hapak, Alexander Huang, Amer Alyasiry, Megan Chan, Wen-rong Lie, Lynn Cornelius et al. « CD40 ligand/interferon-γ matured DC immunization with gp100 antigen HLA class I A *0201 restricted peptides in patients with newly diagnosed metastatic melanoma. » Journal of Clinical Oncology 30, n^o 15_suppl (20 mai 2012) : 2525. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.2525.

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2525 Background: CD40L/IFN-γ matured Dendritic Cells (DCs) produce IL-12 and are potent antigen-presenting cells for naïve resting T cells. We sought to determine the magnitude and kinetics of CD8+ T cell growth in patients receiving autologous CD40L/IFN-γ matured DC and identify biomarkers associated with clinical outcome. Methods: A phase I clinical trial (NCT00683670) incorporating CD40L/IFN-γ for the ex vivo maturation of autologous DCs pulsed with three well characterized gp100 melanoma antigen derived peptides (G154, G209-2M, G280-9V) was initiated with enrollment from 2008-11 at a single center. HLA-A*0201+ individuals with treatment naïve metastatic melanoma were immunized every 3 weeks by intravenous infusion for six doses after a single dose of cyclophosphamide (300 mg/m2 iv). CT imaging was performed at baseline, week 9 and 18 for clinical assessment using RECIST. Responding patients were eligible for maintenance doses every 2-4 months. PBMC were taken weekly for immune monitoring by tetramer analysis and functional assays. DC preparations were characterized to assess for biomarkers of response. Results: 10 patients were screened. Among the 7 treated patients, there were 3 confirmed responses (independently verified), including one durable CR >3 years and 2 PR. Three patients had rapid disease progression and received only 3 doses. Four patients (1 CR, 2 PR, 1 PD) received 6 or more vaccine doses. No SAEs were noted. There was no correlation between tumor volume and response. Using pre-specified immune response criteria, 6 (86%) treated patients developed CD8+ T cell immunity to all three peptides as assessed by tetramer analysis. The vaccine-induced T cells from all 6 individuals were polyfunctional and killed gp100+, HLA-A2+ human melanoma targets in a standard 51Cr release assay. IL-12 production by DCs correlated with TTP (p=0.0198, likelihood ratio test) but not OS (p=0.08). Conclusions: Weekly immune monitoring reveals the rapid onset of CD8+ T cell immunity against gp100 among the responder patients. This is the first DC vaccine clinical trial in melanoma to demonstrate a correlation of IL-12 production and TTP.

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Dryuchko, Oleksandr, Natalia Bunyakina, Bogdan Korobko, Oleksandr Shefer, Kateryna Kytaihora et Iryna Ivanytska. « SEARCH FOR WAYS OF CONTROLLED MODIFICATION OF CHARACTERISTICS OF FUNCTIONAL UNITS OF ADAPTIVE AIR PURIFICATION SYSTEMS ». Bulletin of the National Technical University "KhPI". Series : Chemistry, Chemical Technology and Ecology, n^o 2(6) (23 décembre 2021) : 34–51. http://dx.doi.org/10.20998/2079-0821.2021.02.06.

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Information on alkaline coordination nitrates of rare-earth elements of the cerium subgroup - precursors of promising modern multifunctional materials - on the conditions of their formation and existence, the nature of the chemical bond, the composition, structure, shape of the Ln coordination polyhedra, the type of ligand coordination, and the existence of isotypic series in stoichiometry are generalized. composition, structure, characteristic properties. The data obtained (as primary information) is the basis for the detection, identification, and control of the phase state of processing objects in the preparatory stages, the choice of criteria for the compatibility of the components in the formation of single-layer and layered nanostructured oxide composite systems of lanthanides and transition elements for general purposes, with catalytic and photocatalytic activity, coatings self-cleaning with hydrophilic properties; development of various combined methods for their activation and identification of technological functional dependencies; controlled modification of the properties of the obtained target products. To increase the photocatalytic activity of coating samples based on highly dispersed anatase TiO2, a methodology for chemical modification of oxidation centers in their surface layer with heat treatment in contact with thermolysis products of alkaline coordination lanthanide nitrate melts is proposed. An effective test photocatalytic destruction of organic substrates vapors has been discovered using ethanol as an example.Effective activation of the functioning of functional units in the composition of self-adjusting air purification complexes using new photocatalytically active three-layer perovskite-like oxide materials M2Ln2Ti3O10 (M - Li, Na, K; Ln - La, Nd) has been proven. The variability of such methods for creating and modifying the characteristics of polyfunctional coatings is determined by the number and individual properties of representatives of the natural series of lanthanides, alkali metals of the periodic system, the peculiarities of their cooperative behavior in the preparatory technological stages, conditions and methods of activation of formation processes, the nature of the substrate, and other factors.

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Akhriff, Y., J. Server-Carrió, A. Sancho, J. García-Lozano, E. Escrivá, J. V. Folgado et L. Soto. « Synthesis, Crystal Structure, and Magnetic Properties of Oxalato−Copper(II) Complexes with 3,3-Bis(2-imidazolyl)propionic Acid, an Imidazole−Carboxylate Polyfunctional Ligand : From Mononuclear Entities to Ladder-Like Chains ». Inorganic Chemistry 38, n^o 6 (mars 1999) : 1174–85. http://dx.doi.org/10.1021/ic980982x.

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Van Caeneghem, Yasmine, Glenn Goetgeluk, Sylvia Snauwaert, Fritz Offner, Reno Debets, Tessa Kerre et Bart Vandekerckhove. « Polyfunctional Tumor Antigen-specific T Cells Generated in Vitro from Human CD34 Positive Precursor Cells Transduced to Express T Cell Receptor αβ Chains Fused to CD28-CD3ζ Signaling Cassette ». Blood 124, n^o 21 (6 décembre 2014) : 3830. http://dx.doi.org/10.1182/blood.v124.21.3830.3830.

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Abstract T cell therapy for the treatment of malignant diseases is based on the lenti- or retroviral introduction of an exogenous receptor in peripheral blood T cells. The exogenous receptor is either antibody based or T cell receptor (TCR) based. Chimeric antigen receptors (CAR) are antibody based receptors that can redirect T cells against membrane antigens expressed by malignant cells. CD19-specific CARs were reported to be very effective in the treatment of CD19+ acute leukemias. To redirect T cells based on cytoplasmic antigens, transduction of a TCR is required. However, this approach still faces technical problems, esp. interference of the endogenous TCR chains may cause loss of avidity and possibly induction of autoimmunity. We here present an alternative strategy, in which, not mature T cells but CD34+ hematopoietic precursor cells are transduced and subsequently differentiated to mature T cells after introduction of a wild type TCR or of a fusion TCR:CD3ζ with or without costimulator signal. When Wilms tumor 1 (WT1)/HLA-A2-specific T cell receptor α and β chain is introduced in CD34+ cells derived from human thymus, cord blood or adult mobilized precursor cells and subsequently induced to differentiate to T cells on OP9 stromal cells expressing Delta-like ligand 1(OP9-DL1) in the presence of stem cell factor, flt3 ligand and interleukin 7, massive proliferation is observed while the cells differentiate to CD4+CD8+double positive (DP) transduced TCR+ immature cells. Few mature T cells are generated in these cultures, but after addition of the specific peptide to HLA-A2+ cultures, DP cells rapidly differentiate to phenotypically mature naïve CD8 single positive T cells. Upon activation, these T cells specifically lyse WT1/HLA-A2 cell lines and produce interferon-γ. Microarray expression analysis revealed these culture-generated T cells to be similar to TCR-transduced peripheral blood T cells, except for 1) the expression of only one TCR α and β chain by the in vitro generated T cells and 2) the underexpression of costimulatory/inhibitory molecules such as CD28, CTLA-4 and PD-L1. The absence of CD28 on the cell membrane was confirmed by flow cytometry. Since it was shown that CD28 signaling is essential for in vivo functionality using CARs, we next generated fusion TCR constructs of a gp100/HLA-A2-specific TCR and the signaling cassettes of CD3ζ and CD28.The following constructs were introduced in CD34+ cells: wild type TCR, TCR:ζ or TCR:CD28ζ α and β chains. The α and β chain double-transduced cells were subsequently cultured on OP9-DL1 in the absence of the specific antigen. It was observed that TCR:ζ transduced precursors proliferated significantly less than wild type TCR transduced cells, but the majority of the cells differentiated towards DP TCR:ζ+ cells, which upon addition of the specific antigen differentiated to phenotypically mature T cells. TCR:CD28ζ transduced cells proliferated least of all and spontaneously matured to functional double negative T cells without passing through the DP stage. These observations are compatible with data obtained in mice showing that strong TCR activation during thymocyte differentiation inhibits the generation of DP cells. In all of these cultures, endogenous TCR rearrangements were suppressed, which resulted in single receptor tumoricidal cells. Functional analysis of these various cell populations showed similar proliferation on T cell growth factors and specific cytolytic activity of gp100+ HLA-A2+ tumor lines. However, the TCR:CD28ζ transduced cells produced significantly higher levels of TNFα and interferon-γ and were the only ones that produced interleukin-2 upon specific stimulation. In conclusion, we have shown that high numbers of polyfunctional single receptor TCR:CD28ζ+ cells can be generated in vitro from clinically relevant stem cell sources. These cells produce interleukin-2, TNFα and interferon-γ and specifically kill gp100/HLA-A2+ tumor cell lines. Disclosures No relevant conflicts of interest to declare.

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Paine, R. T., G. S. Conary, A. A. Russell, D. J. McCabe, E. N. Duesler, S. Karthikeyan, R. Schaeffer, R. R. Ryan et D. Cromer. « SYNTHESIS OF POLYFUNCTIONAL ORGANOPHOSPHONATE LIGANDS ». Solvent Extraction and Ion Exchange 7, n^o 5 (janvier 1989) : 767–81. http://dx.doi.org/10.1080/07360298908962336.

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Berezina, Nadezhda, et Egor Kolesov. « Assessment of polyfunctional macrocyclic compounds in solution by cryoscopic method ». From Chemistry Towards Technology Step-By-Step 4, n^o 3 (23 septembre 2023) : 76–80. http://dx.doi.org/10.52957/2782-1900-2024-4-3-76-80.

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The article considers the synthesis of meso-tetrakis(1'-methyl-pyrid-4-yl)porphyrin tetratosylate and meso-tetrakis(1'-methyl-carboxymethylpyrid-4-yl)porphyrin tetrabromide. The authors qualified the porphyrin ligands in terms of the electron and 1H NMR spectroscopy. The research determines the decrease of freezing point (ΔTfr) of aqueous solutions of porphyrins, as well as a model N-methyl-pyridinium salt (1 methyl-pyridinium iodide). We used the obtained experimental values of ΔT3 to determine the isotonic coefficient. The obtained results indicate the compounds are almost completely dissociated in the indicated concentration range in dilute solutions.

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Zhang, Ri, Wenjin Gao, Yuanyuan Sun, Jingcheng Miao et Xueguang Zhang. « Study of In Vitro Proliferation Potential of CD133 Positive Cells Derived from Umbilical Cord Blood. » Blood 110, n^o 11 (16 novembre 2007) : 4039. http://dx.doi.org/10.1182/blood.v110.11.4039.4039.

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Abstract Transforming growth factor-beta 1 (TGF-β1) is known to maintain primitive human hematopoietic stem/progenitor cells with polyfunctional role in a quiescent state and CD133 is a new stem cell antigen that may provide an alternative to CD34 for the selection and expansion of hematopoietic cells for transplantation. To investigate the specific effect of TGF-β1 on proliferation and differentiation of CD133 positive cells derived from umbilical cord blood (UCB) during short-term culture in vitro, CD133 positive cells from 20 fresh UCB samples were selected using Miltenyi Biotec’s CliniMACS separation device and were cultured in IMDM medium with 20% FCS in the presence of a cytokine combination of SCF, IL-6, thrombopoietin, IL-3 and Flt3-ligand for up to 2 weeks and TGF-β1 with low concentration was also added to the mediumon day 4. The proliferative response was assessed at day 7, day 10 and day 14 by evaluating the following parameters: nucleated cells (NC), clonogenic progenitors (CFU-GEMM,CFU-GM and BFU-E), and immunophenotypes (CD133 and CD34). The results showed that efficacious expansion of various hematopoietic stem/progenitor cells was constantly observed during the culture. The fold expansion of NC on day7, day10 and day14 expansion were 33.59,224.26 and 613.48, respectively. The fold expansion of CFU-GEMM, CFU-GM and BFU-E on day 10 were 24.89, 41.62 and 49.28, respectively, obviously higher than that without ex vivo expansion (P<0.05). The expansions of CD133+, CD133+CD34+ and CD34+ subpopulation on day 14 were up to 25.83-fold, 16.16-fold and 60.54-fold, respectively. Furthermore the expansion systems with TGF-β1 showed more CD133+ cells than control at every time points. Our datas suggested that the CD133+ cells from human UCB have great expansion potential for ex-vivo expansion. The low concentration of TGF-β1 may delay over-differentiation of hematopoietic stem/progenitor cells.

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Bodensieck, Ulf, Heinrich Vahrenkamp, Gerd Rheinwald et Helen Stoeckli-Evans. « Ruthenium carbonyl complexes with polyfunctional phosphine ligands ». Journal of Organometallic Chemistry 488, n^o 1-2 (février 1995) : 85–90. http://dx.doi.org/10.1016/0022-328x(94)00026-9.

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Ramani, Vijay, Shruthi Nooka, Yu-An Zhang, Serena Gibbs, Hai-Cheng Huang, Melanie Hullings, Suzanne Conzen, Carlos L. Arteaga, Isaac Chan et Sangeetha M. Reddy. « Abstract 4197 : Treatment with chemotherapy, CD40 agonist, and Flt3 ligand triplet combination enhances antigen presentation and leads to cures in triple negative breast cancer ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 4197. http://dx.doi.org/10.1158/1538-7445.am2022-4197.

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Abstract Introduction: Triple negative breast cancers (TNBC) have shown limited responses to immune checkpoint blockade (ICB). Breast cancer is associated with defects in antigen presentation which may contribute to resistance to ICB. Flt3 ligand (Flt3L) is a growth factor that increases differentiation of DC1 dendritic cells, critical mediators of antigen presentation. CD40 agonist activates all 3 classes of antigen presenting cells - dendritic cells, B cells, and macrophages. Synergy has been demonstrated between Flt3L and CD40 agonist as well as between CD40 agonist and chemotherapy in other cancers, however the combination of all three has not been studied in breast cancer. Methods: 6-8 week old Balb/c mice were injected with 4T1 triple negative breast cancer cells. When tumors were 50 mm3, mice were first treated with intraperitoneal pegylated liposomal doxorubicin (PLD) once and subcutaneous Flt3L daily for 5 days in different sequencing schedules (PLD first followed by Flt3L immediately or 4 days later or Flt3L first followed by PLD 7 days or 10 days later). Based on optimal scheduling of PLD and Flt3L, mice were treated with PLD alone, Flt3L alone, CD40 agonist alone, PLD + Flt3L, PLD + CD40 agonist, PLD + PD-1 blockade, or PLD + CD40 agonist + Flt3L. In addition to serial tumor measurements, mice were sacrificed and tumors and lymphoid organs harvested for flow cytometry analyses. Results: Treatment with PLD at least 4 days before Flt3L led to an optimal increase in intra-tumoral DC1 cells (p=0.0002), increase in polyfunctional CD8 T cell response (p<0.0001), reduced PD-L1 expression on DC1 cells (p<0.0001), and reduced PD-1 expression on CD8 T cells (p<0.0001) compared to other sequencing schedules. Therefore, this regimen was advanced for further study. Treatment with novel triplet combination of PLD, Flt3L, and CD40 agonist resulted in improved tumor control and survival compared to PLD alone (p<0.0001 and p<0.0001, respectively), Flt3L alone (p<0.0001 and p<0.0001), CD40 agonist alone (p <0.0001 and p<0.0001), PLD + Flt3L (p<0.0001 and p<0.0001), PLD + CD40 agonist (p<0.0001 and p<0.0001), and PLD + PD-1 blockade (p<0.0001 and p<0.0001). 22% of mice were tumor-free in the triplet therapy group only and were resistant to tumor re-challenge. Treatment with triplet therapy was associated with an increase in antigen specific CD8 T cells. Additional mechanistic studies will also be presented. Conclusions: Novel triplet combination with PLD, CD40 agonist, and Flt3L leads to enhanced tumor control in the 4T1 TNBC mouse model. A clinical trial with this combination in metastatic TNBC patients is expected to begin recruitment soon (NCT05029999). Citation Format: Vijay Ramani, Shruthi Nooka, Yu-An Zhang, Serena Gibbs, Hai-Cheng Huang, Melanie Hullings, Suzanne Conzen, Carlos L. Arteaga, Isaac Chan, Sangeetha M. Reddy. Treatment with chemotherapy, CD40 agonist, and Flt3 ligand triplet combination enhances antigen presentation and leads to cures in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4197.

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O'Hara, Samantha, Teisha Rowland, Ryan Koning, David Vereide, Michele Hoffmann, Ashley Yingst, Chris Nicolai et al. « Abstract 547 : Generation of synthetic cytokine receptor-induced cytotoxic innate lymphocytes (iCILs) from iPSCs as off-the-shelf cancer therapeutics ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 547. http://dx.doi.org/10.1158/1538-7445.am2022-547.

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Abstract Off-the-shelf immune cell products derived from induced pluripotent stem cells (iPSC) have the potential to address many of the current limitations of engineered autologous and allogeneic blood-derived cell therapies. IPSC-based platforms offer a scalable and renewable source of allogeneic cells that can be engineered to augment cell phenotype and function. Current approaches to generating iPSC-derived immune effector cells have focused on recapitulating natural differentiation pathways to defined effector cell types (e.g., CD8 T cells or NK cells) utilizing feeder cells and exogenous cytokines. By engineering cells to express an artificial cytokine receptor, termed rapamycin activated cytokine receptor (RACR), we can control immune effector cell differentiation and expansion through synthetic signals independent of endogenous receptor expression, reducing the complexity and variability of cell differentiation while deriving cells with unique phenotypic and functional features not found in conventionally defined native immune cells. Here we demonstrate the ability to differentiate and expand synthetic cytotoxic innate lymphoid cells through engineering progenitor cells to express an artificial cytokine receptor, the RACR system, that is activated by a non-native small molecule ligand, rapamycin. This approach involves a period of feeder cell free hematopoietic and lymphoid progenitor specification followed by rapamycin-mediated activation of the artificial cytokine receptor (RACR), inducing an IL-2/IL-15-like signal to drive cytotoxic innate lymphocyte differentiation and feeder cell free expansion resulting in approximately 3000-fold expansion from the iPSC starting material. The protocol has demonstrated robustness in the small-scale setting with multiple research-grade iPSC lines and enables extensive effector cell expansion at low cost, enabled by the stability of the rapamycin ligand and elimination of complex raw materials such as exogenous cytokines. The resulting RACR-induced cytotoxic innate lymphocytes (RACR-iCILs) exhibit potent polyfunctional anti-tumor activity driven by the synergistic activity of innate immune receptors and the engineered expression of a chimeric antigen receptor (CAR), including cytolytic activity and the secretion of IFNγ and TNFα. The artificial cytokine receptor system can be used ex vivo to generate cells but also has the potential to enable rapamycin-controlled and selective expansion and survival of the engineered cells in vivo. Taken together, our data demonstrate the potential for de novo engineering of novel synthetic cytotoxic effector cells that show significant potential as “off the shelf” cancer therapeutics. We are currently moving these novel cells into humanized mouse models to further evaluate their unique properties and in vivo anti-tumor activity. Citation Format: Samantha O'Hara, Teisha Rowland, Ryan Koning, David Vereide, Michele Hoffmann, Ashley Yingst, Chris Nicolai, Mark Pankau, Kristen Mittelsteadt, Kathryn Michels, Seungjin Shin, Laurie Beitz, Byoung Ryu, Ryan Crisman, Andrew Scharenberg, Chris Garbe, Ryan Larson. Generation of synthetic cytokine receptor-induced cytotoxic innate lymphocytes (iCILs) from iPSCs as off-the-shelf cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 547.

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Goldberg, Zelanna, Christian Maine, Gabrielle P. Dailey, Christine Domingo, Gaelle Picarda, Hunter Little, Annie Chou et al. « Abstract 6403 : A self-replicating RNA precision medicine approach to overcoming resistance to endocrine therapy in ER+BC ». Cancer Research 83, n^o 7_Supplement (4 avril 2023) : 6403. http://dx.doi.org/10.1158/1538-7445.am2023-6403.

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Abstract Drug resistance remains the major driving factor behind the clinical failure of targeted therapeutics. Current oncology precision medicine approaches rely on targeting known acquired resistance mutations, such as EGFR T790M or ALK/ROS mutations in NSCLC with 2nd and 3rd generation molecules designed to overcome or prevent resistance. These next generation targeted therapeutic approaches have increasingly long and complex drug development timelines and burdensome toxicities from off target effects (e.g. wild-type receptor targeting) or drug-drug interactions (DDI). The toxicities limit tolerability, compliance and combinability of different targeted therapeutics. RNA-based immunotherapy approaches offer an increasingly attractive alternative to next generation small molecule targeted therapeutics approaches: (1) RNA-based approaches only require a known acquired resistance sequence, (2) drug development timelines, cost and complexity can be meaningfully condensed, and (3) multiple acquired resistance mutations can be targeted with the same candidate. RBI-1000 is a candidate using a novel type of self-replicating RNA (srRNA) to generate robust immunity directed against acquired resistance mutations that develop in ER+ breast cancer (ER+ BC) in response to endocrine therapy. RBI-1000 includes on-target mutations within the estrogen receptor ligand binding domain, and bypass mutations either in the form of activating mutations in the PI3K kinase domain or amplifications of HER2/HER3. Here, we demonstrate that this srRNA encapsulated in a lipid nanoparticle primes polyfunctional CD4 and CD8 T cells leading to tumor growth inhibition and improved survival in a mouse model expressing the targeted acquired resistance mutation. Priming of T cells against acquired mutations is also confirmed in human HLA-transgenic mice. The immune cell-mediated elimination of clones expressing the acquired resistance mutations is predicted to prolong endocrine control of ER+BC, in an analogous manner to small molecule or monoclonal antibody targeted therapies, but with a more favorable dosing and adverse event profile due to precise immunologic targeting and no DDI. Citation Format: Zelanna Goldberg, Christian Maine, Gabrielle P. Dailey, Christine Domingo, Gaelle Picarda, Hunter Little, Annie Chou, Jessica Sparks, Darina Spasova, Shigeki Miyake-Stoner, Zachary C. Hartman, Christopher A. Rabiola, Erika J. Crosby, Herbert K. Lyerly, Nathaniel Wang, Parinaz Aliahmad. A self-replicating RNA precision medicine approach to overcoming resistance to endocrine therapy in ER+BC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6403.

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