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1.
Super Secondary Structures of Proteins with Post-Translational Modifications in Colon Cancer.
Tikhonov, D, Kulikova, L, Kopylov, A, Malsagova, K, Stepanov, A, Rudnev, V, Kaysheva, A
Molecules (Basel, Switzerland). 2020;(14)
Abstract
New advances in protein post-translational modifications (PTMs) have revealed a complex layer of regulatory mechanisms through which PTMs control cell signaling and metabolic pathways, contributing to the diverse metabolic phenotypes found in cancer. Using conformational templates and the three-dimensional (3D) environment investigation of proteins in patients with colorectal cancer, it was demonstrated that most PTMs (phosphorylation, acetylation, and ubiquitination) are localized in the supersecondary structures (helical pairs). We showed that such helical pairs are represented on the outer surface of protein molecules and characterized by a largely accessible area for the surrounding solvent. Most promising and meaningful modifications were observed on the surface of vitamin D-binding protein (VDBP), complement C4-A (CO4A), X-ray repair cross-complementing protein 6 (XRCC6), Plasma protease C1 inhibitor (IC1), and albumin (ALBU), which are related to colorectal cancer developing. Based on the presented data, we propose the impact of the observed modifications in immune response, inflammatory reaction, regulation of cell migration, and promotion of tumor growth. Here, we suggest a computational approach in which high-throughput analysis for identification and characterization of PTM signature, associated with cancer metabolic reprograming, can be improved to prognostic value and bring a new strategy to the targeted therapy.
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2.
Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome.
Augé, H, Notarantonio, AB, Morizot, R, Quinquenel, A, Fornecker, LM, Hergalant, S, Feugier, P, Broséus, J
Frontiers in immunology. 2020;:594841
Abstract
INTRODUCTION Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. METHODS We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. RESULTS Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results. CONCLUSION RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
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3.
MALT1 induced immune response is governed by miR-2909 RNomics.
Kaul, D, Arora, M, Garg, A, Sharma, S
Molecular immunology. 2015;(1):210-7
Abstract
The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) has been widely recognized to play crucial role in lymphocyte activation, development and the generation of lymphomas through the modulation of innate and adaptive immune responses. Our results reported here provide evidence for the first time to support the view that MALT1 exerts its effect upon immune response involving genes coding for retinoic acid-inducible gene 1 (RIG1); interferon-β (IFN-β); apo-lipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G); IFN-γ; chemokine (C-C motif) ligand 5 (CCL5) and interleukin-17 (IL-17) through the initiation of cellular miR-2909 RNomics. This ensures sustained expression of specificity protein 1 (SP1)-dependent regulation of genes that in-turn governs MALT1 induced immune response. Based upon these results, a mechanistic-pathway is proposed that links the epigenomic-interplay between MALT1 and miR-2909.
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4.
Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases.
Sala-Rabanal, M, Yurtsever, Z, Berry, KN, Brett, TJ
Mediators of inflammation. 2015;:497387
Abstract
Chloride transport proteins play critical roles in inflammatory airway diseases, contributing to the detrimental aspects of mucus overproduction, mucus secretion, and airway constriction. However, they also play crucial roles in contributing to the innate immune properties of mucus and mucociliary clearance. In this review, we focus on the emerging novel roles for a chloride channel regulator (CLCA1), a calcium-activated chloride channel (TMEM16A), and two chloride exchangers (SLC26A4/pendrin and SLC26A9) in chronic inflammatory airway diseases.
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5.
Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells.
Rapoport, AP, Aqui, NA, Stadtmauer, EA, Vogl, DT, Xu, YY, Kalos, M, Cai, L, Fang, HB, Weiss, BM, Badros, A, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;(5):1355-65
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Abstract
PURPOSE Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells. EXPERIMENTAL DESIGN In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant. RESULTS T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%). CONCLUSIONS A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.
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Bone marrow of neuroblastoma patients shows downregulation of CXCL12 expression and presence of IFN signature.
Scaruffi, P, Morandi, F, Gallo, F, Stigliani, S, Parodi, S, Moretti, S, Bonassi, S, Fardin, P, Garaventa, A, Zanazzo, G, et al
Pediatric blood & cancer. 2012;(1):44-51
Abstract
BACKGROUND At diagnosis, children with neuroblastoma (NB) present with either localized or metastatic disease. Since the mechanisms responsible for BM invasion are not well known, we investigated the transcriptome of resident BM cells from NB patients as compared to healthy children. PROCEDURE Ninety-two and 88 children with localized and metastatic NB, respectively, and 15 healthy children were included in the study. BM resident cells recovered from BM aspirates by immunomagnetic bead manipulation were subjected to genome-wide microarray analysis. After validation in an independent set of samples, the genes significantly modulated in resident BM cells from NB patients were tested for their diagnostic/prognostic values. RESULTS BM resident cells, irrespective of neoplastic cell invasion, significantly overexpressed genes involved in innate immune responses, and interferon (IFN) and IFN-DRS signatures were enriched. Genes coding for metallothioneins and zinc finger proteins, and involved in histone and nucleosome/chromatin organization were also overexpressed. Resident BM cells from NB patients significantly downregulated genes involved in cell adhesion, and in erythrocyte, myeloid, and platelet differentiation pathways. Among downregulated genes, CXCL12 expression reached near complete silencing in patients with metastatic disease. The downregulation of CXCL12 expression was independent of contact between NB cell and resident BM cell. CONCLUSIONS We demonstrated that NB tumor growth at the primary site can alter the BM microenvironment, and the presence of BM-infiltrating NB cells makes the alterations more pronounced. Therefore, the restoration of a BM physiological state by means of IFN-α monoclonal antibody, Sifalimumab, and selective noradrenaline receptor blockers should be further studied to ameliorate patients' clinical management.
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Blood peptidome-degradome profile of breast cancer.
Shen, Y, Tolić, N, Liu, T, Zhao, R, Petritis, BO, Gritsenko, MA, Camp, DG, Moore, RJ, Purvine, SO, Esteva, FJ, et al
PloS one. 2010;(10):e13133
Abstract
BACKGROUND Cancer invasion and metastasis are closely associated with activities within the degradome; however, little is known about whether these activities can be detected in the blood of cancer patients. METHODOLOGY AND PRINCIPAL FINDINGS The peptidome-degradome profiles of pooled blood plasma sampled from 15 breast cancer patients (BCP) and age, race, and menopausal status matched control healthy persons (HP) were globally characterized using advanced comprehensive separations combined with tandem Fourier transform mass spectrometry and new data analysis approaches that facilitated top-down peptidomic analysis. The BCP pool displayed 71 degradome protein substrates that encompassed 839 distinct peptidome peptides. In contrast, the HP 50 degradome substrates found encompassed 425 peptides. We find that the ratios of the peptidome peptide relative abundances can vary as much as >4000 fold between BCP and HP. The experimental results also show differential degradation of substrates in the BCP sample in their functional domains, including the proteolytic and inhibitory sites of the plasmin-antiplasmin and thrombin-antithrombin systems, the main chains of the extracellular matrix protection proteins, the excessive degradation of innate immune system key convertases and membrane attack complex components, as well as several other cancer suppressor proteins. CONCLUSIONS Degradomics-peptidomics profiling of blood plasma is highly sensitive to changes not evidenced by conventional bottom-up proteomics and potentially provides unique signatures of possible diagnostic utility.
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[Ocular infiltrating CD 4+ T cells from patients with Vogt-Koyanagi-Harada disease recognize human melanocyte antigens].
Sugita, S
Nippon Ganka Gakkai zasshi. 2008;(11):953-64
Abstract
Vogt-Koyanagi-Harada (VKH) disease is a systemic disorder affecting systemic melanocytes including those in the eyes, meninges, ears, skin, and hair. Although the pathogenic mechanisms of the disease are still controversial, there is clinical and experimental evidence that the disease is an autoimmune disease involving melanocytes. In this study, we investigated whether patients with VKH disease have immune responses specific to melanocyte antigens, and whether T lymphocytes of these patients cross-react with peptides of melanocytes and with exogenous antigens. Cells infiltrating the eyes in HLA-DR 4+ patients with VKH contained a population of CD 4+ T lymphocytes that recognized tyrosinase and gp 100 peptides and produced cytokines in response to these two peptides. The CD 8+ T cells recognized the MART-1 melanocyte peptide, but not the CD 4+ T cells. When a search was made for molecular mimicry between melanocyte antigens and exogenous antigens by database screening, cytomegalovirus envelope glycoprotein H (CMV-egH) had high amino acid homology with the tyrosinase peptide. Some of the T cells taken from VKH patients recognized melanocyte peptides including the tyrosinase peptide as well as the CMV-egH290-302 peptide, which had a high amino acid homology to the tyrosinase peptide. CMV peptide-specific T cells showed significant proliferation in response not only to CMV-egH290-302, but also to tyrosinase450-462. The seroprevalence of CMV was significantly higher in VKH patients. In addition, all tested samples of VKH patients were negative for CMV-DNA. These results indicate that CMV infection may stimulate the production of T cells that crossreact with tyrosinase by molecular mimicry. These events may be responsible for the onset of VKH disease.
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A Comparison of 3 tumor markers (MIA, TA90IC, S100B) in stage III melanoma patients.
Faries, MB, Gupta, RK, Ye, X, Lee, C, Yee, R, Leopoldo, Z, Essner, R, Foshag, LJ, Elashoff, D, Morton, DL
Cancer investigation. 2007;(5):285-93
Abstract
PURPOSE There is no consensus regarding the optimal tumor markers for melanoma. We compared 3 tumor markers, TA90-immune complex (TA90IC), melanoma-inhibiting activity (MIA) protein, and S100B protein in Stage III melanoma patients undergoing adjuvant vaccine immunotherapy. EXPERIMENTAL DESIGN The serum of 75 patients representing 3 prognostic cohorts was assayed for the tumor markers prior to initiating immunotherapy and at 6 follow-up time points. Upper limits of normal for TA90IC, MIA and S100B were set at OD 0.41, 8.5 ng/ml, and 2.5 microg/l, respectively. RESULTS At least 1 marker became elevated prior to 41 (80 percent) of 51 recurrences. TA90IC was the earliest elevated marker in 29 (57 percent), MIA in 11 (22 percent), and S100B in 4 (8 percent). Multivariate regression analysis revealed that TA90IC was an independent predictor of survival when elevation occurred between 2 weeks and 3 months, whereas MIA was an independent predictor at 4-6 months. In the poor prognostic cohort, mean values for MIA and S100B increased progressively, whereas TA90IC exhibited a parabolic curve. CONCLUSION In this patient population, TA90IC and MIA were complementary; elevation of the immune complex preceded elevation of the tumor antigen in patients who developed recurrence. Additional studies in populations not receiving vaccine will further clarify the clinical utility of these assays.
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10.
Ex vivo detectable activation of Melan-A-specific T cells correlating with inflammatory skin reactions in melanoma patients vaccinated with peptides in IFA.
Liénard, D, Rimoldi, D, Marchand, M, Dietrich, PY, van Baren, N, Geldhof, C, Batard, P, Guillaume, P, Ayyoub, M, Pittet, MJ, et al
Cancer immunity. 2004;:4
Abstract
The purpose of this study was to test melanoma vaccines consisting of peptides and immunological adjuvants for optimal immunogenicity and to evaluate laboratory immune monitoring for in vivo relevance. Forty-nine HLA-A2 positive patients with Melan-A positive melanoma were repeatedly vaccinated with Melan-A peptide, with or without immune adjuvant AS02B (QS21 and MPL) or IFA. Peptide-specific CD8 T cells in PBLs were analyzed ex vivo using fluorescent HLA-A2/Melan-A multimers and IFN-gamma ELISPOT assays. The vaccines were well tolerated. In vivo expansion of Melan-A-specific CD8 T cells was observed in 13 patients (1/12 after vaccination with peptide in AS02B and 12/17 after vaccination with peptide in IFA). The T cells produced IFN-gamma and downregulated CD45RA and CD28. T-cell responses correlated with inflammatory skin reactions at vaccine injection sites (P < 0.001) and with DTH reaction to Melan-A peptide (P < 0.01). Twenty-six of 32 evaluable patients showed progressive disease, whereas 4 patients had stable disease. The two patients with the strongest Melan-A-specific T-cell responses experienced regression of metastases in skin, lymph nodes, and lung. We conclude that repeated vaccination with Melan-A peptide in IFA frequently leads to sustained responses of specific CD8 T cells that are detectable ex vivo and correlate with inflammatory skin reactions.