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Li S, Liu J, Peyton M, Lazaro O, McCabe SD, Huang X, Liu Y, Shi Z, Zhang Z, Walker BA, Johnson TS. Multiple Myeloma Insights from Single-Cell Analysis: Clonal Evolution, the Microenvironment, Therapy Evasion, and Clinical Implications. Cancers (Basel) 2025; 17:653. [PMID: 40002248 PMCID: PMC11852428 DOI: 10.3390/cancers17040653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/05/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Multiple myeloma (MM) is a complex and heterogeneous hematologic malignancy characterized by clonal evolution, genetic instability, and interactions with a supportive tumor microenvironment. These factors contribute to treatment resistance, disease progression, and significant variability in clinical outcomes among patients. This review explores the mechanisms underlying MM progression, including the genetic and epigenetic changes that drive clonal evolution, the role of the bone marrow microenvironment in supporting tumor growth and immune evasion, and the impact of genomic instability. We highlight the critical insights gained from single-cell technologies, such as single-cell transcriptomics, genomics, and multiomics, which have enabled a detailed understanding of MM heterogeneity at the cellular level, facilitating the identification of rare cell populations and mechanisms of drug resistance. Despite the promise of advanced technologies, MM remains an incurable disease and challenges remain in their clinical application, including high costs, data complexity, and the need for standardized bioinformatics and ethical considerations. This review emphasizes the importance of continued research and collaboration to address these challenges, ultimately aiming to enhance personalized treatment strategies and improve patient outcomes in MM.
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Affiliation(s)
- Sihong Li
- Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | - Jiahui Liu
- Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | - Madeline Peyton
- Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Regenstrief Institute, Indianapolis, IN 46202, USA
| | - Olivia Lazaro
- Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA
| | - Sean D. McCabe
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | - Xiaoqing Huang
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA
| | - Yunlong Liu
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN 46202, USA
| | - Zanyu Shi
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA
| | - Zhiqi Zhang
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | - Brian A. Walker
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN 46202, USA
| | - Travis S. Johnson
- Indiana Bioscience Research Institute, Indianapolis, IN 46202, USA
- School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN 46202, USA
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Zahedi H, Jowshan MR, Rasekhi H, Amini M, Sadeghi O, Mehdizadeh M, Parkhideh S, Payab M, Zamani E, Shadnoush M, Hajifathali A. The association between the dietary inflammatory index and multiple myeloma: a case-control study. Sci Rep 2025; 15:3123. [PMID: 39856166 PMCID: PMC11759680 DOI: 10.1038/s41598-025-87494-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025] Open
Abstract
The dietary inflammatory index (DII) is a common grading system for diet inflammatory potential. Recent investigations link DII to hematopoietic malignancies. However, the relationship between DII and Multiple myeloma (MM) is unknown. DII and MM were examined in a present case-control study of Iranian adults. This case-controlstudy was conducted on adults aged 20 to 75 years, selecting 149 cases with newly diagnosed multiple myeloma and 359 healthy individuals. Dietary assessment was conducted using a validated semi-quantitative food frequency questionnaire (FFQ) including 154 items, and energy-adjusted DII scores were calculated to determine the level of inflammatory properties in each individual's diet using 29 dietary parameters. Conditional logistic regression models were used to investigate the relationship between DII and MM. The case group participating in the study was on average 54 years old and mostly male (52.3%). After adjusting for age, sex, and energy intake, we found that individuals with the highest DII scores were significantly less likely to have MM compared to those with the lowest scores (OR: 0.02; 95% CI 0.01, 0.08). Additional adjustment with other confounders confirmed this association (OR: 0.03; 95% CI 0.01, 0.13). This association did not change significantly with further adjustment for BMI (OR: 0.04; 95% CI 0.01, 0.14). In conclusion, our research showed that a pro-inflammatory diet was associated with a significantly higher risk of MM. If our findings are confirmed in other large studies, these data will provide personalized approaches for MM patients, particularly for physicians and registered cancer dietitians.
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Affiliation(s)
- Hoda Zahedi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Jowshan
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Rasekhi
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Amini
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Omid Sadeghi
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahshid Mehdizadeh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sayeh Parkhideh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Zamani
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Shadnoush
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Xiang Q, Li L, Ji W, Gawlitta D, Walboomers XF, van den Beucken JJJP. Beyond resorption: osteoclasts as drivers of bone formation. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:22. [PMID: 39392536 PMCID: PMC11469995 DOI: 10.1186/s13619-024-00205-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024]
Abstract
Emerging evidence illustrates that osteoclasts (OCs) play diverse roles beyond bone resorption, contributing significantly to bone formation and regeneration. Despite this, OCs remain mysterious cells, with aspects of their lifespan-from origin, fusion, alterations in cellular characteristics, to functions-remaining incompletely understood. Recent studies have identified that embryonic osteoclastogenesis is primarily driven by osteoclast precursors (OCPs) derived from erythromyeloid progenitors (EMPs). These precursor cells subsequently fuse into OCs essential for normal bone development and repair. Postnatally, hematopoietic stem cells (HSCs) become the primary source of OCs, gradually replacing EMP-derived OCs and assuming functional roles in adulthood. The absence of OCs during bone development results in bone structure malformation, including abnormal bone marrow cavity formation and shorter long bones. Additionally, OCs are reported to have intimate interactions with blood vessels, influencing bone formation and repair through angiogenesis regulation. Upon biomaterial implantation, activation of the innate immune system ensues immediately. OCs, originating from macrophages, closely interact with the immune system. Furthermore, evidence from material-induced bone formation events suggests that OCs are pivotal in these de novo bone formation processes. Nevertheless, achieving a pure OC culture remains challenging, and interpreting OC functions in vivo faces difficulties due to the presence of other multinucleated cells around bone-forming biomaterials. We here describe the fusion characteristics of OCPs and summarize reliable markers and morphological changes in OCs during their fusion process, providing guidance for researchers in identifying OCs both in vitro and in vivo. This review focuses on OC formation, characterization, and the roles of OCs beyond resorption in various bone pathophysiological processes. Finally, therapeutic strategies targeting OCs are discussed.
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Affiliation(s)
- Qianfeng Xiang
- Radboudumc, Dentistry - Regenerative Biomaterials, Philips Van Leijdenlaan 25, Nijmegen, 6525EX, the Netherlands
| | - Lei Li
- Radboudumc, Dentistry - Regenerative Biomaterials, Philips Van Leijdenlaan 25, Nijmegen, 6525EX, the Netherlands
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wei Ji
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Debby Gawlitta
- Department of Oral and Maxillofacial Surgery & Special Dental Care, University Medical Center Utrecht, Utrecht University, Utrecht, GA, 3508, The Netherlands
- Regenerative Medicine Center Utrecht, Utrecht, CT, 3584, The Netherlands
| | - X Frank Walboomers
- Radboudumc, Dentistry - Regenerative Biomaterials, Philips Van Leijdenlaan 25, Nijmegen, 6525EX, the Netherlands
- Research Institute for Medical Innovation, Radboudumc, Nijmegen, the Netherlands
| | - Jeroen J J P van den Beucken
- Radboudumc, Dentistry - Regenerative Biomaterials, Philips Van Leijdenlaan 25, Nijmegen, 6525EX, the Netherlands.
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de Jong MME, Chen L, Raaijmakers MHGP, Cupedo T. Bone marrow inflammation in haematological malignancies. Nat Rev Immunol 2024:10.1038/s41577-024-01003-x. [PMID: 38491073 DOI: 10.1038/s41577-024-01003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2024] [Indexed: 03/18/2024]
Abstract
Tissue inflammation is a hallmark of tumour microenvironments. In the bone marrow, tumour-associated inflammation impacts normal niches for haematopoietic progenitor cells and mature immune cells and supports the outgrowth and survival of malignant cells residing in these niche compartments. This Review provides an overview of our current understanding of inflammatory changes in the bone marrow microenvironment of myeloid and lymphoid malignancies, using acute myeloid leukaemia and multiple myeloma as examples and highlights unique and shared features of inflammation in niches for progenitor cells and plasma cells. Importantly, inflammation exerts profoundly different effects on normal bone marrow niches in these malignancies, and we provide context for possible drivers of these divergent effects. We explore the role of tumour cells in inflammatory changes, as well as the role of cellular constituents of normal bone marrow niches, including myeloid cells and stromal cells. Integrating knowledge of disease-specific dynamics of malignancy-associated bone marrow inflammation will provide a necessary framework for future targeting of these processes to improve patient outcome.
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Affiliation(s)
- Madelon M E de Jong
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Lanpeng Chen
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | | | - Tom Cupedo
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
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Khilwani R, Singh S. Traversing through the Mechanistic Event Analysis in IL-6 and IL-17 Signaling for a New Therapeutic Paradigm in NSCLC. Int J Mol Sci 2024; 25:1216. [PMID: 38279220 PMCID: PMC10816370 DOI: 10.3390/ijms25021216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/28/2024] Open
Abstract
IL-6 and IL-17 are paradoxical cytokines that progress inflammatory states in chronic diseases, including cancer. In lung cancer, their role has been elucidated to favor cancer development by modulating signaling mechanisms critical to cellular growth. The intrinsic ability of these cytokines to influence macroautophagy is yet another reason to facilitate lung cancer. Here, we employed a systems immunology approach to discover the mechanistic role of these cytokines in cancer development. In a biological system, at later stages, the activation of NFkB stimulates immunosuppressive phenotypes to achieve tolerating effects in a transformed cell. We found that the upregulation of cytokines signaled M2 macrophages to modulate tumor responses through the activation of autophagic intermediates and inflammasome mediators. This caused immune perturbations in the tumor microenvironment, which were associated with cancer inflammation. To address these inflammatory states, we performed triggered event analysis to examine whether overexpressing immune effectors or downregulating immune suppressors may have an effect on cancer reversal. Interestingly, the inhibition of immune regulators opposed the model outcome to an increased immune response. Therefore, IL6-IL17-mediated regulation of lung cancer may address tumor malignancy and potentiate the development of newer therapeutics for NSCLC.
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Affiliation(s)
| | - Shailza Singh
- Systems Medicine Laboratory, National Centre for Cell Science, NCCS Complex, Ganeshkhind, SPPU Campus, Pune 411007, India;
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Khan M, Sharma A, Sharma A, Singh G, Khan S, Ahmad S, Alrashidi AAM, Sherwani S, Mishra H, Alsulimani A. The effect of non-surgical periodontal therapy on salivary IL-6 levels in patients with moderate to severe generalized chronic periodontitis. Ir J Med Sci 2023; 192:2981-2986. [PMID: 36869249 DOI: 10.1007/s11845-023-03325-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 02/22/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND Gene regulation of IL-6 is characterized by the presence of inflammatory cytokines, bacterial products, viral infection, and activation of the diacylglycerol-, cyclic AMP-, or Ca + + -activated signal transduction pathways. AIM Scaling and root planning (SRP), a non-surgical periodontal therapy, was studied in connection to several clinical parameters for its effect on salivary IL-6 levels in patients with generalized chronic periodontitis. METHODS For this study, a total of 60 GCP patients were included. Plaque index (PI), gingival index (GI), pocket probing depth (PPD), bleeding on probing percentage (BOP%), and clinical attachment loss were among the clinical indicators covered (CAL). RESULTS Following SRP, mean IL-6 levels in patients with GCP were significantly higher in the pre-treatment group (2.93 5.17 pg/ml; p 0.05) than in the posttreatment group (5.78 8.26 pg/ml; baseline). Pre- and post-treatment IL-6 levels for PI (pre), BOP percent (pre/post), GI (post), and PPD were found to be positively correlated (post). In patients with GCP, the study showed a statistically significant correlation between periodontal metrics and salivary IL-6. CONCLUSIONS Changes in periodontal indices and IL-6 levels that are statistically significant over time indicate that non-surgical treatment is effective, and IL-6 can be regarded as a potent disease activity marker.
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Affiliation(s)
- Mahvish Khan
- Department of Biology, College of Science, Ha'il University, Ha'il, 2440, Saudi Arabia
| | - Anamika Sharma
- Department of Dentistry, LLRM Medical College, CCS University Meerut, Uttar Pradesh, India.
| | - Ananya Sharma
- Department of Dentistry, LLRM Medical College, CCS University Meerut, Uttar Pradesh, India
| | - Ganesh Singh
- Department of Community Medicine, LLRM Medical College, CCS University Meerut, Uttar Pradesh, India
| | - Saif Khan
- Department of Basic Dental and Medical sciences, College of Dentistry, Ha'il University, Ha'il, 2440, Saudi Arabia
| | - Saheem Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of , Hail, Saudi Arabia
| | | | - Subuhi Sherwani
- Department of Biology, College of Science, Ha'il University, Ha'il, 2440, Saudi Arabia
| | - Hemlata Mishra
- Kailash Hospital, Sector-27, Noida, Uttar Pradesh, India
| | - Ahmad Alsulimani
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Jazan University, Jazan, 45142, Saudi Arabia
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Kulkarni A, Bazou D, Santos-Martinez MJ. Bleeding and Thrombosis in Multiple Myeloma: Platelets as Key Players during Cell Interactions and Potential Use as Drug Delivery Systems. Int J Mol Sci 2023; 24:15855. [PMID: 37958838 PMCID: PMC10647631 DOI: 10.3390/ijms242115855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/25/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy originated in the bone marrow and characterized by unhindered plasma cell proliferation that results in several clinical manifestations. Although the main role of blood platelets lies in hemostasis and thrombosis, platelets also play a pivotal role in a number of other pathological conditions. Platelets are the less-explored components from the tumor microenvironment in MM. Although some studies have recently revealed that MM cells have the ability to activate platelets even in the premalignant stage, this phenomenon has not been widely investigated in MM. Moreover, thrombocytopenia, along with bleeding, is commonly observed in those patients. In this review, we discuss the hemostatic disturbances observed in MM patients and the dynamic interaction between platelets and myeloma cells, along with present and future potential avenues for the use of platelets for diagnostic and therapeutic purposes.
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Affiliation(s)
- Anushka Kulkarni
- The School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, The University of Dublin, D02 PN40 Dublin, Ireland;
| | - Despina Bazou
- School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland;
| | - Maria José Santos-Martinez
- The School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, The University of Dublin, D02 PN40 Dublin, Ireland;
- School of Medicine, Trinity College Dublin, D02 R590 Dublin, Ireland
- Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland
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Diedrich JD, Cole CE, Pianko MJ, Colacino JA, Bernard JJ. Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival. Cancers (Basel) 2023; 15:5255. [PMID: 37958428 PMCID: PMC10649826 DOI: 10.3390/cancers15215255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors-monoclonal gammopathy of undetermined significance-and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor-adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured by CYP1A1 and CYP1B1 gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reduced CYP1B1 expression and increased cellular growth. This tumor-suppressing role of CYP1A1 and CYP1B1 was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression.
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Affiliation(s)
- Jonathan D. Diedrich
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA;
| | - Craig E. Cole
- Department of Medicine, Division of Hematology/Oncology, Michigan State University, East Lansing, MI 48910, USA;
- Karmanos Cancer Institute, McLaren Greater Lansing, Lansing, MI 48910, USA
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Matthew J. Pianko
- Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Justin A. Colacino
- Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI 48109, USA;
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jamie J. Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA;
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
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Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol 2023; 23:666-681. [PMID: 37069261 PMCID: PMC10108826 DOI: 10.1038/s41577-023-00856-y] [Citation(s) in RCA: 168] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2023] [Indexed: 04/19/2023]
Abstract
Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling - known as cluster signalling - involves preformed complexes of membrane-bound IL-6-mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.
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Affiliation(s)
- Stefan Rose-John
- Biochemical Institute, Medical Faculty, Christian-Albrechts-University, Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Christoph Garbers
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GC:I3), Otto-von-Guericke-University, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
| | - Jens M Moll
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
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10
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Forster S, Radpour R, Ochsenbein AF. Molecular and immunological mechanisms of clonal evolution in multiple myeloma. Front Immunol 2023; 14:1243997. [PMID: 37744361 PMCID: PMC10516567 DOI: 10.3389/fimmu.2023.1243997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.
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Affiliation(s)
- Stefan Forster
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ramin Radpour
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Adrian F. Ochsenbein
- Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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Jigoranu RA, Roca M, Costache AD, Mitu O, Oancea AF, Miftode RS, Haba MȘC, Botnariu EG, Maștaleru A, Gavril RS, Trandabat BA, Chirica SI, Haba RM, Leon MM, Costache II, Mitu F. Novel Biomarkers for Atherosclerotic Disease: Advances in Cardiovascular Risk Assessment. Life (Basel) 2023; 13:1639. [PMID: 37629496 PMCID: PMC10455542 DOI: 10.3390/life13081639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Atherosclerosis is a significant health concern with a growing incidence worldwide. It is directly linked to an increased cardiovascular risk and to major adverse cardiovascular events, such as acute coronary syndromes. In this review, we try to assess the potential diagnostic role of biomarkers in the early identification of patients susceptible to the development of atherosclerosis and other adverse cardiovascular events. We have collected publications concerning already established parameters, such as low-density lipoprotein cholesterol (LDL-C), as well as newer markers, e.g., apolipoprotein B (apoB) and the ratio between apoB and apoA. Additionally, given the inflammatory nature of the development of atherosclerosis, high-sensitivity c-reactive protein (hs-CRP) or interleukin-6 (IL-6) are also discussed. Additionally, newer publications on other emerging components linked to atherosclerosis were considered in the context of patient evaluation. Apart from the already in-use markers (e.g., LDL-C), emerging research highlights the potential of newer molecules in optimizing the diagnosis of atherosclerotic disease in earlier stages. After further studies, they might be fully implemented in the screening protocols.
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Affiliation(s)
- Raul-Alexandru Jigoranu
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Department of Cardiology, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Mihai Roca
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Alexandru-Dan Costache
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Ovidiu Mitu
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Department of Cardiology, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Alexandru-Florinel Oancea
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Department of Cardiology, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Radu-Stefan Miftode
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Department of Cardiology, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Mihai Ștefan Cristian Haba
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Department of Cardiology, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Eosefina Gina Botnariu
- Department of Internal Medicine II, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania;
- Department of Diabetes, Nutrition and Metabolic Diseases, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Alexandra Maștaleru
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Radu-Sebastian Gavril
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Bogdan-Andrei Trandabat
- Department of Surgery II, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania;
- Department of Orthopedics and Trauma, Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Sabina Ioana Chirica
- Faculty of General Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (S.I.C.); (R.M.H.)
| | - Raluca Maria Haba
- Faculty of General Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (S.I.C.); (R.M.H.)
| | - Maria Magdalena Leon
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Irina-Iuliana Costache
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Department of Cardiology, “St. Spiridon” Emergency County Hospital, 700111 Iasi, Romania
| | - Florin Mitu
- Department of Medical Specialties I, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iasi, Romania; (R.-A.J.); (O.M.); (A.-F.O.); (R.-S.M.); (M.Ș.C.H.); (A.M.); (R.-S.G.); (M.M.L.); (I.-I.C.); (F.M.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania
- Romanian Academy of Medical Sciences, 030167 Bucharest, Romania
- Romanian Academy of Scientists, 050045 Bucharest, Romania
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12
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Krishnan SR, Bebawy M. Circulating biosignatures in multiple myeloma and their role in multidrug resistance. Mol Cancer 2023; 22:79. [PMID: 37120508 PMCID: PMC10148481 DOI: 10.1186/s12943-022-01683-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 11/14/2022] [Indexed: 05/01/2023] Open
Abstract
A major obstacle to chemotherapeutic success in cancer treatment is the development of drug resistance. This occurs when a tumour fails to reduce in size after treatment or when there is clinical relapse after an initial positive response to treatment. A unique and serious type of resistance is multidrug resistance (MDR). MDR causes the simultaneous cross resistance to unrelated drugs used in chemotherapy. MDR can be acquired through genetic alterations following drug exposure, or as discovered by us, through alternative pathways mediated by the transfer of functional MDR proteins and nucleic acids by extracellular vesicles (M Bebawy V Combes E Lee R Jaiswal J Gong A Bonhoure GE Grau, 23 9 1643 1649, 2009).Multiple myeloma is an incurable cancer of bone marrow plasma cells. Treatment involves high dose combination chemotherapy and patient response is unpredictable and variable due to the presence of multisite clonal tumour infiltrates. This clonal heterogeneity can contribute to the development of MDR. There is currently no approved clinical test for the minimally invasive testing of MDR in myeloma.Extracellular vesicles comprise a group of heterogeneous cell-derived membranous structures which include; exosomes, microparticles (microvesicles), migrasomes and apoptotic bodies. Extracellular vesicles serve an important role in cellular communication through the intercellular transfer of cellular protein, nucleic acid and lipid cargo. Of these, microparticles (MPs) originate from the cell plasma membrane and vary in size from 0.1-1um. We have previously shown that MPs confer MDR through the transfer of resistance proteins and nucleic acids. A test for the early detection of MDR would benefit clinical decision making, improve survival and support rational drug use. This review focuses on microparticles as novel clinical biomarkers for the detection of MDR in Myeloma and discusses their role in the therapeutic management of the disease.
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13
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Marques-Mourlet C, Di Iorio R, Fairfield H, Reagan MR. Obesity and myeloma: Clinical and mechanistic contributions to disease progression. Front Endocrinol (Lausanne) 2023; 14:1118691. [PMID: 36909335 PMCID: PMC9996186 DOI: 10.3389/fendo.2023.1118691] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/02/2023] [Indexed: 02/25/2023] Open
Abstract
Obesity and obesogenic behaviors are positively associated with both monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM). As the only known modifiable risk factor, this association has emerged as a new potential target for MM prevention, but little is known about the mechanistic relationship of body weight with MM progression. Here we summarize epidemiological correlations between weight, body composition, and the various stages of myeloma disease progression and treatments, as well as the current understanding of the molecular contributions of obesity-induced changes in myeloma cell phenotype and signaling. Finally, we outline groundwork for the future characterization of the relationship between body weight patterns, the bone marrow microenvironment, and MM pathogenesis in animal models, which have the potential to impact our understanding of disease pathogenesis and inform MM prevention messages.
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Affiliation(s)
- Constance Marques-Mourlet
- MaineHealth Institute for Research, Center for Molecular Medicine, Scarborough, ME, United States
- University of Strasbourg, Pharmacology Department, Strasbourg, France
| | - Reagan Di Iorio
- MaineHealth Institute for Research, Center for Molecular Medicine, Scarborough, ME, United States
- University of New England, College of Osteopathic Medicine, Biddeford, ME, United States
| | - Heather Fairfield
- MaineHealth Institute for Research, Center for Molecular Medicine, Scarborough, ME, United States
- University of Maine, Graduate School of Biomedical Science and Engineering, Orono, ME, United States
- Tufts University, School of Medicine, Boston, MA, United States
| | - Michaela R. Reagan
- MaineHealth Institute for Research, Center for Molecular Medicine, Scarborough, ME, United States
- University of Maine, Graduate School of Biomedical Science and Engineering, Orono, ME, United States
- Tufts University, School of Medicine, Boston, MA, United States
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14
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Aksoy O, Lind J, Sunder-Plaßmann V, Vallet S, Podar K. Bone marrow microenvironment- induced regulation of Bcl-2 family members in multiple myeloma (MM): Therapeutic implications. Cytokine 2023; 161:156062. [PMID: 36332463 DOI: 10.1016/j.cyto.2022.156062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/19/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022]
Abstract
In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today's most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.
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Affiliation(s)
- Osman Aksoy
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Judith Lind
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Vincent Sunder-Plaßmann
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Sonia Vallet
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria
| | - Klaus Podar
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria.
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15
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de Gruijter NM, Jebson B, Rosser EC. Cytokine production by human B cells: role in health and autoimmune disease. Clin Exp Immunol 2022; 210:253-262. [PMID: 36179248 PMCID: PMC9985175 DOI: 10.1093/cei/uxac090] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/01/2022] [Accepted: 09/29/2022] [Indexed: 02/06/2023] Open
Abstract
B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. Indeed, similarly to T cells, there is significant heterogeneity in cytokine-driven responses by B cells, ranging from the production of pro-inflammatory effector cytokines such as IL-6, through to the release of immunosuppressive cytokines such as IL-10. In this review, focusing on human B cells, we summarize the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases.
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Affiliation(s)
- Nina M de Gruijter
- Centre for Adolescent Rheumatology Versus Arthritis at University College London, University College London Hospital and Great Ormond Street Hospital, London, UK
- Centre for Rheumatology Research, Division of Medicine, University College London, London, UK
| | - Bethany Jebson
- Centre for Adolescent Rheumatology Versus Arthritis at University College London, University College London Hospital and Great Ormond Street Hospital, London, UK
- University College London Great Ormond Street Institute of Child Health, London, UK
| | - Elizabeth C Rosser
- Centre for Adolescent Rheumatology Versus Arthritis at University College London, University College London Hospital and Great Ormond Street Hospital, London, UK
- Centre for Rheumatology Research, Division of Medicine, University College London, London, UK
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16
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Miller CL, Madsen JC. Targeting IL-6 to prevent cardiac allograft rejection. Am J Transplant 2022; 22 Suppl 4:12-17. [PMID: 36453706 PMCID: PMC10191185 DOI: 10.1111/ajt.17206] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/28/2022] [Accepted: 10/04/2022] [Indexed: 12/05/2022]
Abstract
Outcomes following heart transplantation remain suboptimal with acute and chronic rejection being major contributors to poor long-term survival. IL-6 is increasingly recognized as a critical pro-inflammatory cytokine involved in allograft injury and has been shown to play a key role in regulating the inflammatory and alloimmune responses following heart transplantation. Therapies that inhibit IL-6 signaling have emerged as promising strategies to prevent allograft rejection. Here, we review experimental and pre-clinical evidence that supports the potential use of IL-6 signaling blockade to improve outcomes in heart transplant recipients.
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Affiliation(s)
- Cynthia L. Miller
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Joren C. Madsen
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
- Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
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17
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Nickerson PW. Rationale for the IMAGINE study for chronic active antibody-mediated rejection (caAMR) in kidney transplantation. Am J Transplant 2022; 22 Suppl 4:38-44. [PMID: 36453707 DOI: 10.1111/ajt.17210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 10/19/2022] [Indexed: 12/02/2022]
Abstract
Chronic active antibody-mediated rejection (caAMR) in kidney transplantation is a major cause of late graft loss and despite all efforts to date, there is no proven effective therapy. Indeed, the Transplant Society (TTS) consensus opinion called for a conservative approach optimizing baseline immunosuppression and supportive care focused on blood pressure, blood glucose, and lipid control. This review provides the rationale and early evidence in kidney transplant recipients with caAMR that supported the design of the IMAGINE study whose goal is to evaluate the potential impact of targeting the IL6/IL6R pathway.
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Affiliation(s)
- Peter W Nickerson
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.,Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
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18
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Beck S, Shin D, Kim SJ, Hedde PN, Zhao W. Digital Protein Detection in Bulk Solutions. ACS OMEGA 2022; 7:37714-37723. [PMID: 36312374 PMCID: PMC9608401 DOI: 10.1021/acsomega.2c04666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 09/21/2022] [Indexed: 06/16/2023]
Abstract
Quick and accurate molecular diagnostics in protein detection can greatly benefit medicine in disease diagnosis and lead to positive patient outcomes. However, specialized equipment used in clinical laboratories often comes with trade-offs between operation and function serving a single role for very specific needs. For example, to achieve high analytical sensitivity and specificity, instruments such as high-performance liquid chromatography and/or liquid chromatography-mass spectrometry use a complex instrument design and require thorough training of the users. On the other hand, simple tests such as protein detection in urinary tract infection using dip-stick assays provide very quick results but suffer from poor analytical sensitivity. Here, we present an application study for the 3D particle counter technology, which is based on optical confocal detection in order to scan large sample volumes (0.5-3 mL) in glass cuvettes, that aims to close the gap between analytical sensitivity and turnover assay time and simplify protein detection by adopting bead-based immunoassays. Combining the 3D particle counter technology with bead-based immunoassays, a subpicomolar limit of detection-ranging from 119 to 346 fM-was achieved within 3.5-hour assay time for recombinant mouse interleukin 6 detection. As an alternative instrument to a flow cytometer, the 3D particle counter takes advantages of bead-based immunoassays and provides unique accessibility and flexibility for users.
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Affiliation(s)
- Sungjun Beck
- Department
of Biological Chemistry, University of California,
Irvine, Irvine, California 92697, United States
| | - Donghae Shin
- Department
of Biological Chemistry, University of California,
Irvine, Irvine, California 92697, United States
| | - Sun Jin Kim
- Department
of Pharmaceutical Sciences, University of
California, Irvine, Irvine, California 92697, United States
| | - Per Niklas Hedde
- Department
of Pharmaceutical Sciences, University of
California, Irvine, Irvine, California 92697, United States
- Laboratory
for Fluorescence Dynamics, University of
California, Irvine, Irvine, California 92697, United States
- Beckman
Laser Institute & Medical Clinic, University
of California, Irvine, Irvine, California 92697, United States
| | - Weian Zhao
- Department
of Biological Chemistry, University of California,
Irvine, Irvine, California 92697, United States
- Department
of Pharmaceutical Sciences, University of
California, Irvine, Irvine, California 92697, United States
- Institute
for Immunology, University of California,
Irvine, Irvine, California 92697, United States
- Sue and Bill
Gross Stem Cell Research Center, University
of California, Irvine, Irvine, California 92697, United States
- Chao
Family Comprehensive Cancer Center, University
of California, Irvine, Irvine, California 92697, United States
- Edwards
Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, California 92697, United States
- Department
of Biomedical Engineering, University of
California, Irvine, Irvine, California 92697, United States
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19
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COVID-19 vs. Cancer Immunosurveillance: A Game of Thrones within an Inflamed Microenviroment. Cancers (Basel) 2022; 14:cancers14174330. [PMID: 36077865 PMCID: PMC9455004 DOI: 10.3390/cancers14174330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The COVID-19 pandemic accounts for more than 500 million confirmed infections and over 6 million deaths worldwide in the last 2 years. SARS-CoV-2 causes a highly complex form of inflammation that affects the human organism both acutely and chronically. In the same line, cancer as an inflammation-induced and immune-editing disease appears to cross-react with immune system at different levels including early interactions during carcinogenesis and later cross-talks within the tumor microenvironment. With all that in mind, a reasonable question one might address is whether the SARS-CoV-2 infection and the derived "long lasting inflammatory status" that is frequently observed in patients, might affect the cancer immunosurveillance mechanisms and consequently their risk of developing cancer, as well as the tumor and immune cell behaviors within the inflamed microenvironment. On this context, this review intends to outline and discuss the existing knowledge on SARS-CoV-2-mediated immunomodulation under the prism of changes that might be able to interfere with cancer cell immunoescape and the overall tumor progression and response to conventional therapeutics. Our goal is to highlight a potential interplay between the COVID-19 immunopathology and cancer immune-microenvironment that may pave the way for thorough investigation in the future.
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20
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Russo S, Scotto di Carlo F, Gianfrancesco F. The Osteoclast Traces the Route to Bone Tumors and Metastases. Front Cell Dev Biol 2022; 10:886305. [PMID: 35646939 PMCID: PMC9139841 DOI: 10.3389/fcell.2022.886305] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/24/2022] [Indexed: 12/31/2022] Open
Abstract
Osteoclasts are highly specialized cells of the bone, with a unique apparatus responsible for resorption in the process of bone remodeling. They are derived from differentiation and fusion of hematopoietic precursors, committed to form mature osteoclasts in response to finely regulated stimuli produced by bone marrow-derived cells belonging to the stromal lineage. Despite a highly specific function confined to bone degradation, emerging evidence supports their relevant implication in bone tumors and metastases. In this review, we summarize the physiological role of osteoclasts and then focus our attention on their involvement in skeletal tumors, both primary and metastatic. We highlight how osteoclast-mediated bone erosion confers increased aggressiveness to primary tumors, even those with benign features. We also outline how breast and pancreas cancer cells promote osteoclastogenesis to fuel their metastatic process to the bone. Furthermore, we emphasize the role of osteoclasts in reactivating dormant cancer cells within the bone marrow niches for manifestation of overt metastases, even decades after homing of latent disseminated cells. Finally, we point out the importance of counteracting tumor progression and dissemination through pharmacological treatments based on a better understanding of molecular mechanisms underlying osteoclast lytic activity and their recruitment from cancer cells.
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Affiliation(s)
| | | | - Fernando Gianfrancesco
- Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research Council of Italy, Naples, Italy
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21
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Zhang X, Yang J, Chen S, Liu C, Wang Z, Ren H, Zhou L. Pre-existing hypertension is associated with poor progression-free survival in newly diagnosed multiple myeloma patients. J Thromb Thrombolysis 2022; 54:542-549. [PMID: 35445377 DOI: 10.1007/s11239-022-02653-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2022] [Indexed: 11/29/2022]
Abstract
Approximately 31% of patients diagnosed with multiple myeloma (MM) have pre-existing hypertension, but its effects on patient survival have not been investigated. We collected data from 228 newly diagnosed patients with MM and found that 71 (31.1%) had pre-existing hypertension. The impact of pre-existing hypertension on MM patients was determined by evaluating progression-free survival (PFS). Kaplan-Meier analyses revealed a significantly lower PFS in the pre-existing hypertension group than their non-hypertensive counterparts (median 22.6 vs 34.8 months, respectively). The multivariable Cox proportional hazards model showed that pre-existing hypertension was an independent risk factor for PFS reduction in MM patients. Moreover, the risk of disease progression in MM patients with pre-existing hypertension was higher than in non-hypertension comparator patients (hazard ratio 1.735, 95% confidence interval 1.261-2.387). In MM patients with pre-existing hypertension, Kaplan-Meier analyses found that those with a higher risk of hypertension had a significantly shorter PFS than those with lower risk (median 19.3 vs 25.4 months, respectively). However, multivariate Cox regression analysis showed that the risk stratification of hypertension was not an independent risk factor for poor PFS in MM patients with pre-existing hypertension. Our study demonstrates that pre-existing hypertension was significantly associated with a lower PFS in newly diagnosed MM patients.
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Affiliation(s)
- Xiaomin Zhang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Jieli Yang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Sai Chen
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Chang Liu
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Zhenhua Wang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Hefei Ren
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Lin Zhou
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
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22
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Kishimoto T, Kang S. IL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19. Annu Rev Immunol 2022; 40:323-348. [PMID: 35113729 DOI: 10.1146/annurev-immunol-101220-023458] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The diverse biological activity of interleukin-6 (IL-6) contributes to the maintenance of homeostasis. Emergent infection or tissue injury induces rapid production of IL-6 and activates host defense through augmentation of acute-phase proteins and immune responses. However, excessive IL-6 production and uncontrolled IL-6 receptor signaling are critical to pathogenesis. Over the years, therapeutic agents targeting IL-6 signaling, such as tocilizumab, a humanized anti-IL-6 receptor antibody, have shown remarkable efficacy for rheumatoid arthritis, Castleman disease, and juvenile idiopathic arthritis, and their efficacy in other diseases is continually being reported. Emerging evidence has demonstrated the benefit of tocilizumab for several types of acute inflammatory diseases, including cytokine storms induced by chimeric antigen receptor T-cell therapy and coronavirus disease 2019 (COVID-19). Here, we refocus attention on the biology of IL-6 and summarize the distinct pathological roles of IL-6 signaling in several acute and chronic inflammatory diseases. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Tadamitsu Kishimoto
- Laboratory of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; ,
| | - Sujin Kang
- Laboratory of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; ,
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23
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Marinac CR, Lee DH, Colditz GA, Rebbeck TR, Rosner B, Bustoros M, Ghobrial IM, Birmann BM. Regular Aspirin Use and Mortality in Multiple Myeloma Patients. Cancer Epidemiol Biomarkers Prev 2021; 31:479-485. [PMID: 34862208 DOI: 10.1158/1055-9965.epi-21-0946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/20/2021] [Accepted: 11/30/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Inflammation is important in multiple myeloma (MM) pathogenesis, and regular aspirin use has been shown to confer a reduced risk of MM. The influence of aspirin on survival after MM diagnosis is unknown. METHODS We identified 436 men and women diagnosed with MM between 1980 and 2016 in the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS) who reported aspirin intake biennially on follow-up questionnaires. Using multivariable Cox proportional hazards regression models, we estimated hazard ratios (HR) and 95% confidence intervals (CI) associated with aspirin use on MM-specific and overall mortality. RESULTS Compared with nonusers, participants who used aspirin after diagnosis had a multivariable HR for MM-specific mortality of 0·61 (95% confidence interval [CI], 0·46, 0·79) and for overall mortality of 0·63 (95% CI, 0·49, 0·80), after adjustment for age at diagnosis, year of diagnosis, sex, body mass index, pre-diagnosis aspirin use, and number of comorbidities. For post-diagnosis aspirin quantity, we observed a modest trend of reduction in MM-specific and all-cause mortality with increasing number of 325 mg tablets of aspirin per week, although the confidence intervals for 1 to <6 and {greater than or equal to}6 tablets overlapped. Results were not materially different before or after the availability of novel therapies (before vs. after the year 2000). Pre-diagnosis frequency or duration of aspirin use was not significantly associated with MM-specific or overall mortality. CONCLUSIONS Findings support the use of aspirin as a complementary strategy to enhance MM survival. IMPACT Confirmation in samples that have comprehensive clinical information is encouraged.
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Affiliation(s)
- Catherine R Marinac
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute
| | - Dong Hoon Lee
- Department of Nutrition, Harvard T.H. Chan School of Public Health
| | - Graham A Colditz
- Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis School of Medicine
| | - Timothy R Rebbeck
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute
| | - Bernard Rosner
- Channing Division of Network Medicine, Brigham and Women's Hospital
| | - Mark Bustoros
- Hematology & Medical Oncology, Weill Cornell Medicine, Meyer Cancer Center, Cornell University
| | | | - Brenda M Birmann
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School
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24
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IL-6 in the Ecosystem of Head and Neck Cancer: Possible Therapeutic Perspectives. Int J Mol Sci 2021; 22:ijms222011027. [PMID: 34681685 PMCID: PMC8540903 DOI: 10.3390/ijms222011027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/25/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
Interleukin-6 (IL-6) is a highly potent cytokine involved in multiple biological processes. It was previously reported to play a distinct role in inflammation, autoimmune and psychiatric disorders, ageing and various types of cancer. Furthermore, it is understood that IL-6 and its signaling pathways are substantial players in orchestrating the cancer microenvironment. Thus, they appear to be potential targets in anti-tumor therapy. The aim of this article is to elucidate the role of IL-6 in the tumor ecosystem and to review the possible therapeutic approaches in head and neck cancer.
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25
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Lee SF, Evens AM, Ng AK, Luque-Fernandez MA. Socioeconomic inequalities in treatment and relative survival among patients with diffuse large B-cell lymphoma: a Hong Kong population-based study. Sci Rep 2021; 11:17950. [PMID: 34504223 PMCID: PMC8429768 DOI: 10.1038/s41598-021-97455-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
The influence of socioeconomic status (SES) on access to standard chemotherapy and/or monoclonal antibody therapy, and associated secular trends, relative survival, and excess mortality, among diffuse large B-cell lymphoma (DLBCL) patients is not clear. We conducted a Hong Kong population-based cohort study and identified adult patients with histologically diagnosed DLBCL between 2000 and 2018. We examined the association of SES levels with the odds and the secular trends of receipt of chemotherapy and/or rituximab. Additionally, we estimated the long-term relative survival by SES utilizing Hong Kong life tables. Among 4017 patients with DLBCL, 2363 (58.8%) patients received both chemotherapy and rituximab and 740 (18.4%) patients received chemotherapy alone, while 1612 (40.1%) and 914 (22.8%) patients received no rituximab or chemotherapy, respectively. On multivariable analysis, low SES was associated with lesser use of chemotherapy (odd ratio [OR] 0.44; 95% CI 0.34-0.57) and rituximab (OR 0.41; 95% CI 0.32-0.52). The socioeconomic disparity for either treatment showed no secular trend of change. Additionally, patients with low SES showed increased excess mortality, with a hazard ratio of 2.34 (95% CI 1.67-3.28). Improving survival outcomes for patients with DLBCL requires provision of best available medical care and securing access to treatment regardless of patients' SES.
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Affiliation(s)
- Shing Fung Lee
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Clinical Oncology, Tuen Mun Hospital, New Territories West Cluster, Hospital Authority, Hong Kong, China
| | - Andrew M Evens
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Andrea K Ng
- Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Miguel-Angel Luque-Fernandez
- Department of Non-Communicable Disease Epidemiology, Cancer Survival Group, London School of Hygiene and Tropical Medicine, London, UK.
- Department of Non-Communicable Disease and Cancer Epidemiology, Instituto de Investigacion Biosanitaria de Granada (Ibs.GRANADA), University of Granada, Granada, Spain.
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26
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Kukkula A, Ojala VK, Mendez LM, Sistonen L, Elenius K, Sundvall M. Therapeutic Potential of Targeting the SUMO Pathway in Cancer. Cancers (Basel) 2021; 13:4402. [PMID: 34503213 PMCID: PMC8431684 DOI: 10.3390/cancers13174402] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 02/07/2023] Open
Abstract
SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.
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Affiliation(s)
- Antti Kukkula
- Cancer Research Unit, FICAN West Cancer Center Laboratory, Institute of Biomedicine, Turku University Hospital, University of Turku, FI-20520 Turku, Finland; (A.K.); (V.K.O.); (K.E.)
| | - Veera K. Ojala
- Cancer Research Unit, FICAN West Cancer Center Laboratory, Institute of Biomedicine, Turku University Hospital, University of Turku, FI-20520 Turku, Finland; (A.K.); (V.K.O.); (K.E.)
- Turku Doctoral Programme of Molecular Medicine, University of Turku, FI-20520 Turku, Finland
- Medicity Research Laboratories, University of Turku, FI-20520 Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland;
| | - Lourdes M. Mendez
- Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Department of Medicine and Pathology, Cancer Research Institute, Harvard Medical School, Boston, MA 02115, USA;
| | - Lea Sistonen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland;
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, FI-20520 Turku, Finland
| | - Klaus Elenius
- Cancer Research Unit, FICAN West Cancer Center Laboratory, Institute of Biomedicine, Turku University Hospital, University of Turku, FI-20520 Turku, Finland; (A.K.); (V.K.O.); (K.E.)
- Medicity Research Laboratories, University of Turku, FI-20520 Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland;
- Department of Oncology, Turku University Hospital, FI-20521 Turku, Finland
| | - Maria Sundvall
- Cancer Research Unit, FICAN West Cancer Center Laboratory, Institute of Biomedicine, Turku University Hospital, University of Turku, FI-20520 Turku, Finland; (A.K.); (V.K.O.); (K.E.)
- Department of Oncology, Turku University Hospital, FI-20521 Turku, Finland
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27
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Immunomodulation: An immune regulatory mechanism in carcinoma therapeutics. Int Immunopharmacol 2021; 99:107984. [PMID: 34303999 DOI: 10.1016/j.intimp.2021.107984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/29/2021] [Accepted: 07/11/2021] [Indexed: 01/01/2023]
Abstract
Cancer has been generally related to the possession of numerous mutations which interrupt important signaling pathways. Nevertheless, deregulated immunological signaling is considered as one of the key factors associated with the development and progression of cancer. The signaling pathways operate as modular network with different components interacting in a switch-like fashion with two proteins interplaying between each other leading to direct or indirect inhibition or stimulation of down-stream factors. Genetic, epigenetic, and transcriptomic alterations maintain the pathological conduit of different signaling pathways via affecting diverse mechanisms including cell destiny. At present, immunotherapy is one of the best therapies opted for cancer treatment. The cancer immunotherapy strategy includes harnessing the specificity and killing mechanisms of the immunological system to target and eradicate malignant cells. Targeted therapies utilizing several little molecules including Galunisertib, Astragaloside-IV, Melatonin, and Jervine capable of regulating key signaling pathways can effectively help in the management of different carcinomas.
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28
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Abstract
Purpose of Review IL-6 is a pleiotropic, pro-inflammatory cytokine that plays an integral role in the development of acute and chronic rejection after solid organ transplantation. This article reviews the experimental evidence and current clinical application of IL-6/IL-6 receptor (IL-6R) signaling inhibition for the prevention and treatment of allograft injury. Recent Findings There exists a robust body of evidence linking IL-6 to allograft injury mediated by acute inflammation, adaptive cellular/humoral responses, innate immunity, and fibrosis. IL-6 promotes the acute phase reaction, induces B cell maturation/antibody formation, directs cytotoxic T-cell differentiation, and inhibits regulatory T-cell development. Importantly, blockade of the IL-6/IL-6R signaling pathway has been shown to mitigate its harmful effects in experimental studies, particularly in models of kidney and heart transplant rejection. Currently, available agents for IL-6 signaling inhibition include monoclonal antibodies against IL-6 or IL-6R and janus kinase inhibitors. Recent clinical trials have investigated the use of tocilizumab, an anti-IL-6R mAb, for desensitization and treatment of antibody-mediated rejection (AMR) in kidney transplant recipients, with promising initial results. Further studies are underway investigating the use of alternative agents including clazakizumab, an anti-IL-6 mAb, and application of IL-6 signaling blockade to clinical cardiac transplantation. Summary IL-6/IL-6R signaling inhibition provides a novel therapeutic option for the prevention and treatment of allograft injury. To date, evidence from clinical trials supports the use of IL-6 blockade for desensitization and treatment of AMR in kidney transplant recipients. Ongoing and future clinical trials will further elucidate the role of IL-6 signaling inhibition in other types of solid organ transplantation.
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29
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Targeted Therapies for Multiple Myeloma. J Pers Med 2021; 11:jpm11050334. [PMID: 33922567 PMCID: PMC8145732 DOI: 10.3390/jpm11050334] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/11/2021] [Accepted: 04/19/2021] [Indexed: 12/30/2022] Open
Abstract
Multiple myeloma continues to be a challenging disorder to treat despite improved therapies and the widespread use of proteasome inhibitors and immunomodulatory drugs. Although patient outcomes have improved, the disease continues to invariably relapse, and in the majority of cases, a cure remains elusive. In the last decade, there has been an explosion of novel drugs targeting cellular proteins essential for malignant plasma cell proliferation and survival. In this review, we focus on novel druggable targets leading to the development of monoclonal antibodies and cellular therapies against surface antigens (CD38, CD47, CD138, BCMA, SLAMF7, GPRC5D, FcRH5), inhibitors of epigenetic regulators such as histone deacetylase (HDAC), and agents targeting anti-apoptotic (BCL-2), ribosomal (eEF1A2) and nuclear export (XPO1) proteins.
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30
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Gupta VA, Ackley J, Kaufman JL, Boise LH. BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma. BLOOD AND LYMPHATIC CANCER-TARGETS AND THERAPY 2021; 11:11-24. [PMID: 33737856 PMCID: PMC7965688 DOI: 10.2147/blctt.s245191] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/26/2021] [Indexed: 12/12/2022]
Abstract
Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.
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Affiliation(s)
- Vikas A Gupta
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA
| | - James Ackley
- Cancer Biology Graduate Program, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathan L Kaufman
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA
| | - Lawrence H Boise
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA, USA
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31
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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32
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Nair JR, Rozanski CH, Lee KP. Under one roof: The bone marrow survival niche for multiple myeloma and normal plasma cells. Oncoimmunology 2021; 1:388-389. [PMID: 22737625 PMCID: PMC3382851 DOI: 10.4161/onci.18746] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Our recently published data demonstrate significant similarities between normal and malignant plasma cells in the cellular and molecular interactions that support their survival in the bone marrow microenvironment, and suggest that the biology of multiple myeloma may largely reflect that of their normal counterparts.
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Affiliation(s)
- Jayakumar R Nair
- Department of Immunology; Roswell Park Cancer Institute; Buffalo, NY USA
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33
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Lanigan LG, Hildreth BE, Dirksen WP, Simmons JK, Martin CK, Werbeck JL, Thudi NK, Papenfuss TL, Boyaka PN, Toribio RE, Ward JM, Weilbaecher KN, Rosol TJ. In Vivo Tumorigenesis, Osteolytic Sarcomas, and Tumorigenic Cell Lines from Transgenic Mice Expressing the Human T-Lymphotropic Virus Type 1 (HTLV-1) Tax Viral Oncogene. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:335-352. [PMID: 33181139 PMCID: PMC7863134 DOI: 10.1016/j.ajpath.2020.10.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 09/17/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia, a disease commonly associated with hypercalcemia and osteolysis. There is no effective treatment for HTLV-1, and the osteolytic mechanisms are not fully understood. Mice expressing the HTLV-1 oncogene Tax, driven by the human granzyme B promoter (Tax+), develop osteolytic tumors. To investigate the progression of the bone-invasive malignancies, wild-type, Tax+, and Tax+/interferon-γ-/- mice were assessed using necropsy, histologic examination, IHC analysis, flow cytometry, and advanced imaging. Tax+ and Tax+/interferon-γ-/- malignancies of the ear, tail, and foot comprised poorly differentiated, round to spindle-shaped cells with prominent neutrophilic infiltrates. Tail tumors originated from muscle, nerve, and/or tendon sheaths, with frequent invasion into adjacent bone. F4/80+ and anti-mouse CD11b (Mac-1)+ histiocytic cells predominated within the tumors. Three Tax+/interferon-γ-/- cell lines were generated for in vivo allografts, in vitro gene expression and bone resorption assays. Two cell lines were of monocyte/macrophage origin, and tumors formed in vivo in all three. Differences in Pthrp, Il6, Il1a, Il1b, and Csf3 expression in vitro were correlated with differences in in vivo plasma calcium levels, tumor growth, metastasis, and neutrophilic inflammation. Tax+ mouse tumors were classified as bone-invasive histiocytic sarcomas. The cell lines are ideal for further examination of the role of HTLV-1 Tax in osteolytic tumor formation and the development of hypercalcemia and tumor-associated inflammation.
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Affiliation(s)
- Lisa G Lanigan
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio; Tox Path Specialists, a StageBio Company, Fredrick, Maryland
| | - Blake E Hildreth
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Wessel P Dirksen
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | - Jessica K Simmons
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | - Chelsea K Martin
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio; Department of Pathology and Microbiology, University of Prince Edward Island, Atlantic Veterinary College, Prince Edward Island, Canada
| | - Jillian L Werbeck
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | - Nandu K Thudi
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | - Tracey L Papenfuss
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | - Prosper N Boyaka
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | - Ramiro E Toribio
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio
| | | | - Katherine N Weilbaecher
- Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Thomas J Rosol
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio.
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34
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Gottschlich A, Endres S, Kobold S. Therapeutic Strategies for Targeting IL-1 in Cancer. Cancers (Basel) 2021; 13:477. [PMID: 33530653 PMCID: PMC7865618 DOI: 10.3390/cancers13030477] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/19/2022] Open
Abstract
Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several clinical trials have been conducted, shedding light on the role of IL-1 blocking agents for the treatment of cancer. Additionally, recent developments in the field of immuno-oncology have implicated IL-1-induced signaling cascades as a major driver of severe chimeric antigen receptor T cell-associated toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity. In this review, we summarize current clinical trials investigating the role of IL-1 blockade in cancer treatment and elaborate the proposed mechanism of these innovative treatment approaches. Additionally, we highlight cutting-edge developments utilizing IL-1 blocking agents to enhance the safety and efficacy of adoptive T cell therapy.
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Affiliation(s)
- Adrian Gottschlich
- Center for Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany; (A.G.); (S.E.)
| | - Stefan Endres
- Center for Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany; (A.G.); (S.E.)
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, 80337 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
| | - Sebastian Kobold
- Center for Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany; (A.G.); (S.E.)
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, 80337 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
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35
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Hanamura I. Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma. Cancers (Basel) 2021; 13:cancers13020256. [PMID: 33445467 PMCID: PMC7827173 DOI: 10.3390/cancers13020256] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/07/2021] [Accepted: 01/09/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy. Gain/amplification of chromosome arm 1q21 (1q21+) is the most common adverse genomic abnormality associated with disease progression and drug resistance. While possible mechanisms of 1q21+ occurrence and candidate genes in the 1q21 amplicon have been suggested, the precise pathogenesis of MM with 1q21+ is unknown. Herein, we review the current knowledge about the clinicopathological features of 1q21+ MM, which can assist in effective therapeutic approaches for MM patients with 1q21+. Abstract Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.
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Affiliation(s)
- Ichiro Hanamura
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1, Karimata, Yazako, Nagakute, Aichi 480-1195, Japan
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Signaling Pathway Mediating Myeloma Cell Growth and Survival. Cancers (Basel) 2021; 13:cancers13020216. [PMID: 33435632 PMCID: PMC7827005 DOI: 10.3390/cancers13020216] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary The bone marrow (BM) microenvironment plays a crucial role in pathogenesis of multiple myeloma (MM), and delineation of the intracellular signaling pathways activated in the BM microenvironment in MM cells is essential to develop novel therapeutic strategies to improve patient outcome. Abstract The multiple myeloma (MM) bone marrow (BM) microenvironment consists of different types of accessory cells. Both soluble factors (i.e., cytokines) secreted from these cells and adhesion of MM cells to these cells play crucial roles in activation of intracellular signaling pathways mediating MM cell growth, survival, migration, and drug resistance. Importantly, there is crosstalk between the signaling pathways, increasing the complexity of signal transduction networks in MM cells in the BM microenvironment, highlighting the requirement for combination treatment strategies to blocking multiple signaling pathways.
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Costa F, Vescovini R, Marchica V, Storti P, Notarfranchi L, Dalla Palma B, Toscani D, Burroughs-Garcia J, Catarozzo MT, Sammarelli G, Giuliani N. PD-L1/PD-1 Pattern of Expression Within the Bone Marrow Immune Microenvironment in Smoldering Myeloma and Active Multiple Myeloma Patients. Front Immunol 2021; 11:613007. [PMID: 33488620 PMCID: PMC7820813 DOI: 10.3389/fimmu.2020.613007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/23/2020] [Indexed: 12/31/2022] Open
Abstract
Background The PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies. Methods The PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients. Results First, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells. Conclusions Our data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.
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Affiliation(s)
- Federica Costa
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Rosanna Vescovini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Paola Storti
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Laura Notarfranchi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Hematology, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy
| | - Benedetta Dalla Palma
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Hematology, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy
| | - Denise Toscani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | | | | | - Nicola Giuliani
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Hematology, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy
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We need CD38 STAT-JAK. Blood 2020; 136:2246-2248. [PMID: 33180919 DOI: 10.1182/blood.2020007467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Gu J, Huang X, Zhang Y, Bao C, Zhou Z, Jin J. Cytokine profiles in patients with newly diagnosed multiple myeloma: Survival is associated with IL-6 and IL-17A levels. Cytokine 2020; 138:155358. [PMID: 33183958 DOI: 10.1016/j.cyto.2020.155358] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/28/2020] [Accepted: 10/26/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Identifying specific risk factors associated with multiple myeloma (MM) remains a significant issue. Different cytokines take part in the pathogenesis, progression, and prognosis of MM. Therefore, this study aimed to investigate the correlations between serum cytokine levels and clinical characteristics and determine their effects on disease progression and survival of MM patients. METHODS We retrospectively analyzed the serum levels of 7 cytokines in 105 patients with newly diagnosed MM and in 20 healthy subjects. Interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were quantitatively determined by cytometric bead assay techniques. The concentrations of each cytokine were compared between the MM patients and healthy subjects using the Mann-Whitney U test. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). RESULTS Serum IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ levels were higher in patients with newly diagnosed MM than in healthy controls. Positively significant correlations were found between IL-6, IL-10, IL-17A, and β2-microglobulin. Significant correlations were also observed between IL-6 and IL-10, and lactate dehydrogenase. The overall response rate of low-IL-6 and IL-17A patients was significantly higher than that of high-IL-10 and IL-17A patients (P < 0.01). Univariate and multivariate analyses revealed that serum IL-6 levels were >3 pg/mL, serum IL-17A levels were >4 pg/mL, and treatment regimens were independent prognostic factors for PFS and OS. CONCLUSIONS Cytokine deregulation, especially that of IL-6 and IL-17A, may be a powerful predictor of clinical prognosis for MM patients.
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Affiliation(s)
- Jiayan Gu
- Institute of Hematology, Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang Province, Hangzhou 310003, China
| | - Xin Huang
- Institute of Hematology, Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang Province, Hangzhou 310003, China
| | - Yi Zhang
- Institute of Hematology, Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang Province, Hangzhou 310003, China
| | - Chenhui Bao
- Institute of Hematology, Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang Province, Hangzhou 310003, China
| | - Ziyang Zhou
- Institute of Hematology, Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang Province, Hangzhou 310003, China
| | - Jie Jin
- Institute of Hematology, Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang Province, Hangzhou 310003, China.
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Vergallo C. Infusion of HLA-matched and static magnetic field-exposed allogenic lymphocytes treating lymphocytopenia and cytokine storm syndrome: A treatment proposal for COVID-19 patients. Electromagn Biol Med 2020; 40:11-25. [PMID: 33073612 DOI: 10.1080/15368378.2020.1830290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Among haematological parameters of patients seriously ill with the coronavirus infectious disease 2019 (COVID-19), leucocytosis, lymphocytopenia, and the abnormal release of circulating cytokines, termed cytokine storm syndrome (CSS, also known as cytokine release syndrome or CRS), were found associated with disease severity. In particular, according to the serum cytokine profiling, pro-inflammatory interleukin 6 (IL-6) and anti-inflammatory interleukin 10 (IL-10) were observed to be considerably higher in patients experiencing respiratory distress, septic shock and/or multi-organ failure, namely "critical cases" requiring intensive care unit (ICU) admission, very often resulting in death. Interestingly, the production of these cytokines from human lymphocytes was found to be modulated by exposure of 24 h to a 554.2-553.8 mT inhomogeneous static magnetic field (SMF), which elicits IL-10 and suppresses IL-6. Thus, herein, with the aim of restoring lymphocyte count and physiological serum levels of IL-6 and IL-10, the infusion of human leukocyte antigen (HLA)-matched and SMF-exposed allogenic lymphocytes is proposed for the first time as an easy and affordable treatment option for COVID-19 patients. Even if the count of lymphocytes in COVID-19 patients is very low, SMF exposure may be a valuable tool for reprogramming autologous lymphocytes towards physiological conditions. Furthermore, the same procedure could be extended to include the whole autologous or allogenic white blood cells (WBCs). Time-varying/pulsed magnetic fields exerting comparable cell effects could also be employed.
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Affiliation(s)
- Cristian Vergallo
- Department of Pharmacy, University of Chieti-Pescara "G. d'Annunzio" , Chieti, Italy
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41
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Tsukamoto H, Kouwaki T, Oshiumi H. Aging-Associated Extracellular Vesicles Contain Immune Regulatory microRNAs Alleviating Hyperinflammatory State and Immune Dysfunction in the Elderly. iScience 2020; 23:101520. [PMID: 32927264 PMCID: PMC7495115 DOI: 10.1016/j.isci.2020.101520] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 06/30/2020] [Accepted: 08/27/2020] [Indexed: 12/16/2022] Open
Abstract
Aging-associated changes in the immune system often lead to immune dysfunction; however, the mechanisms that underlie this phenomenon have yet to be fully elucidated. This study found that the microRNA-192 (miR-192) is an aging-associated immune regulatory microRNA whose concentration was significantly increased in aged extracellular vesicles (EVs) due to the hyperinflammatory state of aged mice. Interestingly, EV miR-192 exhibited anti-inflammatory effects on macrophages. In our aged mouse model, aging was associated with prolonged inflammation in the lung upon stimulation with inactivated influenza whole virus particles (WVP), whereas EV miR-192 alleviated the prolonged inflammation associated with aging. The hyperinflammatory state of aged mice resulted in reduced production of specific antibodies and efficacy of vaccination with WVP; however, EV miR-192 attenuated this hyperinflammatory state and improved vaccination efficacy in aged mice. Our data indicate that aged EVs constitute a negative feedback loop that alleviates aging-associated immune dysfunction.
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Affiliation(s)
- Hirotake Tsukamoto
- Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takahisa Kouwaki
- Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiroyuki Oshiumi
- Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
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Ota A, Hanamura I, Karnan S, Inaguma S, Takei N, Lam VQ, Mizuno S, Kanasugi J, Wahiduzzaman M, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Ikeda H, Takami A, Hosokawa Y. Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells. J Interferon Cytokine Res 2020; 40:389-405. [PMID: 32721246 PMCID: PMC7462034 DOI: 10.1089/jir.2020.0111] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan–Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.
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Affiliation(s)
- Akinobu Ota
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Ichiro Hanamura
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Sivasundaram Karnan
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shingo Inaguma
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Norio Takei
- Institute for Animal Experimentation, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Vu Quang Lam
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shohei Mizuno
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Jo Kanasugi
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Md Wahiduzzaman
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Md Lutfur Rahman
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Toshinori Hyodo
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hiroyuki Konishi
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shinobu Tsuzuki
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hiroshi Ikeda
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Akiyoshi Takami
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshitaka Hosokawa
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
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Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e752-e768. [PMID: 32651110 DOI: 10.1016/j.clml.2020.05.026] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/22/2020] [Accepted: 05/29/2020] [Indexed: 01/10/2023]
Abstract
Multiple myeloma (MM) is a cancer of the plasma cells within the bone marrow (BM). Studies have shown that the cellular and noncellular components of the BM milieu, such as cytokines and exosomes, play an integral role in MM pathogenesis and progression by mediating drug resistance and inducing MM proliferation. Moreover, the BM microenvironment of patients with MM facilitates cancer tolerance and immune evasion through the expansion of regulatory immune cells, inhibition of antitumor effector cells, and disruption of the antigen presentation machinery. These are of special relevance, especially in the current era of cancer immunotherapy. An improved understanding of the supportive role of the MM BM microenvironment will allow for the development of future therapies targeting MM in the context of the BM milieu to elicit deeper and more durable responses. In the present review, we have discussed our current understanding of the role of the BM microenvironment in MM progression and resistance to therapy and discuss novel potential approaches to alter its pro-MM function.
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Nickerson PW. What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation? Am J Transplant 2020; 20 Suppl 4:12-22. [PMID: 32538535 DOI: 10.1111/ajt.15859] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/26/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023]
Abstract
Antibody-mediated rejection (ABMR) in kidney transplantation is a major cause of late graft loss, and despite all efforts to date the "standard of care" remains plasmapheresis, IVIg, and steroids, which itself is based on low quality evidence. This review focuses on the risk factors leading to memory and de novo donor-specific antibody (DSA)-associated ABMR, the optimal prevention strategies for ABMR, and advances in adjunctive and emerging therapies for ABMR. Because new agents require regulatory approval via a Phase 3 randomized control trial (RCT), an overview of progress in innovative trial design for ABMR is provided. Finally, based on the insights gained in the biology of ABMR, current knowledge gaps are identified for future research that could significantly affect our understanding of how to optimally treat ABMR.
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Affiliation(s)
- Peter W Nickerson
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.,Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
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Børset M, Sundan A, Waage A, Standal T. Why do myeloma patients have bone disease? A historical perspective. Blood Rev 2020; 41:100646. [DOI: 10.1016/j.blre.2019.100646] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/19/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
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Abstract
In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still’s disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases. In this Perspective article, the authors recount the earliest stages of translational research into IL-6 biology and the subsequent development of therapeutic IL-6 pathway inhibitors for the treatment of autoimmune rheumatic diseases and potentially numerous other indications.
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Raj V, Aboumanei MH, Rai A, Verma SP, Singh AK, Keshari AK, Saha S. Pharmacophore and 3d-Qsar Modeling of new 1,3,4-Thiadiazole Derivatives: Specificity to Colorectal Cancer. Pharm Chem J 2020. [DOI: 10.1007/s11094-020-02149-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Nakamura K, Nakamura T, Iino T, Hagi T, Kita K, Asanuma K, Sudo A. Expression of Interleukin-6 and the Interleukin-6 Receptor Predicts the Clinical Outcomes of Patients with Soft Tissue Sarcomas. Cancers (Basel) 2020; 12:cancers12030585. [PMID: 32138303 PMCID: PMC7139480 DOI: 10.3390/cancers12030585] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 02/27/2020] [Accepted: 03/02/2020] [Indexed: 12/27/2022] Open
Abstract
Interleukin-6 (IL-6) affects the key parameters of oncogenesis, which increases the cell resistance to apoptosis, the proliferation of cancer cells, angiogenesis, invasion, malignancy, and the ability of tumor cells to respond to anticancer therapy. This study aimed to elucidate the association between IL-6 and IL-6 receptor (IL-6R) expression in tissues and clinical outcomes in patients with soft tissue sarcomas (STSs) because, to our knowledge, this has not been done before. We enrolled 86 patients with histologically-proven localized STSs who underwent surgical resection. The cohort included 48 men and 38 women, with a mean age of 65.6 years. The mean follow-up duration was 40.5 months. The expression of IL-6 and IL-6R was immunohistochemically determined. We analyzed prognostic factors for overall survival (OS) and metastasis-free survival (MFS). High IL-6 expression was observed in 23.3% (20/86), high IL-6R expression in 44.2% (38/86), and high expression of both in 16.3% (14/86) of patients. Multivariate analysis showed that a high expression of both IL-6 and IL-6R was a prognostic factor for OS and MFS. We found that this high expression indicated that the patient had a poor prognosis for OS and MFS.
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Lee DH, Fung TT, Tabung FK, Marinac CR, Devore EE, Rosner BA, Ghobrial IM, Colditz GA, Giovannucci EL, Birmann BM. Prediagnosis dietary pattern and survival in patients with multiple myeloma. Int J Cancer 2020; 147:1823-1830. [PMID: 32067221 DOI: 10.1002/ijc.32928] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/10/2020] [Accepted: 02/03/2020] [Indexed: 11/11/2022]
Abstract
Inflammation and endogenous growth factors are important in multiple myeloma (MM) pathogenesis. Although diets that modulate these biologic pathways may influence MM patient survival, studies have not examined the association of dietary patterns with MM survival. We conducted pooled prospective survival analyses of 423 MM patients from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-up Study (1988-2016) using Cox regression models. We used data from repeated food frequency questionnaires (FFQ) to compute dietary patterns as of the last prediagnosis FFQ, including the Alternate Healthy Eating Index (AHEI)-2010, alternate Mediterranean Diet, Dietary Approaches to Stop Hypertension, Prudent, Western and empirical dietary inflammatory patterns and empirical dietary indices for insulin resistance and hyperinsulinemia. During follow-up, we documented 295 MM-related deaths among 345 total deaths. MM-specific mortality was 15-24% lower per one standard deviation (SD) increase (e.g., toward healthier habits) in favorable dietary pattern scores. For example, the multivariable-adjusted hazard ratio [HR] and 95% confidence interval [CI] per 1-SD increase in AHEI-2010 score were 0.76, 0.67-0.87 (p < 0.001). In contrast, MM-specific mortality was 16-24% higher per 1-SD increase (e.g., toward less healthy habits) in "unhealthy" diet scores; for example, the multivariable-adjusted HR, 95% CI per 1-SD increase in Western pattern score were 1.24, 1.07-1.44 (p = 0.005). Associations were similar for all-cause mortality. In conclusion, our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier prediagnosis dietary habits may have longer survival than those with less healthy diets.
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Affiliation(s)
- Dong Hoon Lee
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Teresa T Fung
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.,Department of Nutrition, Simmons University, Boston, MA
| | - Fred K Tabung
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.,Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH
| | - Catherine R Marinac
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Elizabeth E Devore
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Bernard A Rosner
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Irene M Ghobrial
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Graham A Colditz
- Department of Public Health Sciences, Washington University School of Medicine, St. Louis, MO
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Brenda M Birmann
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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Hou J, Qian J, Li Z, Gong A, Zhong S, Qiao L, Qian S, Zhang Y, Dou R, Li R, Yang Y, Gu C. Bioactive Compounds from Abelmoschus manihot L. Alleviate the Progression of Multiple Myeloma in Mouse Model and Improve Bone Marrow Microenvironment. Onco Targets Ther 2020; 13:959-973. [PMID: 32099399 PMCID: PMC6999766 DOI: 10.2147/ott.s235944] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 01/08/2020] [Indexed: 01/15/2023] Open
Abstract
Purpose Abelmoschus manihot (L.) Medik. (Malvaceae) derived Huangkui capsules (HKC) represent a traditional Chinese medicine that has been widely applied to the clinical therapy of kidney and inflammatory diseases. The present study aimed to determine the potential therapeutic effects and underlying mechanisms of the ingredients on Multiple Myeloma (MM), an incurable disease that exhibits malignant plasma cell clonal expansion in the bone marrow. Methods A 5TMM3VT syngeneic MM-prone model was established and treated with HKC. Murine pre-osteoblast MC3T3-E1 and pre-osteoclast Raw264.7 cells were treated with nine flavonoid compounds extracted from the flowers of Abelmoschus manihot. MC3T3-E1 and Raw264.7 cells were then examined by alizarin red staining and tartrate-resistant acid phosphatase activity staining, respectively. The proliferation of two human MM cells (ARP1, H929) was examined by performing an MTT assay following treatment with flavonoid compounds. Additionally, the cell cycle was analyzed via staining and flow cytometry. The differential expressions of certain proteins were detected via Western blotting, transcriptomic RNA-sequencing as well as RT-qPCR. Results The results revealed that MM-prone animals appeared to be protected following HKC treatment, as evidenced by a prolonged survival rate. Furthermore, four of the nine flavonoid compounds [Hyperin/Hyperoside, HK-2; Cannabiscitrin, HK-3; 3-O-kaempferol-3-O-acetyl-6-O-(p-coumaroyl)-β-D-glucopyranoside, HK-11; 8-(2’’-pyrrolidione-5’’-yl)-quercetin, HK-B10] induced the differentiation of murine pre-osteoblast MC3T3-E1 cells. In addition, two compounds [Isomyricitrin, HK-8; quercetin-8-(2’’-pyrrolidione-5”-yl)-3ʹ-O-β-D-glucopyranosid, HK-E3] suppressed osteoclastogenesis in murine Raw264.7 cells. HK-11 directly inhibited MM cells (ARP1 and H929) proliferation and induced G0/G1 cell cycle arrest, which may have involved the suppressing β-catenin protein, increasing expressions of IL-6 and TNF-α, as well as activating mature TGF-β1 and some other metabolic pathways. Conclusion These results of the present study indicated that the bio-active ingredients of HKC exerted protective effects on MM mouse survival through promoting osteoblastogenesis and suppressing osteoclastogenesis, thus improving the bone marrow microenvironment to inhibit MM cell proliferation.
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Affiliation(s)
- Jianhao Hou
- The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, People's Republic of China.,School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Jinjun Qian
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Zhenlin Li
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, People's Republic of China.,Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing 210028, People's Republic of China
| | - Aixiu Gong
- Department of Stomatology, Children's Hospital of Nanjing Medical University, Nanjing 210009, People's Republic of China
| | - Sixia Zhong
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Li Qiao
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Shihui Qian
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, People's Republic of China.,Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing 210028, People's Republic of China
| | - Yanxin Zhang
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Renjie Dou
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Rui Li
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Ye Yang
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
| | - Chunyan Gu
- The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, People's Republic of China.,School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China
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