scholarly journals Quantification of plasma cell dynamics using mathematical modelling

2018 ◽  
Vol 5 (1) ◽  
pp. 170759 ◽  
Author(s):  
Marcel Mohr ◽  
Dirk Hose ◽  
Anja Seckinger ◽  
Anna Marciniak-Czochra
Keyword(s):  
Mathematical Model ◽  
Bone Marrow ◽  
Mathematical Modelling ◽  
Plasma Cells ◽  
Cell Dynamics ◽  
Growth And Survival ◽  
Specific Antibodies ◽  
Health And Disease ◽  
Potential Basis ◽  
The Impact

Plasma cells (PCs) are the main antibody-producing cells in humans. They are long-lived so that specific antibodies against either pathogens or vaccines are produced for decades. PC longevity is attributed to specific areas within the bone marrow micro-environment, the so-called ‘niche’, providing the cells with required growth and survival factors. With antigen encounters, e.g. infection or vaccination, new PCs are generated and home to the bone marrow where they compete with resident PCs for the niche. We propose a parametrized mathematical model describing healthy PC dynamics in the bone marrow. The model accounts for competition for the niche between newly produced PCs owing to vaccination and resident PCs. Mathematical analysis and numerical simulations of the model allow explanation of the recovery of PC homoeostasis after a vaccine-induced perturbation, and the fraction of vaccine-specific PCs inside the niche. The model enables quantification of the niche-related dynamics of PCs, i.e. the duration of PC transition into the niche and the impact of different rates for PC transitions into and out of the niche on the observed cell dynamics. Ultimately, it provides a potential basis for further investigations in health and disease.

scholarly journals Bone Marrow Plasma Cells Are a Primary Source of Serum HIV-1–Specific Antibodies in Chronically Infected Individuals

2015 ◽  
Vol 194 (6) ◽  
pp. 2561-2568 ◽  
Author(s):  
Jairo M. Montezuma-Rusca ◽  
Susan Moir ◽  
Lela Kardava ◽  
Clarisa M. Buckner ◽  
Aaron Louie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Primary Source ◽  
Specific Antibodies ◽  
Bone Marrow Plasma ◽  
Hiv 1

The Role of B Cell-Activating Factor (BAFF) in the Biology of Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3380-3380 ◽  
Author(s):  
Noopur Raje ◽  
Shaji Kumar ◽  
Teru Hideshima ◽  
Kenji Ishitsuka ◽  
Hiroshi Yasui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
B Cell ◽  
Cell Lines ◽  
Plasma Cells ◽  
Cell Development ◽  
Newly Diagnosed ◽  
Growth And Survival ◽  
Affymetrix U133a ◽  
Apoptotic Proteins

Abstract BAFF is a member of the tumor necrosis factor (TNF) family and is critical for the maintenance and homeostasis of normal B-cell development. Importantly, BAFF promotes the generation of rapidly dividing immunoglobulin secreting plasmablasts from activated memory B cells by enhancing their survival. Given that MM is a cancer of plasma cells and that the signaling cascades implicated in receptor ligand interactions of BAFF are crucial in MM cell biology, we hypothesized that this cytokine may play a critical role in MM cell development, survival, and proliferation. We performed gene expression profiling (GEP) on CD 138+ plasma cells isolated from 90 MM patients (45 newly diagnosed and 45 relapsed) and 11 healthy controls using the Affymetrix U133A arrays. Our data demonstrates increased expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), 2 receptors used by BAFF to exert its effects. Our data also shows an increased expression of a proliferation-inducing ligand (APRIL), another member of the TNF family with homology to BAFF. Expression levels of BAFF and BAFF-R could not be determined because of lack of these probe sets on the Affymetrix U133A arrays. GEP analysis shows increased BCMA expression (p<0.0001, student T test) on newly diagnosed and relapsed MM versus normal plasma cells. Flow cytometry on MM cell lines demonstrated a differential expression of the three receptors of BAFF, with BCMA present on most cell lines but BAFF-R expressed at low levels only on LR5 cells and DOX40 MM cells. In contrast, flow cytometry performed on MM patient cells demonstrated the presence of all 3 receptors on CD 138+ cells. ELISA assays performed on 30 MM sera demonstrated a mean BAFF level of 618 pg/ml (range: 128–2126pg/ml) versus 235pg/ml (range: 158–326pg/ml) in 7 normal donor sera. Fifty six% (17/30) of MM patients had BAFF levels in excess of the highest value noted in normals. To understand the role BAFF might play in the biology of MM, we studied the effects of recombinant BAFF (rh-BAFF) on MM cells directly and in the context of its bone marrow microenvironment. (abstract # 554746) rh-BAFF conferred a survival advantage to MM cells and protected them against dexamethasone-induced cytotoxicity. Importantly, anti-apoptotic proteins Bcl2 and Mcl-1 were upregulated, as were growth and survival signals belonging to the JAK/STAT and MAPKinase pathways. Conversely, neutralizing antibody to BAFF blocked, at least in part, blocked the upregulation of anti-apoptotic proteins with associated growth and survival, confirming that these effects were due to BAFF. Importantly, all of these signals were downregulated even in the presence of bone marrow stromal cells (BMSCs). These data therefore show a role for BAFF mediating MM cell survival and provide the framework for inhibiting BAFF, either alone or in combination with dexamethasone, to improve patient outcome in MM.

Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 601-604 ◽  
Author(s):  
Rogier M. Reijmers ◽  
Richard W. J. Groen ◽  
Henk Rozemuller ◽  
Annemieke Kuil ◽  
Anneke de Haan-Kramer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Heparan Sulfate ◽  
Cell Fate ◽  
Plasma Cells ◽  
Core Protein ◽  
Strong Increase ◽  
Growth And Survival ◽  
Xenotransplantation Model

Abstract Expression of the heparan sulfate proteoglycan syndecan-1 is a hallmark of both normal and multiple myeloma (MM) plasma cells. Syndecan-1 could affect plasma cell fate by strengthening integrin-mediated adhesion via its core protein and/or by accommodating and presenting soluble factors via its HS side chains. Here, we show that inducible RNAi-mediated knockdown of syndecan-1 in human MM cells leads to reduced growth rates and a strong increase of apoptosis. Importantly, knockdown of EXT1, a copolymerase critical for HS chain biosynthesis, had similar effects. Using an innovative myeloma xenotransplantation model in Rag-2−/−γc−/− mice, we demonstrate that induction of EXT1 knockdown in vivo dramatically suppresses the growth of bone marrow localized myeloma. Our findings provide direct evidence that the HS chains of syndecan-1 are crucial for the growth and survival of MM cells within the bone marrow environment, and indicate the HS biosynthesis machinery as a potential treatment target in MM.

scholarly journals The role of bone marrow microenvironment in the progression of multiple myeloma from monoclonal gammopathy of undetermined significance

2021 ◽  
Vol 16 (3) ◽  
pp. 26-32
Author(s):  
A. S. Khudovekova ◽  
Ya. A. Rudenko ◽  
A. E. Dorosevich
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Bone Marrow Microenvironment ◽  
Genetic Mutations ◽  
Microbiome Composition ◽  
The Impact ◽  
Undetermined Significance

Multiple myeloma is a tumor of plasma cells, one of the most common malignant blood diseases. It is preceded by a stage called monoclonal gammopathy of undetermined significance, from which true multiple myeloma develops in only a small percentage of cases. It was assumed that this process is associated with the accumulation of genetic mutations, but in recent years there is increasing evidence that the bone marrow microenvironment plays a key role in progression and that it can become a target for therapy that prevents the myeloma development. The review considers the role of mesenchymal stem cells, immune system cells, endotheliocytes, fibroblasts, adipocytes, osteoclasts and osteoblasts in multiple myeloma progression, as well as the impact of the sympathetic nervous system and microbiome composition.

scholarly journals The Healthy and Diseased Equine Endometrium: A Review of Morphological Features and Molecular Analyses

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 625 ◽  
Author(s):  
Sandra Schöniger ◽  
Heinz-Adolf Schoon
Keyword(s):  
Molecular Markers ◽  
Microscopic Examination ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Endometrial Biopsy ◽  
Diagnostic Biomarkers ◽  
Molecular Analyses ◽  
Horse Breeding ◽  
Health And Disease ◽  
The Impact

Mares are seasonally polyestric. The breeding season in spring and summer and the winter anestrus are flanked by transitional periods. Endometrial diseases are a frequent cause of subfertility and have an economic impact on the horse breeding industry. They include different forms of endometrosis, endometritis, glandular maldifferentiation, and angiosis. Except for suppurative endometritis, these are subclinical and can only be diagnosed by the microscopic examination of an endometrial biopsy. Endometrosis is characterized by periglandular fibrosis and nonsuppurative endometritis by stromal infiltration with lymphocytes and plasma cells. The pathogenesis of endometrosis and nonsuppurative endometritis is still undetermined. Some mares are predisposed to persistent endometritis; this has likely a multifactorial etiology. Glandular differentiation has to be interpreted under consideration of the season. The presence of endometrial diseases is associated with alterations in the expression of several intra- and extracellular molecular markers. Some of them may have potential to be used as diagnostic biomarkers for equine endometrial health and disease. The aim of this review is to provide an overview on pathomorphological findings of equine endometrial diseases, to outline data on analyses of cellular and molecular mechanisms, and to discuss the impact of these data on reproduction and treatment.

Clinical and Prognostic Impact of (11;14)(q13;q32) Translocation on Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5507-5507
Author(s):  
Daisuke Miura ◽  
Kentaro Narita ◽  
Ayumi Kuzume ◽  
Rikako Tabata ◽  
Toshiki Terao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Clinical Characteristics ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Stage Iii ◽  
Prognostic Impact ◽  
Cd20 Expression ◽  
The Impact

Introduction. Translocations involving chromosome 14 at band q32, the immunoglobulin heavy chain (IgH) locus, are considered to be the most important initiating events for the development of multiple myeloma (MM). Among the IgH translocations in MM, t(11;14)(q13;q32) is the most frequently reported, and associated with a lymphoplasmacytic morphology. This translocation have been traditionally considered as standard-risk chromosomal abnormality compared to other translocations such as t(4;14) or t(14;16), although some controversies on the prognostic impact of this translocation still remain. This study aimed to clarify the clinical and prognostic impact of t(11;14) in Japanese patients in relation to other clinical variables such as immunophenotype of the tumor cells, other cytogenetic abnormalities, and use of stem cell transplantation (SCT). Patients and methods. Among the 244 consecutive patients with newly diagnosed MM, treated at Kameda Medical Center between April 2009 and July 2019, 234 patients, having cytogenetic analysis data (including t(11;14), t(4;14), t(14;16), and del(17p) by interphase fluorescence in situ hybridization (iFISH)) fully available, were included in this study. Data regarding the patients' clinical and laboratory characteristics, including the International Staging System (ISS), immunophenotype of the tumor cells, baseline circulating plasma cells (CPCs), treatment responses, disease progression, and survival status, were collected. iFISH was performed with CD138-purified bone marrow plasma cells, and the cut off values for translocation were ≥ 10% and for del(17p) ≥ 20%. Using multicolor flow cytometry, surface marker analysis of bone marrow samples and quantification of pre-treatment CPCs on peripheral blood mononuclear cells were simultaneously performed. CPCs were reported as the percentage of total mononuclear cells. Patients were considered to be negative for clonal CPCs at a sensitivity of 10−4 (0.01%) clonal plasma cells for all events evaluated. Results. The incidence of patients harboring t(11;14) was 24.4% (n = 57); t(11;14) was detected significantly high in light-chain-only subtypes (P < 0.001). We compared clinical characteristics of patients carrying t(11;14) with others. Myeloma cells with t(11;14) were associated with negative expression of CD56 (P < 0.001), CD117 (P = 0.046), and CD200 (P = 0.006), and positive expression of CD20 (P = 0.01) and CD81 (P = 0.035). Patients with t(11;14) were associated with positive CPCs (P = 0.011). In order to focus on the impact of t(11;14), we divided the patients into 4 groups: (A) no specific cytogenetic abnormality listed above (n = 137), (B) t(11;14) group (n = 57), (C) t(4;14) or t(14;16) group (n = 29), and (D) del(17p) only (n = 10), and the clinical characteristics and survival of the patients were compared across the three groups (A), (B), and (C). Almost all the patients (> 95%) in this cohort received bortezomib-based therapy. Median progression-free survival (PFS) and overall survival (OS) of patients in (A), (B), and (C) groups were 55.6, 34.2, and 30.2 months (m) (A vs. B, P = 0.036, and A vs. C, P = 0.031), and not reached, 51.2, and 79.8 m (A vs. B, P = 0.11, and A vs. C, P = 1.00), respectively. However, patients harboring t(11;14) were further divided into CD20-positive and -negative groups, the latter having poor prognosis (36.1 vs. 26.7, P = 1.0 for median PFS, and not reached vs. 44.2, P = 0.029 for median OS). Compared to other groups, patients without CD20 expression had significantly shorter OS (vs. A, vs. B, P = 0.024, 0.035, respectively), whereas those with CD20 expression tended to have longer OS, without statistical significance (Figure 1).Univariate analysis revealed ISS stage III, creatinine > 2.0 mg/dL, use of SCT, t(11;14) without CD20 expression, and age ≥ 70 years to be associated with shorter OS, whereas multivariate analysis demonstrated ISS stage III, use of SCT, and t(11;14) without expression CD20 (HR 1.88; 95% CI 1.10-3.21; P = 0.021) to be independent prognostic factors for poor OS. Conclusions. Our findings demonstrated that patients harboring t(11;14) had distinct clinical and immunophenotypic characteristics, two subsets of the disease entities with a clearly different survival according to CD20 expression. Disclosures Matsue: Ono Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria.

High-Throughput Microrna Profiling in Patients with Waldenstrom’s Macroglobulinemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1704-1704
Author(s):  
Sophia Adamia ◽  
Samir B Amin ◽  
Cheng Li ◽  
Christopher J Patterson ◽  
Herve AvetLoiseau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Healthy Donor ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Protein Coding ◽  
Growth And Survival ◽  
Small Noncoding Rnas ◽  
Marrow Cells

Abstract Waldenström’s macroglobulinemia (WM) is an incurable B cell malignancy characterized by the accumulation of IgM secreting clonally related bone marrow lymphoplasmacytic cells (LPC) including CD19+ B-cells and CD138+ plasma cells. Despite intense research efforts, the pathogenetic basis for this disease remains to be clarified. MicroRNAs are small noncoding RNAs that regulate the expression of protein-coding genes by inducing translational inhibition and through cleavage of targeted transcripts by partial or complete base pairing. We therefore evaluated the expression of 384 microRNAs in CD19+ and CD138+ sorted bone marrow lymphoplasmacytic from 13 untreated WM patients, and compared their expression profiling to analogous lymphoplasmacytic cells taken from the bone marrows of 13 healthy donors. Data obtained from microRNA arrays was analyzed using SDS, RQ manager, R and dChip softwares. Relative expression was calculated using the comparative Ct method through RQ manager and dChip softwares. Of the 384 microRNAs evaluated in CD19+ patient cells, miR-192, -125b, -21, -155 demonstrated significant upregulation, whereas miR-181c, -572, and -650 were significantly down regulated compared to healthy donor CD19+ bone marrow cells (p&lt;0.05). Analysis of bone marrow derived CD138+ cells from WM patients demonstrated significant upregulation in miR-192, -193b, -17-3p, -585, -148b, whereas miR-29c, -155, -126, -148a, -125a, -181d, -30a-3p, let-7b, let-7c were downregulated in comparison to healthy donor CD138+ bone marrow cells (p&lt;0.05). Importantly, characterization of the modulated microRNAs found in these studies demonstrated a critical role in growth and survival pathways through modulation of several genes including HOX, BCL-2 and c-myc. Taken together, these studies demonstrate significant differences in microRNA expression between comparable WM and healthy donor lymphoplasmacytic cell populations, and identify aberrancies in microRNAs with a pivotal role in the growth and survival of B-cells.

scholarly journals Influence of metformin on HIF-1 pathway in multiple myeloma

2020 ◽  
Vol 72 (5) ◽  
pp. 1407-1417
Author(s):  
Kinga A. Kocemba-Pilarczyk ◽  
Sonia Trojan ◽  
Barbara Ostrowska ◽  
Małgorzata Lasota ◽  
Paulina Dudzik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Treatment Strategies ◽  
Annexin V ◽  
Growth And Survival ◽  
Hypoxic Conditions ◽  
New Treatment ◽  
First Time ◽  
Pcr Techniques

Abstract Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

scholarly journals On Mathematical Modelling of the Indian Human Hair Industry in the Post-COVID-19 Era

2021 ◽  
Vol 8 (3) ◽  
pp. 447-452
Author(s):  
Shibam Manna ◽  
Tanmay Chowdhury ◽  
Asoke Kumar Dhar ◽  
Juan Jose Nieto
Keyword(s):  
Mathematical Model ◽  
Mathematical Modelling ◽  
Human Hair ◽  
Control Parameter ◽  
Employment Opportunities ◽  
Alternative Employment ◽  
Job Opportunities ◽  
Proposed Model ◽  
The Stability ◽  
The Impact

An attempt to model the human hair industry in the post-COVID-19 pandemic situation using mathematical modelling has been the goal of this article. Here we introduce a novel mathematical modelling using a system of ordinary differential equations to model the human hair industry as well as the human hair waste management and related job opportunities. The growth of human hair in the months of nationwide total lockdown has been taken into account and graphs have been plotted to analyze the effect of Lockdown in this model. The alternative employment opportunities that can be created for collecting excessive hair in the post-pandemic period has been discussed. A probable useful mathematical model and mechanism to utilize the migrant labours who became jobless due to the pandemic situation and the corresponding inevitable lockdown situation resulting out of that crisis has been discussed in this paper. We discussed the stability analysis of the proposed model and obtained the criteria for an optimal profit of the said model. Graphs have also been plotted to analyze the impact of the control parameter on the optimal profit.

Emerging of Valproic Acid as an Anti-Myeloma Agent.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3482-3482
Author(s):  
Kenichi Kitazoe ◽  
Masahiro Abe ◽  
Masahito Choraku ◽  
Kumiko Kagawa ◽  
Jin Asano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Valproic Acid ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Bone Destruction ◽  
Bone Marrow Microenvironment ◽  
Cytotoxic Effects ◽  
Growth And Survival ◽  
The Impact

Abstract Multiple myeloma (MM) expands in a manner dependent on the bone marrow microenvironment, and develops devastating bone destruction. MM is still an incurable disease, and preferentially arises in the elderly. Therefore, novel well-tolerated therapeutic alternatives are wanted especially for elderly patients with MM. Valproic acid (VPA), a well-tolerated and safe anti-epileptic agent with extensive clinical experience, has recently been shown to be a class I- and IIa-specific HDAC inhibitor, and induce cytotoxic effects on various types of tumor cells. In the present study, we evaluated the impact of VPA on MM cell growth and survival as well as MM-induced bone marrow microenvironment. VPA reduced viable cell numbers to less than 50 % from the baseline at day 2 in all MM cell lines (5/5) as well as primary CD138-positive MM cells (4/4) tested, and a portion of B cell (2/5) and T cell (1/3) lines, but not in AML cell lines (0/4) at 100 microg/ml, a therapeutic concentration for epilepcy, which raises a possibility for VPA as a therapeutic agent against MM. Interestingly, CD138-negative non-MM bone marrow cells remained intact and CFU-GM numbers were not affected by VPA, suggesting tumor-specific actions of VPA. VPA induced death receptor- but not mitochondrial pathway-mediated apoptosis with down-regulation of cellular FLICE-inhibitory protein (c-FLIP) and cleavage of caspase 8 in RPMI8226 MM cells. Furthermore, VPA down-regulated cyclin D1, and up-regulated the cyclin-dependent kinase inhibitor p21(Cip1) with accumulation of MM cells at G0/G1 phase, suggesting the involvement of cell cycle arrest in anti-proliferation actions of VPA. Notably, VPA at therapeutically relevant concentrations potentiated the induction of apoptosis by dexamethasone which triggers the release of Smac from mitochondria. However, VPA did not enhance the cytotoxic effects of cell cycle-specific agents including doxorubicine and melphalan. The VPA-induced tumor cell dormancy may reduce the susceptibility of MM cells to such cell cycle-specific agents. In parallel with MM progression, angiogenesis as well as osteoclastogenesis are enhanced in the bone marrow. We previously demonstrated that MM cell-osteoclast (OC) interactions enhance the growth and survival of MM cells as well as angiogenesis. Therefore, we next investigated the effects of VPA on MM cell-OC interactions and angiogenesis. Although VPA showed no significant effects on osteoclastogenesis induced by MM cells, VPA suppressed the growth and survival of RPMI8226 and U266 MM cells in the presence of OCs generated from monocytes to the levels similar to those without OCs. Furthermore, VPA potently inhibited in vitro vascular tubule formation enhanced by conditioned media from co-cultures of MM cells and OCs. Such anti-angiogenic effects of VPA was further potentiated in concert with thalidomide. Collectively, the present study suggests that VPA exerts multi-factorial anti-MM actions and may serve as a novel well-tolerated therapeutic alternative against MM.

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