bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Apoptosis by Didox Via Down-Regulation of Bcl-2 Family Proteins in Multiple Myeloma (MM).
Authors: Raje Noopur , Kumar Shaji , Hideshima Teru , Ishitsuka Kenji , Roccaro Aldo , Yasui Hiroshi , Hamasaki Makoto , Shiraisi Norihiko , Munshi Nikhil C. , Elford Howard , Anderson Kenneth C. 
Published: April 2020

Abstract
Ribonucleotide reductase is the rate-limiting enzyme of deoxynucleoside triphosphate synthesis and is therefore an excellent target for cancer chemotherapy. Inhibition of ribonucleotide reductase results in inhibition of DNA synthesis and has anti-neoplastic effects. Here we examine the anti-MM activity of the novel ribonucleotide reductase inhibitors (RRIs) Didox, Imidate, and Trimidox. All three RRIs showed potent cytotoxicity against MM cells in 48-hour cultures. Didox was studied further due to its potential for clinical development. Apoptosis was induced in MM cell lines exposed to Didox (200mmol/l), evidenced by increased sub-G1 cell fraction. Didox-induced cytotoxicity was associated with caspase-8 and poly ADP-ribosepolymerase (PARP) cleavage, as demonstrated by western blot analysis. Didox induced apoptosis even in cell lines resistant to conventional chemotherapy (doxorubicin, melphalan, dexamethasone) and overcame the proliferation of MM cells triggered by interleukin-6 (IL-6), insulin like growth factor-1 (IGF-1) and tumor cell binding to bone marrow stromal cells (BMSCs). Importantly, apoptosis of MM cells triggered by Didox was accompanied by a down-regulation of anti-apoptotic proteins Bcl-2, Bclxl, and XIAP. Cell signaling data indicated that Didox induced a time- and dose-dependent inhibition of pSTAT3. Although, Didox has been reported to inhibit radiation-induced NF-KB activation in prostate cancer cell lines, here we found that it triggered activation of NF-KB, associated with a degradation of IKBa, in MM. Ongoing pre-clinical studies are providing the rationale for a clinical trial of Didox either as a single agent or in combination with specific NF-KB/ IKB inhibitors, to improve patient outcome in MM.
Roles of CD19 Molecules That Suppress Proliferation and Induce Apoptosis in Human Myeloma Cells.
Authors: Zheng Xu , Ishikawa Hideaki , Tsuyama Naohiro , Abroun Saeid , Liu Shangqin , Li Fu-Jun , Otsuyama Ken-ichiro , Ma Zi , Maki Yasuko , Obata Msanori , Kawano Michio M. 
Published: April 2020

Abstract
CD19 is a B cell-specific membrane protein belonging to immunoglobulin superfamily, and acts as a positive or negative regulator in B cell signaling. Although plasma cells still express CD19, CD19 expression is lost in malignant plasma cells with the progression of multiple myeloma (MM) including monoclonal gammopathy of undermined significance (MGUS). To understand the pathological significance of loss of CD19 in human myelomas, we examined the biological effect of CD19 expression on myeloma cells by generating CD19 transfectants of a myeloma cell line, U266. CD19 transfectants showed slower growth rate in vitro than controls, such as mock and ΔCD19 transected with a truncated form of CD19. The growth-inhibitory effect was CD19-specific and presumably due to the intracellular signaling events via CD19 because this effect was not observed in ΔCD19. Furthermore, serum withdrawal rapidly induced the apoptosis of the CD19-transfectants that was rescued by insulin-like growth factor (IGF-I) as compared with CD19− controls. These may suggest that the CD19 transfectants are likely to be dependent on the growth factors, such as IGF-I, to survive and proliferate, and thus, susceptible to the serum deprivation-induced apoptosis. IGF-I activates extracellular signal-regulated kinase (ERK) 1/2 and phosphatidylinositol-3-kinase (PI-3K) that are important for proliferation of myeloma cells. Western bolt analysis showed that IGF-1-induced activation of ERK1/2 was reduced in the CD19 transfectants, although the similar levels of IGF-I receptors were expressed in the CD19 transfectants and CD19− controls. In contract, CD19 failed to inhibit the IGF-I-mediated PI-3K/AKT activation, whereas a downstream target in the PI-3K pathway, p70S6 kinase activation was decreased in the CD19 transfectants. However, the p70S6 kinase activity could be influenced by both ERK1/2 and PI-3K pathways after IGF-1 stimulation, and the MAPK pathway seems to be a major regulator for myeloma cell growth. Our results, therefore, suggest that the recovering expression of CD19 molecules and genes in human myeloma cells may be an important consideration in therapeutic approaches in human MM.
c-kit D816V Provides a Strong Signal for Myelomastocytic Differentiation and Cluster Formation in Murine Ba/F3 Cells.
Authors: Mayerhofer Matthias , Aichberger Karl J. , Florian Stefan , Krauth Maria-Theresa , Bilban Martin , Esterbauer Harald , Wagner Oswald , Kodym Reinhard , Sotlar Karl , Longley Jack B. , Horny Hans-Peter , Sillaber Christian , Valent Peter 
Published: April 2020

Abstract
The pathologic hallmark of systemic mastocytosis (SM) is differentiation and cluster formation of mast cells (MC) in hematopoietic tissues. The somatic c-kit mutation D816V is detectable in a majority of all SM patients independent of the proliferation-status of MC or subtype (indolent or aggressive) of disease. To investigate the role of c-kit D816V in the pathogenesis of SM, we established a Ba/F3 cell line with doxycycline-inducible expression of c-kit D816V. We found that c-kit D816V provides a strong signal for mast cell differentiation and cluster formation in Ba/F3 hematopoietic progenitor cells without enhancing their growth thereby resembling the clinical presentation of indolent SM (ISM). As assessed by gene chip analysis, induction of c-kit D816V resulted in expression of various differentiation antigens including mouse mast cell protease 5, mi transcription factor, histidine decarboxylase (HDC), secretory granule proteoglycan, IL-4 receptor, ICAM-1, and CD63 consistent with an early phase of mastopoiesis. By contrast, c-kit D816V did neither induce expression of granulo-monocytic antigens such as myeloperoxidase, IL-3 receptor, or GM-CSF receptor, nor expression of ‘late stage’ mast cell antigens such as FcεRI. The c-kit D816V-induced synthesis of histamine in Ba/F3 cells was confirmed by RIA. To examine the role of c-kit D816V in the pathogenesis of mastocytosis, we extended our analysis to bone marrow biopsy sections obtained from patients with ISM. In these experiments, the D816V-mutated form of c-kit was detected more frequently in micro-dissected tryptase-positive MC obtained from dense compact infiltrates (44.2%) than in diffusely spread MC in these patients (22.6%) (p&lt;0.05). In summary, our data establish a role for c-kit D816V in differentiation and cluster formation of neoplastic (mast) cells. Additional genetic hits, apart from c-kit D816V, may be responsible for aggressive growth of MC in advanced MC neoplasms.
Expression of the CD117 Antigen on Multiple Myeloma and Its Significance.
Authors: Li Juan , Luo Shaokai , Zhang Guocai , Hong Wende , Tong Xiuzhen 
Published: April 2020

Abstract
BACKGROUND & OBJECTIVE: Leukocyte differentiation antigen CD117 is one of the targets that tyrosine kinase selective inhibitors work on. CD117, whether the cell surface is expressed and the quality of its expression, is highly correlated with the tyrosine kinase selective inhibitors. And whether Multiple myeloma (MM) cells express CD117 and its expression quality is not reported domestic yet but only several reported overseas. In this study, CD117 expressed in MM cells is evaluated, which provide an theoretical evidence for tyrosine kinase selective inhibitors used in the MM, meanwhile, the value of the CD117 expressed in MM cells is estimated.
METHODS:CD117,CD56,CD54 were measured by three -color flow cytometry with CD45/SSC gating strategy.
RESULTS:Of 48 patients with MM, 17(35.5%) CD117 expression was positive in myeloma cells, and CD56, CD54 expression was positive in 39(81.2%), 48(100.0%), respectively. CD117 expression in myeloma cells was low compared with CD56, CD54 in 48 patients with MM; CD117 positive expression showed a positive correlation with myeloma cells in the bone marrow; CD117 positive in IgG type of MM was 64%, higher than other types such as light chain or IgA.CD117 positive showed no significant difference in different stage, untreated, relapsed and refractory patients (P&gt;0.05, P&gt;0.01); In untreated MM patient, chemotherapy of VAD in CD117 positive patient, the effectiveness was 71.4%, compared with the reaction rate 66.7% in CD117 negative, showed no significant difference (P&gt;0.05).
CONCLUSIONS:CD117 &lt;/SU
The Proteomic Analysis of Sera for the Discovery of Biomarkers for Multiple Myeloma.
Authors: Kwak Jae-Yong , Lee Na-Ri , Song Eun-Gi , Yim Chang-Yeol , Kwak Yong-Geun 
Published: April 2020

Abstract
Multiple Myeloma (MM) fits in the group of plasm cell disorders characterized by neoplastic proliferation of single clone of plasma cell engaged in the production of a monoclonal immunoglobulin. The cause of MM is unclear, but a genetic predisposition may play a role and cytogenetic abnormalities are considered to be the most important prognostic factor. The proteomic analysis of MM emerges as a key complement to gene expression profiling, primarily because regulation of protein expression can buffer the magnitude of changes occurring at the gene transcription level. In the present study, to identify biomarkers of initial diagnosis, detection of relapse, monitoring for minimal residual disease and prognostic marker in MM by a lesser invasive method, serum proteins reflecting alteration in their proteomes were analyzed. We compared two-dimensional electrophoresis patterns of human sera of twelve patients with multiple myeloma with that of normal twelve subjects. The differentially expressed spots were identified by matrix-assisted laser desorption/ionization-time-of flight (MALDI-TOF) and electrospray ionization quadupole time of flight (ESI-Q-TOF) mass spectrometry. We identified several proteins altered in sera of MM patients. These results suggest that these proteins can be used as a lesser invasive diagnostic, monitoring and prognositic biomarkers of MM if further studies were done.
Pre-Transplantation Level of Minimal Residual Disease Detected by Quantitative Real-Time IgH-PCR Is a Prognostic Parameter in Patients with Multiple Myeloma.
Authors: Fenk Roland , Korthals Mark , Kobbe Guido , Steidl Ulrich , Graef Thorsten , Rohr Ulrich-Peter , Ruf Leilani , Hoyer Barbara , Neumann Frank , Haas Rainer , Kronenwett Ralf 
Published: April 2020

Abstract
Background: High-dose chemotherapy with autologous stem cell transplantation has improved outcome and survival of patients with multiple myeloma. However, the majority of patients suffer from relapse. Using real-time quantitative (RQ) PCR we have shown before (Haematologica 89,2004) that the amount of residual tumor cells in the bone marrow of patients before transplantation is of prognostic relevance. In this study we evaluated in a larger group of patients with multiple myeloma whether a pre-transplantation level of clonotypic cells in the bone marrow is predictive for time-to-progression (TTP) and overall survival (OS). Further, we compared results with known prognostic factors.
Patients and Methods: Bone marrow samples of 19 patients with stage II/III multiple myeloma were obtained after induction therapy but before transplantation. Immunoglobulin heavy chain (IgH) RQ-PCR using patient-specific Taqman probes was performed to quantify pre-transplantation tumor levels. The proportion of clonotypic cells was assessed as IgH/2 beta-actin ratio in percent. Medical records of patients were reviewed for prognostic factors and outcome.
Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.3 %. At 23 month median follow-up after transplantation the median TTP and OS in our study were 14 and 36 month, respectively. The threshold level of 0.03% clonotypic cells identified two prognostic groups (p&lt;0.0001, log rank). Twelve patients in the bad prognostic group had an early relapse with a median TTP of 9 month (range: 3 – 17 month). All patients in the good prognostic group (n=7) had ongoing remissions after a median follow-up of 24 month (range: 13–44 month). Univariat analysis was performed including other prognostic factors at the time before transplantation such as cytogenetic abnormalities, beta2-microglobulin, hemoglobulin, platelet count, LDH, CRP, serum albumine and age. Besides the pre-transplant level of minimal residual disease, CRP level was predictive for TTP. In multivariat analysis using a step-wise cox regression model grouping by pre-transplantation tumor level was the only prognostic factor for TTP (p = 0.05). Moreover, low pre-transplantation tumor levels also showed a trend for a better OS, but in multivariat analysis only normal cytogenetics were predictive for a superior outcome (p = 0.03).
Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for the progression-free survival of patients with multiple myeloma and thus helps to guide therapeutic interventions
Soluble Factors Secreted from CD40 Ligand-Transfected Dendritic Cells Enhance TRAIL-Induced Apoptosis of Multiple Myeloma.
Authors: Tomihara Kei , Kato Kazunori , Hamada Hirofumi 
Published: April 2020

Abstract
Dendritic cells (DCs) belong to a family of antigen presenting cells that play a crucial role in the regulation of cellular and humoral immune responses to bacteria, virus and cancer. Recent studies also revealed that IFN-stimulated monocyte-derived DCs expressed functional TNF-related apoptosis-inducing ligand (TRAIL), suggesting that DCs may become cytotoxic effector cells to tumors. In this study, we investigate whether gene transfer of CD40-ligand (CD40L), that is known to be a potent stimulator in DC maturation, could induce cytotoxic activity of DCs or modulate susceptibility to TRAIL that is expressed on cytotoxic T and NK cells. Human monocyte-derived DCs infected with adenovirus vector encoding human CD40L (CD40L-DC) were induced to express superior higher levels of T-cell costimulatory molecules, DC maturation markers, MHC molecules and the production of IL-12 than soluble CD40L or TNF-alpha treated DCs. In addition to the phenotypic alternation of CD40L-DC, we found that cultivation of multiple myeloma cells ARH-77 with CD40L-DC significantly inhibited the expression of phospho-AKT and induced apoptosis in vitro. However, we could not detect the expression of TRAIL and Fas-ligand on CD40L-DC by flow cytometry, suggesting that these molecules are not involved. To examine whether soluble factors produced by CD40L-DC contribute to tumor cell apotosis, we cultured myeloma cells MM1S or ARH-77 with CD40L-DC in transwell plates. We found that myeloma cells in transwell culture were not lysed for 48 hours, but the susceptibility of apoptosis by recombinant TRAIL protein could be increased. To investigate soluble factors that could affect TRAIL sensitivity of myeloma cells, we next tested the effect of neutralizing antibodies specific for CD40L and TRAIL or recombinant IFN-gamma that might modulate TRAIL sensitivity. However, antibodies and recombinant protein did not affect, indicating that these factors might be not involved. Our findings suggest that CD40L-transduced DCs have the ability of induction of TRAIL susceptibility of multiple myeloma cells mediated by soluble factors that are currently investigated.
The Chromosomal Pattern 14q-Translocation Plus 13q-Deletion Is Characteristic for Multiple Myeloma after a Preceding Monoclonal Gammopathy of Undetermined Significance.
Authors: Drach Johannes , Ackermann Jutta , Baldia Catrin , Kaufmann Hannes , Noesslinger Thomas , Gisslinger Heinz , Seidl Sonja , Sagaster Verena , Keck Andrea , Ludwig Heinz , Jaeger Ulrich , Zielinski Christoph 
Published: April 2020

Abstract
Multiple myeloma (MM) may be preceded by a monoclonal gammopathy of undetermined significance (MGUS), but it is at present unclear whether or not MM post-MGUS is biologically and clinically different from MM de-novo. To address this issue, we have performed a molecular cytogenetic analysis of 32 cases of MM post-MGUS (median time between recognition of MGUS and transition to MM, 7.6 years; range, 2.6 years to 19.5 years) and compared the findings with those of 256 patients with MM de-novo, in whom no previous history of MGUS had been documented. FISH studies of clonal plasma cells (cytoplasmic Ig positive) with probes for IgH translocations [t(14q32)], t(11;14)(q13;q32), t(4;14)(p16;q32), and deletion of 13q14 [del(13q14)] revealed results summarized in Table 1:
Serial studies of MGUS plasma cells and MM post-MGUS plasma cells from 12 of these patients have thus far indicated that all chromosomal abnormalities observed at MM post-MGUS were already present in the MGUS plasma cells; most notably, there was one patient with t(4;14) plus del(13q) who had both abnormalities at the time of MGUS 94 months prior to transition to MM. Collectively, our data suggest that MM post-MGUS is characterized by a distinct chromosomal pattern, in particular a high frequency of t(14q32) plus del(13q14), frequent occurrence of a t(11;14), but low frequency of a t(4;14). We are currently studying the t(14q32) plus del(13q) chromosomal pattern in MGUS to investigate its potential value as a risk factor for transition from MGUS to MM.
Table 1: FISH of MM post-MGUS versus MM de novo
Abnormality MM post-MGUS MM de-novo P-value Any t(14q32) 24/32 (75%) 114/256 (44.5%) .05 t(11;14)(q13;q32) 9/32 (28.1%) 32/256 (12.5%) .05 t(4;14)(p16;q32) 2/32 (6.3%) 27/256 (10.6%) .37 del(13q14) 19/32 (59.4%) 102/256 (39.8%) .13 del(13q14) plus t(14q32) 18/19 (94.7%) 57/102 (55.8%) .11 del(13q14) plus t(11;14) 6/19 (31.6%) 9/102 (8.8%) .03
High Levels of Soluble Immunoregulatory Receptors in Patients with WaldenströM’s Macroglobulinemia.
Authors: Hunter Zachary R. , Branagan Andrew R. , Santos Daniel Ditzel , Tournilhac Olivier , Hatjiharissi Evdoxia , Xu Lian , Manning Robert J. , Treon Steven P. 
Published: April 2020

Abstract
CD25, CD27, CD30 and CD40 are receptors for IL-2, CD70, CD153 and CD154, respectively, which provide important signaling for both B- and T-cell immune responses. We therefore examined the sera of patients with Waldenstrom’s macroglobulinemia (WM), a B-cell disorder characterized by excess IgM secreting bone marrow lymphoplasmacytic cells (LPC) for the presence of soluble CD25, CD27, CD30, CD40, IL-2, CD153, and CD154. Sera were from patients with active disease and off-therapy. Sera from healthy age matched donors (HD) was used for controls. The results of these studies were as follows:
WM ELISA Results HD ELISA Results p-value n= median range n= median range sCD25 pg/ml 2.647x10−6 41 3418.99 3–19756.2 20 573.6 184.96–891.03 IL-2 pg/ml 0.72385 41 22.96 3–76.83 20 11.07 5.64–64.7 sCD27 U/ml 2.4727x10−7 26 7.45 0–19.42 10 0 0–2.78 sCD70 ND ND ND ND ND ND ND sCD30 U/ml 0.00088 25 89.25 0–550.81 15 39.12 0–135.25 sCD153 ng/ml 0.68388 25 8.18 0–43.8 15 5.65 0–24.82 sCD40 pg/ml 0.02484 25 101.39 11.76–584.99 11 50.73 0–150.5 sCD154 pg/ml 0.81317 55 949.58 92–4973.16 17 1078.03 351.88–2323.38
Considering our recent studies demonstrating a role for mast cells (MC) in supporting WM cell growth (JCO 2004 22:571S), we examined bone marrow LPC along with MC from WM patients for expression of CD25, CD27 and CD40 and/or their ligands by flow cytometry and RT-PCR analysis. The results of these studies are as follows:
Flow Cytometry RT-PCR WM MC WM MC CD25 4/10 (40%) 2/7 (29%) 7/9 (78%) 7/15 (47%) IL-2 ND ND ND ND CD27 5/12 (42%) 2/8 (25%) 7/7 (100%) 4/7 (57%) CD70 6/6 (100%) 10/11 (91%) 7/7 (100%) 2/7 (29%) CD30 1/21 (4.7%) ND ND ND CD153 3/7 (43%) 12/13 (92%) 2/2 (100%) 9/11 (82%) CD40 25/30 (83%) ND ND ND CD154 2/3 (67%) 9/13 (69%) 7/9 (78%) ND
The above studies demonstrate high levels of circulating immunoregulatory receptors, and expression of these receptors and/or their ligands on WM tumor and mast cells. Studies addressing their role in immune dysregulation in WM are underway.
CD52 Is Expressed on Human Mast Cells and Is a Therapeutic Target for the Anti-CD52 Monoclonal Antibody Campath-1H in Waldenstrom’s Macroglobulinemia and Mast Cell Disorders.
Authors: Santos Daniel Ditzel , Hatjiarissi Evdoxia , Tournilhac Olivier , Xu Lian , Branagan Andrew , Hunter Zachary , Catsells Mayan , Anderson Kenneth C. , Treon Steven P. 
Published: April 2020

Abstract
Campath-1H is a monoclonal antibody used in the treatment of CD52 expressing B-cell malignancies. Recently, we and others have observed that Campath-1H shows unusually high activity in patients with relapsed/refractory Waldenstrom’s macroglobulinemia (WM), a B-cell malignancy with excess bone marrow mast cells (BMMC). Importantly, as we have recently shown, BMMC appear to provide direct support for WM tumor cell growth (Tournilhac et al, JCO 2004 22:571S), and are therefore a potential therapeutic target in WM. We therefore examined BMMC from patients with WM and other mast cell disorders for cell surface expression of CD52, and targeting by Campath-1H in preclinical studies. Multicolor flow cytometric analysis demonstrated CD52 expression on BMMC (FceRI+, CD117+) from 13/15 WM; 2/2 systemic mastocytosis (SM) patients; 2/4 healthy donors; as well as on the LAD and HMC MC lines. Moreover, RT-PCR analysis confirmed CD52 expression in sorted BMMC from 6/7 WM, along with 6/6 healthy donors. Importantly, Campath-1H induced high levels of antibody dependent cell mediated cytotoxicity (ADCC) actvity against LAD mast cells using activated NK effector cells. No direct cytotoxicity or antiproliferative activity by Campath-1H on LAD cells was observed. These studies demonstrate that CD52 is widely expressed on human MC and provide support for the use of Campath-1H in the treatment of WM and other systemic mast cell disorders.
IgA and IgG Hypogammaglobulinemia Persists in Most Patients with Waldenstrom’s Macroglobulinemia Despite Therapeutic Responses, Including Complete Remissions.
Authors: Treon Steven , Branagan Andrew , Hunter Zachary , Santos Daniel Ditzel , Tournilhac Olivier , Hatjiharissi Evdoxia , Xu Lian , Manning Robert 
Published: April 2020

Abstract
Recurrent infections are common in pts with Waldenstrom’s macroglobulinemia (WM) and may be related to IgA and IgG hypogammaglobulinemia. The impact of therapy and therapeutic responses on humoral immunity in WM is therefore of clinical interest. We examined IgA and IgG levels before and after therapy in 92 serially treated and responding WM patients. Their median age was 59 yrs and 70/92 (76.1%) were previously untreated. Median follow-up for all patients was 11 (range 3-134) months. Pre-therapy, 72/92 (78.2%) and 70/92 (76.1%), and post-therapy 82/92 (89.1%) and 80/92 (86.9%) pts demonstrated IgG (&lt;700 mg/dL) and IgA (&lt;70 mg/dL) hypogammaglobulinemia, respectively. Changes in median IgG and IgA levels by therapy were as follows:
N= Pre-IgG Post-IgG T-Test Pre-IgA Post-IgA T-Test Nucleoside analogue 5 438 399 0.63 32 38 0.35 Rituximab 17 455 358 0.29 35 29 0.43 Rituximab/Thalidomide 19 388 374 0.3 28 24 0.32 Rituximab/Nucleoside 21 571 423 0.006 55 29 0.05 CHOP 3 702 568 0.62 48 30 0.82 CHOP/Rituximab 14 537 383 0.1 61 36 0.21 Chlorambucil ± steroids 5 837 659 0.57 129 66 0.52 Campath-1H 7 521 444 0.62 28 27 0.61 HD Dexamethasone 1 269 173 NA 27 28 NA All therapies 92 480 398 0.008 38 28 0.01
Changes in median IgG and IgA levels by response category were as follows:
N= Pre-IgG Post-IgG T-Test Pre-IgA Post-IgA T-Test CR 8 644 472 0.05 75 37 0.08 PR 70 415 349 0.09 27 28 0.91 MR 14 474 394 0.01 38 26 0.02
These studies demonstrate that IgA and IgG hypogammaglobulinemia persists despite therapeutic responses, including complete remissions in patients with WM. Futhermore, the therapeutic regimen employed may aggravate persistent IgA and IgG hypogammaglobulinemia.