bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of T Cell Costimulatory and Downregulatory Gene Polymorphisms and Susceptibility to Multiple Myeloma.
Authors: Frydecka Irena , Pawlak Edyta , Karabon Lidia , Sowinska Ewa , Jonkisz Anna , Lebioda Arleta , Dobosz Tadeusz , Suwalska Katarzyna , Tutak Anna , Kuliczkowski Kazimierz 
Published: April 2020

Abstract
Multiple myeloma (MM) is a B-lineage malignancy characterized by an accumulation of isotype-switched, immunoglobulin-producing monoclonal plasma cells. Additionaly phenotype and functional abnormalities of T cell are observed. The implication of T cells in the development of plasmocytoma has been shown in murine model. The study was undertaken to evaluate the association between polymorphisms of the genes encoding major T cell costimulatory (CD28, ICOS) and downregulatory (CTLA-4) molecules and susceptibility to MM in a Polish population. One hundred patients with MM and 202 healthy subjects were studied. Genomic DNA was isolated from whole frozen blood using the NucleoSpinR Blood kit. Allele identification was achieved by PCR amplification. The amplified product for SNP loci was purified and minisequenced using the commercial kit SNapShot (PE Applied Biosystems). The dinucleotide repeat polymorphism was studied by PCR and fluorescence based technique. The products were analyzed on the ABI PRISM 310 Genetic Analyzer (ABI PRISM 310 capillary electrophoresis system).
We found an association of 49G in exon 1 and (AT)82 alleles in 3′untranslated region in the CTLA-4 gene with MM [p=0.018, OR=1.57, 95% CI=1.08–2.29 and p=0.0013, OR=1.85, 95% CI=1.27–2.72, respectively] while no association between T/C substitution in intron 3 of the CD28 gene, the dinucleotide (GT)n repeat polymorphism in intron 4 in ICOS gene and C/T base exchange in the promoter (position −318) in the CTLA-4 gene and MM was observed. Our results indicate that the A/G substitution in exon 1 and microsatelite polymorphism in the 3′untranslated region in the CTLA-4 gene might be a susceptibility locus for MM.
The present study is the largest and comprehensive to date to evaluate the association between genetic polymorphisms of genes encoding T cell costimulatory and downregulatory molecules and susceptibility to MM.
Monoclonal Gammopathy (MG) Associated with Gaucher Disease (GD). Report of 16 Cases from the French Observatoire on Gaucher Disease (FROG Study).
Authors: Grosbois Bernard , Leone Jean , Camou Fabrice , Dalbies Florence , Harle Jean Robert , Lamy Thierry , Luca Luminita , Plane Christophe , Robin Jean Pierre , Rose Christian , deRoux-Serratrice Christine , Solary Eric , Steiger Jean Marie 
Published: April 2020

Abstract
In addition to its common bone and visceral manifestations GD is frequently associated with B cell proliferation leading possibly to MG. The objective of our study was to determine the frequency and presentation of MG in GD patients.
Material and methods. FROG is a cross-sectionnal epidemiological study on adult GD involving 64 French centers. Standard clinical, biological(including serum protein electrophoresis) and imaging data performed as part of usual management within the 3 previous years were collected at the time of a routine visit. In patients with suspected MG specific additionnal data were studied:immunofixation, dosage of immunoglobulins, bone marrow aspiration.
Results. From 05/2005 to 06/2006 seventy seven adult GD type 1(38 male,39 female;mean age 47.3 years, range 18 to 78 years) were included. Sixteen cases of MG(20.8%) were observed (10 male and 6 female;mean age 61.25 years, range 47 to 79 years). Mean age of 61 cases of GD without MG(43.8 years;range 18 to 70 years)was significantly lower(p&lt;0.0001). Thirteen cases(17%)were classified as MGUS and 3 (3.8%) as B cell malignancy:1 multiple myeloma, 1 Chronic Lymphocytic Leukemia, 1 Non Hodgkin Lymphoma. In 3 cases MG and GD were diagnosed simultaneously. In 13 cases MG was diagnosed in the course of GD(mean interval 12.2 years;range 6.7 to 16 years). MG immunochemical typing revealed 75 % Ig G, 12.5 %Ig A, 12.5 %Ig M, 75 % Kappa and 25 % Lambda. We observed one biclonal gammopathy(IgG and IgA Kappa). One case of MGUS was associated with capillary leak syndrome. In two patients MG level decreased with enzyme replacement therapy.
Conclusion. Frequency of MG in GD observed in our study (20.8%)is largely higher than in general population (1%). Furthermore this frequency is higher than in previous series of GD. However in GD patients, as observed in general population, frequency of MG seems to be related to age as mean age of patients with MG is significantly higher than mean age of patients without MG. Finally these data assess the need of specific follow-up regarding the high frequency of MG and the risk of B cell malignancy in GD patients.
Novel Etodolac Analog SDX-308 (CEP-18082) Induces Cytotoxicity in Multiple Myeloma Cells Associated with Inhibition of Wnt/β-Catenin Pathway.
Authors: Yasui Hiroshi , Hideshima Teru , Ikeda Hiroshi , Ocio Enrique M. , Kiziltepe Tanyel , Vallet Sonia , Okawa Yutaka , Chhetri Shweta , Sukhdeo Kumar , Ishitsuka Kenji , Podar Klaus , Raje Noopur , Chauhan Dharminder , Cattasco Daniel R. , Anderson Kenneth C. 
Published: April 2020

Abstract
In a previous study we reported that R-enantiomer of etodolac (R-etodolac) which is under investigation in Phase II clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in both drug-sensitive and drug-resistant multiple myeloma (MM) cell lines, as well as in patient MM tumor cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of etodolac, has more potent cytotoxicity than R-etodolac against MM cell lines and tumor cells from patients with refractory MM. It also induces cytotoxicity against bortezomib-resistant tumor cells. The molecular mechanisms whereby SDX-308 triggers MM cell cytotoxicity were next delineated. SDX-308 induces apoptosis via caspase-8/-9/-3 activation and poly(ADP-ribose) polymerase PARP cleavage. It strongly inhibits Wnt/β-catenin pathway by blockade of nuclear translocation of β-catenin, followed by significant inhibition of transcription and expression of target proteins. These target proteins include cell cycle regulatory c-myc molecules and anti-apoptotic survivin molecules. Neither interleukin-6 nor insulin-like growth factor-1, which induce MM cell growth and abrogate Dex-induced apoptosis, protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel etodolac analog SDX-308 has more potent cytotoxicity in MM cells than R-etodolac even in the context with BM microenvironment, providing the preclinical rationale to conduct clinical trials of this agent to improve patient outcome in MM.
Correlation of Serum Free Light Chain Levels with Other Parameters in Myeloma.
Authors: Stein Regina , Mehta Jayesh , Vickrey Eric , Resseguie William , Singhal Seema 
Published: April 2020

Abstract
Estimation of serum free light chains (SFLC; SFKLC - kappa, SFLLC - lambda, SFKLR - kappa:lambda ratio; normal 0.26–1.65.) is useful in selected patients with non-secretory myeloma, and in light chain disease with anuric renal failure. Its utility in other clinical situations is unclear. 489 SFLC levels in 135 myeloma patients were analyzed to see if there was a significant correlation between them and other, more conventional immunologic parameters such as serum total light chain (STLC; STKLC - kappa, STLLC - lambda) levels and immunoglobulin (Ig) levels. The underlying premise was that lack of significant correlation would suggest potential value of SFLC independent of standard tests, whereas significant correlation would suggest questionable independent value of SFLC. The table below shows SFLC and STLC levels and ratios.
Parameter Median (range) Correlation with SFKLC Correlation with SFLLC Correlation with free k:l ratio SFKLC 14.4 (0.59–11525) SFLLC 18.2 (0.72–10100) Free k:l ratio 0.83 (0–1211.76) STKLC 745 (11–8810) r=0.08; P=0.07 STLLC 256 (11.6–11000) r=0.11; P=0.01 Total k:l ratio 2.51 (0–245) r=0.12; P=0.008
Poor correlation between free and total results within each light chain subtype (Figure 1 - log scale) and between free and total ratios (Figure 2- log scale) suggests that SFLC values provide information that is independent of STLC values because STLC values cannot be used to predict SFLC values.
Figure Figure Figure Figure
The table below shows correlation between Ig and SFLC/STLC levels. For these analyses, the total Ig of the specific heavy chain subtype and SFLC/STLC of the specific light chain subtype were studied (IgG and SFKLC with IgG kappa monoclonal protein, IgA and STLLC with IgA lambda monoclonal protein, etc). Very strong correlation between STLC and Ig levels suggests that STLC values do not provide information that is independent of Ig levels. On the other hand, poor correlation between SFLC and Ig levels suggests that SFLC values do provide information that is independent of Ig values.
Monoclonal protein SFLC correlation STLC correlation IgG kappa r=0.04; P=0.66 r=0.89; P&lt;0.0001 IgG lambda r=0.13; P=0.51 r=0.99; P&lt;0.0001 IgA kappa r=0.49; P=0.004 r=0.77; P&lt;0.0001 IgA lambda r=-0.04; P=0.89 r=0.94; P&lt;0.0001
These data show that SFLC estimation provides information that is independent of standard quantitative serologic tests used in plasma cell dyscrasias. However, rigorous prospective evaluation of the test is needed to see if this additional information is of any clinical relevance in settings other than non-secretory disease and light chain disease with anuria.
Role and Regulation of Heat Shock Proteins 90alpha and 90beta in Multiple Myeloma.
Authors: Chatterjee Manik , Jain Sarika , Stühmer Thorsten , Andrulis Mindaugas , Ungethüm Ute , Kuban Ralf-Jurgen , Bommert Kurt , Topp Max , Krämer Doris , Müller-Hermelink Hans K. , Einsele Herrmann , Axel Greiner , Bargou Ralf C. 
Published: April 2020

Abstract
The combined blockade of the IL-6R/STAT3 and the MAPK signaling pathways has been shown to inhibit bone marrow microenvironment-mediated survival of multiple myeloma (MM) cells. Here, we identify the molecular chaperones heat shock protein (Hsp) 90alpha and beta as target genes of both pathways. Interestingly, in situ overexpression of both Hsp90 proteins was observed in the majority of MM, but not in MGUS or in normal plasma cells. SiRNA-mediated knockdown of Hsp90 or treatment with the novel Hsp90 inhibitor 17-DMAG attenuated the levels of phospho-STAT3 and phospho-ERK and decreased the viability of MM cells. Although knockdown of Hsp90beta unlike knockdown of Hsp90alpha was sufficient to induce apoptosis, this effect was strongly increased when both Hsp90s were targeted, indicating a cooperation of both. Given the importance of the bone marrow microenvironment for drug resistance and MM cell survival, apoptosis induced by Hsp90 inhibition was not mitigated in the presence of bone marrow stromal cells, osteoclasts or endothelial cells. These observations suggest, that a positive feedback loop consisting of Hsp90alpha/beta and major signaling pathways supports the survival of MM cells. Our results emphasize a role for Hsp90alpha and Hsp90beta in MM pathogenesis.
No Adverse Impact of 13q14 and P53 Deletion, t(4;14)(p16;q32) or Overrepresentation of CMYC(8q24) as Detected by Fluorescence In Situ Hybridization on Outcome in Patients with Multiple Myeloma Following Dose-Reduced Allogeneic Stem Cell Transplantation.
Authors: Hansen Timon , Schilling Georgia , Liebisch Peter , Schwerdtfeger Rainer , Perez-Simon Jose Antonio , Bornhaeuser Martin , Otterstetter Svenja , Dierlamm Judith , Nagler Arnon , Hossfeld Dieter Kurt , Bokemeyer Carsten , Zander Axel R. , Kroeger Nicolaus 
Published: April 2020

Abstract
Deletions of chromosome bands 13q14 and 17p13 (P53) as well as t(4;14)(p16;q32) or overrepresentation of CMYC are known to be adverse prognostic factors for time to progression (TTP) and overall survival (OS) in myeloma patients receiving conventional or high-dose chemotherapy followed by autologous stem cell transplantation. We investigated the impact of these chromosomal abnormalities as detected by fluorescence in situ hybridization combined with immunofluorescent cytoplasm immunoglobulin staining (cIg-FISH) on outcome after dose-reduced melphalan/fludarabin based allogeneic stem cell transplantation (SCT) in 64 patients (pts) with multiple myeloma (MM). Median age was 52 years (34 – 67 ys.), 38 patients were male, 26 female. 45 pts received stem cell graft from an unrelated donor and 19 pts from HLA-identical sibling. Deletion of 13q14 was found in 35 out of 64 pts (55%), P53 deletion in 7 out of 64 pts (11%), t(4;14)(p16;q32) in 11 out of 56 pts (20%) and trisomy of CMYC in 12 out of 55 pts (22%). The following strong correlations among the genetic changes have been seen: six out of seven pts with P53 deletion also showed deletion in chromosome band 13q14 (86%), which was also found in nine out of eleven pts with t(4;14) (82% del 13) and nine out of twelve pts with CMYC trisomy (75% del 13). The estimated event-free (EFS) and overall survival (OS) at four years for the entire study population was 48% and 57%, respectively. No significant difference of the estimated event-free survival at 3 years was seen for pts with del 13 (42% vs 54%, p=0,4), with P53 deletion (43% vs 49%, p=0,27) and for pts with t(4;14) (46% vs 62%, p=0,69) or CMYC overrepresentation (37% vs 50%, p=0,35). Comparison of pts showing both del 13 and P53 deletion, del 13 and t(4;14), del 13 and trisomy of CMYC or t(4;14) and CMYC trisomy with the rest of the study population did not show a significantly reduced EFS either. Even the comparison of pts with any chromosomal abnormalities and pts without any genetic changes detected by FISH did not show a significant difference in EFS (48% vs 50%, p=0,8). These preliminary data suggest that the negative prognostic impact of chromosomal abnormalities such as deletion of 13q14, P53 deletion, t(4;14) and overrepresentation of CMYC may be overcome by allogeneic SCT probably due to the graft versus myeloma effect.
Leukemia Associated Mutants of SHP2 Protein Tyrosine Phosphatase Prevent HoxA10 Tyrosine Phosphorylation in Differentiating Myeloid Cells, Thereby Blocking Transcription of the Gene Encoding Gp91phox.
Authors: Lindsey Stephan , Wang Hao , Eklund Elizabeth A. 
Published: April 2020

Abstract
Gp91phox is a component of the membrane bound, catalytic unit of the phagocyte respiratory burst oxidase. Transcription of the CYBB gene, which encodes gp91phox, is restricted to phagocytes that have differentiated beyond the promyelocyte stage. Transcription continues in mature myeloid cells until cell death and is increased by inflammatory mediators such as LPS or interferon gamma as part of the system of host defense. Previously, we determined that a negative cis element in the CYBB promoter binds a multi-protein complex in undifferentiated myeloid cells which includes the homeodomain proteins HoxA10 and Pbx1, and the histone deacetylase HDAC2. During cytokine induced differentiation, binding of this complex decreases, permitting binding of positive trans factors which activate an adjacent cis element in the CYBB promoter. In previous studies, we also determined that tyrosine phosphorylation decreases HoxA10 binding affinity for the CYBB repressor element. We found that HoxA10 is tyrosine phosphorylated in response to treatment of myeloid progenitor cells and myeloid cell lines with hematopoietic cytokines such as G-CSF, M-CSF and interferon gamma. In undifferentiated myeloid cells, HoxA10 is maintained in a non-tyrosine phosphorylated state by the protein tyrosine phosphatases SHP1 and SHP2. We find that activity of these PTPs decreases during myeloid differentiation. This decrease in PTP activity contributes to increased HoxA10 tyrosine phosphorylation, resulting in CYBB gene transcription as differentiation proceeds. Recently, leukemia associated, activating mutations of SHP2-PTP have been described in human subjects with Juvenile Chronic Myelomonocytic Leukemia (JMMoL), AML and MDS. These SHP2 mutations induce a conformational change which unmasks the PTP domain, resulting in constitutive activation. In these studies, we find that expression of one such leukemia associated SHP2-mutant impairs HoxA10 tyrosine phosphorylation during myelopoiesis. This results in sustained repression of CYBB transcription and decreased gp91phox expression in differentiating cells. Since gp91phox is one of the rate limiting oxidase component proteins during myeloid differentiation and the inflammatory response, activating mutants of SHP2-PTP would therefore be expected to impair respiratory burst competence in malignant myeloid cells. This could contribute to immuno-deficiency in some forms of myeloid malignancy where differentiation appears histologically preserved, such as JMMoL or MDS. Further investigation of the role of SHP2-mutation in phagocyte functional competence may identify rationale molecular targets to ameliorate immuno-deficiency in chronic myeloid diseases.
Role of c-Kit in Multiple Myeloma.
Authors: Montero Juan Carlos , Miguel J.F. San , Pandiella Atanasio 
Published: April 2020

Abstract
C-Kit is a receptor tyrosine kinase whose activation occurs by interaction with its ligand, the Stem Cell Factor (SCF). Two distinct isoforms of c-Kit have been identified, and are characterized by the presence or absence of the tetrapeptide sequence Gly-Asn-Asn-Lys (GNNK) in the juxtamembrane domain of the extracellular region. These isoforms signal with distinct properties. c-Kit has been reported to be expressed in the plasma cells of about 20% of patients with Multiple myeloma (MM), but not in normal plasma cells. Yet, its functional and biochemical signalling properties in myeloma cells have not been described. In this study we show that patients and cell lines of MM co-expressed both c-Kit isoforms (GNNK+ and GNNK−), being predominant the GNNK− isoform. c-Kit was activated by SCF in the cell line RPMI8226, and in cell lines derived from patients. To study the properties of the two c-Kit isoforms, we have expressed these isoforms in the cell line MM1S which do not express these receptors in a significantly high level. Both receptors types were expressed by retroviral infection. Addition of SCF provoked their tyrosine phosphorylation. Imatinib mesylate, that is a known inhibitor of c-Kit, inhibited the phosphorylation induced by SCF of both isoforms. Both receptors coupled to the PI3K/Akt pathway, but were unable to substantially activate the Erk1/2 MAPKs. Differences in the kinetics of phosphorylation between the isoforms GNNK+ and GNNK− were observed. The variant GNNK− was more rapidly and highly phosphorylated than the GNNK+ isoform, which was activated more slowly but this activation persisted a longer time. In MM1S-GNNK+ cells the principal substrate of Akt activated by SCF was the p70S6K, and this activation was dependent on the activity of the mammalian Target Of Rapamycin (mTOR). Finally, the expression of the c-Kit isoforms in MM1S partially prevented their death induced by dexamethasone. These data indicate that c-Kit expression in MM cells is functional and couples to survival pathways that may modulate cell death in response to therapeutic compounds used in the treatment of this disease.
Green Tea Polyphenol (−)-Epigallocatechin Gallate Inhibits IL-6 Mediated Signalling Pathways in Human Myeloma Cells.
Authors: Burger Renate , Czekalla Hanna , Richter Kathrin , Ahrens Tanja , Guenther Andreas , Gramatzki Martin 
Published: April 2020

Abstract
Epigallocatechin-3-gallate (EGCG) is the predominant active ingredient of green tea leaves and has been shown to possess anti-tumor, anti-inflammatory, and anti-oxidant properties. EGCG confers its effects through potentially multiple mechanisms including inhibition of growth factor receptor signalling and decrease of cellular levels of anti-apoptotic proteins of the Bcl-2 family. We examined the effects of EGCG on a panel of human myeloma cell lines using EGCG concentrations ranging from 6.25–100 μM. After three days of culturing with EGCG, basal cell growth was inhibited in most of the cell lines as measured in an MTS based assay. IC50 concentrations were between 25 μM and 50 μM. IL-6 mediated growth of the IL-6 dependent INA-6 cell line was inhibited at similar doses. In these cells, stimulation with IL-6 leads to upregulation of Mcl-1 expression (Brocke-Heidrich et al., Blood.2004;103:242–251). Another green tea catechin, (−)-catechin gallate, seemed to be less active when used at identical concentrations. When INA-6 cells were pretreated for two hours with EGCG, a dose-dependent inhibition of IL-6 induced STAT3 tyrosine phosphorylation was observed as revealed by Western blot analysis. In contrast, phosphorylation of p44/p42 MAPK, which is constitutively activated in INA-6 cells, was not affected. The precise mechanism by which EGCG inhibits STAT3 phosphorylation remains to be determined. In conclusion, our results suggest to further evaluate the effect of EGCG not only in B-cell chronic lymphocytic leukemia, but also in plasma cell tumors.