bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Prognostic Data on Rare Cytogenetic Abnormalities in MDS: A Collaborative Study of the International Working Group on MDS Cytogenetics
Authors: Schanz Julie , Slovak Marilyn L. , Ohyashiki Kazuma , Solé Francesc , Mallo Maria del Mar , Steidl Christian , Pfeilstoecker Michael , Noesslinger Thomas , Hildebrandt Barbara , Luebbert Michael , Andersen Mette K , Giagounidis Aristoteles , Valent Peter , Fonatsch Christa , Germing Ulrich , Haase Detlef 
Published: April 2020

Abstract
Introduction: Several recent publications have advanced our knowledge of the prognostic significance of clonal cytogenetic abnormalities in MDS, yet the genetic risk assessment of the rare karyotypic aberrations in MDS patients (pts) remains unknown. Using the German-Austrian (G-A) Cytogenetics Database, we previously defined 24 cytogenetic prognostic subgroups; however, 12 subgroups characterized by non-complex (isolated or one additional abnormality only) karyotypes with del(9q), del(15q), t(15q), del(12p), −X, t(1q), t(7q), t(17q), −21, t(11q23), +19, t(5q) were observed infrequently (&lt;10 pts) and considered too few for an informative risk assessment. To increase the number of informative pts and expand/validate the statistical robustness of these rare cytogenetic subgroups, an international collaboration was initiated and promoted under the auspices of the MDS Foundation.
Patients and Methods: A total of 90 new MDS pts with rare recurring abnormalities was collected from 12 MDS Foundation Centers of Excellence, of which 66 pts fulfilled the non-complex requirement. Survival was estimated by Kaplan-Meier analysis and restricted to pts treated by supportive care only. The final analysis included 108 pts: del(9q)(n=10); del(12p)=17; −X=10; t(1q)=13; t(7q)=14; −21=12; t(11q23)=12; +19=10; t(5q)=10. The frequency of non-complex del(15q), t(15q) and t(17q) remained below ten pts and deemed ineligible for further analysis at this time.
Results: The pooled international data showed an excellent correlation with the G-A data set in 6 of 10 cytogenetic subgroups: t(7q): 34.7 months (mo.) median survival (G-A) vs. 34.7 mo. (new data), del(9q): not reached vs. 63.1 mo., t(11q23): 20.0 vs. 28.0 mo, del(12p): 108.0 mo. vs. not reached, +19: 19.8 vs. 21.7 mo., −21: 32.0 vs. 35.0 mo. A moderate correlation was found for t(1q): 34.7 mo. vs. not reached and for del(15q): not reached vs. 26.7 mo. Discordant median survival was observed for t(5q): 4.4 mo. vs. not reached and −X: 56.4 mo. vs. 15.7 mo.
Conclusions: Through an international collaboration, we were able to define the prognostic impact of nine distinct yet infrequent, recurring cytogenetic aberrations observed in MDS pts. The discordant median survival differences observed in two subgroups may be attributed to various translocation partners and/or secondary abnormalities. Even though data collection remains ongoing, the current results expand and refine the cytogenetic prognostic classification system for pts suffering from MDS and underscore the need for standardized cytogenetic testing in MDS for further international collaborations.
Prevalence and Cause of Death in Patients with Monoclonal Gammopathy in Atomic Bomb Survivors in Hiroshima
Authors: Fujimura Kingo , Kasagi Fumiyoshi , Sasaki Hideo , Ito Chikako 
Published: April 2020

Abstract
Purpose: To examine the effect of Atomic bomb (A-bomb) radiation exposure condition on the development M-proteinemia in A-bomb survivors in Hiroshima.
Back ground: The influence of radiation exposure on the development of M-proteinemia remained unclear. The screening test for monoclonal gammopathy in A- bomb survivors in Hiroshima was started from Sep. 1988 at the Hiroshima Atomic Bomb Casualty Council Health management center to challenge this problem with the free access policy.
Materials: The peak year of the examined population was 1989, which was examined 42915 survivors. This population was designed as study population. This population consisted of five groups of irradiated conditions as follows, 60% was exposed directly in all over the Hiroshima city at A- bombing, 27% entered to center of Hiroshima city within 14 days after A-bombing, 9% helped the victims of A- bombing at the suburbs and 1% was exposed in prenatal state.
Examination study: Each participant was examined one test yearly. Routine laboratory tests, such as complete blood cell counts, serum biochemical examination and serum protein electrophoresis on cellulose acetate were performed for the first step screening. M-protein or low level of gammaglobulin was subsequently assessed in a detailed analysis by immunoelectrophoresis of serum and urine, and measurement of serum concentration of immunoglobulin andβ2-Microglobulin.
Results: One thousand and hundred eighty two cases of M-proteinemia were detected for 18 years. The over all prevalence rate was 2.75%, and 4.1% in males and 2.1% in females. Nine hundred twenty nigh cases of MGUS(78.6%), 147 cases of MM(12.4%), 80 cases of IgM Macroglobulinemia(6.8%) and 26 cases of two clone M-proteinemia(2.2%) were detected. Of these M-proteinemia, 669cases(2.6%) were developed in directly exposed population, 368cases(3.1%) were in entered population and 133 cases(3.4%) were in helper population. The prevalence rate of these M-proteinemia was increased depend on aging. Forty three cases (4.6%) of MGUS moved to overt MM for 18 years. The mean duration time from MGUS to overt MM was 8.9 years (2~18 years). Four hundred sixteen cases (35.2%) were died with MM or lymphoproliferative diseases (99cases,23.8%), cancer (93cases,22.3%), infection (50cases,12%), cardio or cerebral vascular diseases (89 cases,21.4%) and others (85cases,21%). The 101 cases (13.2%) of 766 living cases combined some cancer throughout the follow up. No significant differences in the prevalence rate of M-proteinemia and death from MM or combination with cancer were observed among any A-bomb irradiated conditions.
Conclusions: There were no clear correlations between the development or disease state of M-proteinemia and the irradiated conditions. We are now starting to analyze the individual radiation dose effects longitudinally on the development of M-proteinemia.
Osteoclast Gene Expression Profiling in Multiple Myeloma
Authors: Moreaux Jerome , Hose Dirk , Rème Thierry , Moine Philippe , Mahtouk Karène , Moos Marion , Requirand Guilhem , De Vos John , Rossi Jean François , Goldschmidt Hartmut , Klein Bernard 
Published: April 2020

Abstract
Multiple myeloma (MM) is a fatal hematologic malignancy associated with clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. The principal cellular mechanisms involved in the development of myeloma bone disease are an increase in osteoclastic bone resorption, and a reduction in bone formation. Myeloma cells (MMC) are found in close association with sites of active bone resorption, and the interactions between myeloma cells and other cells within the specialized bone marrow microenvironment are essential, both for tumor growth and the development of myeloma bone disease. In order to investigate the gene expression profile (GEP) of osteoclastic cells, we compare GEP of osteoclastic cells (7 samples) with normal B cells (7 samples), normal bone marrow plasma cells (7 samples), bone marrow stromal cells (5 samples), bone marrow CD3 cells (5 samples), CD14 cells (7 samples), CD15 cells (7 samples), CD34 cells (7 samples) and primary MMC (123 samples). Using SAM analysis, a set of 552 genes was overexpressed in osteoclasts compared to others cell subpopulations with a FDR ≤ 1% and a ratio ≥ 2. Osteoclasts specifically overexpressed genes coding for chemokines (CCL2, CCL7, CCL8, CCL13, CCL18, CXCL5 and CCL23) and MMC growth factors (IGF-1, APRIL and IL-10). Anti- IGF-1 receptor and TACI-Fc inhibit MMC growth induced by osteoclasts. Among the chemokines overexpressed by osteoclasts, the majority of them have a common receptor: CCR2 expressed by MMC. Anti-CCR2 MoAb inhibits migration of the CCR2+ HMCL in response to osteoclasts. Expression data of purified MMC were analyzed by supervised clustering of group with higher (CCR2high) versus lower (CCR2low) CCR2 expression level. Patients in the CCR2high group are characterized by a higher bone disease. A set of 176 genes was differentially expressed between CCR2high and CCR2low MMC. CCR2high displayed a gene signature linked to the dependency of MMC on the interactions with the BM osteoclastic subpopulation and the osteoclastic bone resorption.
Taken together, our findings suggest addition of chemokine antagonists to current treatment regimens for MM should result in better therapeutic responses because of the loss of both the protective effect of the bone marrow environment on the MMC and the osteoclastic cells activity.
OH-2, a Hyperdiploid Myeloma Cell Line without An IGH Translocation, Has a Complex Translocation Juxtaposing MYC near MAFB and the IGK Locus
Authors: Våtsveen Thea Kristin , Tian Erming , Kresse Stine H , Meza-zepeda Leonardo A , Gabrea Ana , Dai Hong Yan , Kuehl Michael , Sundan Anders , Borset Magne 
Published: April 2020

Abstract
Despite heterogeneity of phenotypes, multiple myeloma (MM) can be classified into two major groups: hyperdiploid (HRD) tumors with 48–74 chromosomes, which typically have extra copies of at least four of the eight odd chromosomes 3, 5, 7, 9, 11, 15, 19, and 21; and non-hyperdiploid (NHRD) tumors, which usually have immunoglobulin heavy chain (IGH) translocations and &lt;46 or &gt;74 chromosomes. Human myeloma cell lines (HMCL) with a typical HRD genotype are lacking. The OH-2 HMCL was derived from extramedullary myeloma, and retains the same HRD phenotype as the primary tumor, with extra copies of chromosomes 3, 7, 15, 19, and 21, as demonstrated by array comparative genomic hybridization. This provides a unique example of an HMCL and the corresponding primary tumor that share the same HRD phenotype. Also Spectral Karyotyping showed the same HRD phenotype. By fluorescence in situ hybridization it was shown that OH-2 does not have an IGH or Ig lambda light chain translocation. Instead, both the HMCL and the primary tumor have complex translocations involving chromosomes 2, 8, and 20. The translocation juxtaposes MAFB near MYC and the Ig kappa (IGK) enhancer. Both MYC and MAFB are highly expressed, as shown by microarray analysis, and are thought to be dysregulated by the IGK enhancer. Both OH-2 HMCL and the primary tumor cells express high levels of Cyclin D2, an expected consequence of the enhanced MAFB level. OH-2 has a phenotype similar to the 20% of HRD MM tumors that express increased levels of Cyclin D2 but not Cyclin D1 and could be a good in vitro model for studies of this subgroup of MM. OH-2 is dependent on medium containing human serum and growth-promoting cytokines like IL-6 or IL-21, reflecting the critical role of the microenvironment for growth of MM cells.
Promoting Osteoblastogenesis Using a Novel Dkk-1 Neutralizing Antibody in the Treatment of Multiple Myeloma Related Bone Disease
Authors: Pozzi Samantha , Yan Hua , Vallet Sonia , Vaghela Nileshwari , Fulciniti Mariateresa , Cirstea Diana , Santo Loredana , Mukherjee Siddhartha , Hideshima Teru , Schirtzinger Linda , Kuhstoss Stuart , Munshi Nikhil C. , Anderson Kenneth C , Scadden David , Raje Noopur 
Published: April 2020

Abstract
Treatment of bone disease in multiple myeloma (MM) has largely focussed on the osteoclast axis while the osteoblast axis has been underexploited. Dkk1, an inhibitor of the wingless int (wnt) pathway, is important in osteoblastogenesis. Increased expression of Dkk1 in a subset of MM patients and its association with lytic bone disease opens up the potential of targeting the osteoblast axis. The aim of this study was to test the effect of a Dkk-1 neutralizing chimeric antibody (Mab B3) on osteoblasts (OB), osteoclasts (OC) and MM cells in the context of the bone microenvironment. First, we tested the expression of Dkk1 in plasma and bone marrow of 16 MM patients and 10 MM cell lines. Dkk1 levels were &gt;18 ng/mL in 2 out of 16 patients; levels were comparable in blood and bone marrow plasma. In contrast, very little Dkk1 (2–9 ng/ml) was produced by bone marrow stromal cells (BMSC). One out of 10 MM cell lines (INA-6) expressed low concentrations of Dkk1 in the supernatant. Next, we tested the effect of Mab B3 on MM cell lines, in the presence or absence of BMSC, and on OB and OC from MM patient derived bone marrow. The effects on OC were evaluated by TRAP staining and pit formation. Effects on OB were assayed by alkaline phosphatase staining and alizarin red assays for calcium deposition. Mab B3 treatment did not demonstrate direct cytotoxic effects on MM cell lines negative for Dkk1. Mab B3, however, enhanced OB differentiation and calcium deposition in a dose dependent manner and inhibited OC differentiation and function, as evidenced by a decrease in number of multinucleated TRAP+ cells and a decrease in pit formation. Ongoing studies are addressing the effect of Mab B3 on MM cells in the context of OC and OB. Mab B3 is also undergoing in vivo testing in a SCID-hu model bearing INA-6 MM cells. These studies and the underlying mechanism of action of Mab B3 will be presented. Our preliminary data suggests that Mab B3 has anabolic bone effects; a corresponding human monoclonal antibody may be useful for the treatment of MM related bone disease. Future studies will evaluate Mab B3 in combination with catabolic agents such as bisphosphonates with the goal of restoring normal bone homeostatsis.
Oncoprotein 18 (Op18) : A Differentially Expressed Gene Is a Novel Therapeutic Target in Multiple Myeloma
Authors: Pelluru Dheeraj , Wang Jingyi , Prabhala Rao , Fulciniti Mariateresa , Shammas Masood A. , Amin Samirkumar B , Anderson Kenneth C. , Munshi Nikhil C. 
Published: April 2020

Abstract
Stathmin(Op18) is a ubiquitous cytosolic 18Kda protein regulating microtubule (MT) dynamics via binding and stabilizing activities. The activity of Op18 is down regulated during cell cycle by phosphorylation at four Ser residues. The phospho-Op18 is unable to bind to tubulin allowing the progression of the cell cycle. Two additional Op18-binding proteins, KIS prevents Op18 dephosphorylation and activation while iASPP (inhibitor of apoptosis stimulatory protein phosphatase) binds to WT-p53 and inhibits p53-related apoptosis. We have identidfied Op18 as a differentially expressed gene by suppression subtractive hybridization in myeloma. We have also confirmed differential expression of KIS in myeloma cells compared to normal plasma cells. Overexpression of Op18 was confirmed at both RNA and at protein level by RT –PCR and Western blotting in human myeloma cell lines as well as primary samples compared to normal plasma cells and normal human fibroblasts. In contrast, none of the tonsillar CD138+ plasma cells and normal bone marrow mononuclear cells showed Op18 overexpression. To establish the role of Op18 overexpression in MM cell transformation, the human MM cell lines were treated with antisense Op18 oligodeoxynucleotides (ODN). The growth rate of the ODN treated human myeloma cells was significantly reduced compared to the control cells along with cell cycle arrest in G2/M phase and increase in apoptosis as measured by immunohistochemical staining. Additionally, we have silenced Op18 by transfecting Op18-specific siRNA in MM cells and observed that KIS is translocated to cytoplasm, from nucleus as well as MM cells are arrested in G2/M. Importantly, Op18 silencing increased sensitivity of MM cells to microtubule drugs suggesting possible combination approach for therapeutic application. Its role in networking cellular signal transduction pathways in myeloma is under investigation. Recent publication identifying Op18 as one of the 15 most relevant genes determining outcome in myeloma (Avet-loiseau et al, JCO 2008) adds to the validity of Op18 as a molecule playing important role in myeloma cell growth and survival and warrant investigation as a novel therapeutic target.
C-Myc- Dependent Stabilization of Hif-1alpha in MM: Therapeutic Implications
Authors: Podar Klaus , Zhang Jing , Tonon Giovanni , Grabher Clemens , Lababidi Samir , Raab Marc S , Vallet Sonia , Zhou Yiming , Cartron Marie-Astrid , Sattler Martin , Chauhan Dharminder , Anderson Kenneth C 
Published: April 2020

Abstract
Bone marrow (BM) angiogenesis has been associated with multiple myeloma (MM) progression. Here we demonstrate that oncogenic c-Myc, also prominently associated with adverse prognosis in MM, regulates Hif-1α promoter activity, Hif-1alpha protein levels, and consequently the expression of pro-angiogenic target genes such as VEGF in MM cells. As observed with c-Myc knockdown, anti-MM agents with known anti-angiogenic activity including bortezomib, lenalidomide, and enzastaurin also downregulate Hif-1alpha and VEGF. Moreover, tyrophostin adaphostin induces similar effects, associated with anti-angiogenic activity, in a zebrafish model. The correlation between c-Myc, Hif-1alpha and tumor angiogenesis was further confirmed in a xenograft mouse model of human MM. Mechanistically, our in vitro data show that oncogenic c-Myc stabilizes caspase-8, and thereby protects Hif-1alpha against caspase-8- dependent degradation and attenuation of VEGF secretion. These sequelae also contribute to enhanced VEGF secretion triggered by MM cell-bone marrow stromal cell binding. Indeed, conditioned media from adaphostin- treated co-cultures inhibit endothelial cell growth and tubule formation. In addition, HIF1alpha gene demonstrated significant increased expression (p=0.02, Mann Whitney test) in tumor cells versus plasma cells derived from healthy donors. Importantly, when tested on a dataset of 559 patients, a significant link between HIF1alpha overexpression and poor prognosis was found (p=0,0069). These data further point to the possible relevance of HIF1alpha in the progression of a subset of MM patients. In summary, our data provide strong evidence of a key role of Hif-1alpha in MM angiogenesis and the therapeutic potential of specific Hif-1alpha and c-Myc inhibitors. Moreover they demonstrate additional biologic sequelae of novel MM therapies.
Mcl-1 Fragment Mcl-1(128–350) Induces Inhibition of Multiple Myeloma Cell Proliferation and Apoptosis Via Both Upregulation of C-Jun as Well as Modulation of Its Transcriptional Activity
Authors: Podar Klaus , Zhang Jing , Zimmerhackl Alexander , Barila Daniela , Vallet Sonia , Sattler Martin , Tai Yu-Tzu , Hideshima Teru , Chauhan Dharminder , Anderson Kenneth C. 
Published: April 2020

Abstract
Myeloid cell leukaemia-1 (Mcl-1) is an anti- apoptotic member of the Bcl-2 family commonly expressed in multiple myeloma (MM). Drugs (e.g. bortezomib) can induce a 28kD Mcl-1 fragment (Mcl-1Δ128–350) in a caspase- dependent manner, which induces inhibition of MM cell proliferation and apoptosis. Here we sought to delineate molecular sequelae downstream of Mcl-1Δ128–350 which mediate its anti- proliferative and pro-apoptotic effects in MM and other malignant cells. Our results demonstrate that exogenous Mcl-1Δ128–350 induces upregulation and nuclear accumulation of c-Jun, as well as generation of a pro-apoptotic 60kD c-Abl fragment (c-Abl Δ). Bortezomib treatment triggered c-Jun upregulation in Mcl-1wt/wt, but not Mcl-1 null, murine embryonic fibroblasts (MEFs), and neither transfection with exogenous c-Jun nor with exogenous 60kD c-Abl Δ triggered the generation of Mcl-1Δ128–350. Moreover, drug-induced generation of Mcl-1Δ128–350 was not abrogated by specific transient knockdown of c-Jun or c-Abl by small interfering RNA, further supporting the requirement of Mcl-1Δ128–350 for c-Jun upregulation. Our studies also identified mechanisms downstream of upregulated c-Jun which trigger inhibition of MM cell proliferation and apoptosis. Interestingly and similar to c-Jun and c-Abl Δ, Mcl-1Δ128–350 accumulates within the nuclear fraction. Indeed, interaction of Mcl-1Δ128–350 with c-Jun, as well as subsequent enhanced AP-1 reporter activity, demonstrate a direct regulatory role of Mcl-1Δ128–350 in c-Jun- dependent gene transcription. Finally, gene profiles in MM cells transfected with either Mcl-1wt or Mcl-1Δ128–350 identify differentially expressed genes associated with MM cell proliferation, survival and drug resistance. Taken together, these data both delineate the role of Mcl-1 in MM pathogenesis and further support targeting Mcl-1 in novel MM treatment strategies.
The Novel, Orally Available Multi-Kinase Inhibitor BAY 73-4506 in Multiple Myeloma
Authors: Breitkreutz Iris , Raab Marc S , Christensen Olaf , Zimmerhackl Alexander , Zhang Jing , Blotta Simona , Hideshima Teru , Chauhan Dharminder , Wilhelm Scott , Anderson Kenneth C , Podar Klaus 
Published: April 2020

Abstract
Agents targeting not only myeloma cells directly but also bone marrow stromal cells (BMSCs), endothelial cells, and osteoclasts (OCLs) that cause enhancement of tumor cell growth, angiogenesis, and MM bone disease, respectively, are promising new treatment modalities for multiple myeloma. Here we investigated the novel, orally available multi-kinase inhibitor BAY 73-4506 (BAY), currently in phase II clinical trials, for its therapeutic effect in MM. BAY is a potent inhibitor of angiogenic (VEGFR 1–3, PDGFR-β), as well as oncogenic, (cKIT, RET, FGFR, Raf) kinases We first tested the ability of BAY to suppress proliferation and survival in a wide array of MM cell lines, including those resistant to conventional chemotherapeutics. Our data show that BAY, in a low micromolar range that is well below concentrations achieved in patient plasma during the first clinical trial in solid tumors, induces apoptosis by caspase-9 and caspase-3 activation in all cell lines tested. Importantly, BAY also overcomes the growth advantage conferred in a BMSC-MM, as well as an endothelial cell-MM, co-culture system. BAY treatment abrogates growth factor-stimulated MEK, ERK and AKT phosphorylation at sub-micromolar concentrations. Since the VEGF signaling pathway is a potent inducer of angiogenesis and BAY targets VEGFR 1–3, we examined its anti-angiogenic properties. BAY inhibits endothelial cell growth and endothelial cell tubule formation in vitro at concentrations less than 1μM; moreover, it also markedly inhibited VEGF-induced cell migration on fibronectin. Activation of MAP kinase is a critical event during OCL differentiation, activation, and survival; and importantly, BAY also inhibits osteoclastogenesis, evidenced by blockade of M-CSF/RANKL-triggered differentiation of mononuclear cells to TRAP-positive osteoclasts. Finally, BAY significantly delays tumor growth and abrogates blood vessel formation in vivo in a xenograft mouse model of human MM. These in vitro and in vivo results provide the basis for further clinical evaluation of BAY to improve patient outcome in MM.