bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Human Anti-CD30 Antibody 5F11 Activates NF-kB and Sensitizes Lymphoma Cells to Bortezomib Induced Apoptosis.
Authors: Pogge Elke , Boell Boris , Tawadros Samir , Reiners Katrin , Borchmann Peter , Hansen Hinrich , Graziano Robert , Yellin Michael , Engert Andreas 
Published: October 2019

Abstract
Purpose: We recently developed a fully human monoclonal antibody (5F11) directed against the CD30 receptor, which is an excellent target for antibody based immunotherapy of malignant lymphoma cells. The antibody is cytotoxic for lymphoma cells in vitro and in vivo, however a partial or even complete resistance of several Hodgkin cell lines has been observed. In this study we analysed, whether the efficacy of 5F11 can be improved by combination with bortezomib.
Methods and Results: Bortezomib is an inhibitor of the ubiquitin-proteasomes pathway that is toxic to multiple solid and hemotologic tumor cells. Using XTT viability assays, TUNEL assays and Facs analysis we demonstrate a synergistic toxic effect of 5F11 and bortezomib on the Hodgkin cell lines tested (L540, L1236, L428) and the CD30 expressing ALCL Karpas299. Moreover the growth of subcutaneous L540 derived tumors in SCID mice is inhibited by 5F11 in combination with bortezomib. The synergy depends on the regime of the drugs and is only seen when a pre-incubation with the antibody is followed by exposure to bortezomib. Immunofluorescence analysis demonstrates that the sensitization of the tumor cells correlates with a 5F11 dependent localisation of the survival factor NF-kB into the cell nuclei. A transfected NF-kB responsive reporter gene is 2–3 fold activated in 5F11 treated L428 cells and enhanced NF-kB binding is detected performing EMSA.. We furthermore measured an increased expression of the NF-kB target gene c-flip, that is down regulated after additional incubation of the tumor cells with bortezomib.
Conclusion: Our data indicate that initial activation of NF-kB and downstream anti-apoptotic proteins in response to 5F11 via CD30 sensitizes the tumor cells to bortezomib induced cell death. The in vitro and in vivo activity of the combination of 5F11 and bortezomib suggests a therapeutic value for the treatment of HD patients.
Patterns of Growth Factor (GF) Usage and Febrile Neutropenia (FN) among Older Patients (pts) with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with CHOP or R-CHOP: An Intergroup Experience (CALGB 9793, ECOG-SWOG 4494).
Authors: Morrison Vicki A. , Weller Edie A. , Habermann Thomas M. , Li Shuli , Horning Sandra J. , Fisher Richard I. , Peterson Bruce A. 
Published: October 2019

Abstract
The use of anthracycline-based combination chemotherapy to treat DLBCL in older pts is complicated by the more common occurrence of therapy-related myelosuppression, which may lead to dose reductions that might impair efficacy. The preliminary results of initial therapy with cyclophosphamide, doxorubicin, vincristine, prednisone alone (CHOP) or with rituximab (R-CHOP) as induction therapy in patients age 60 years (yrs) or greater with DLBCL have been reported (Blood2003;102:6a, Abstr 8). Pts were randomized at induction to receive 6–8 cycles of CHOP or R-CHOP. Responding patients were then randomized to receive either no treatment or maintenance rituximab. Per protocol, GF was not to be given with the 1st cycle of therapy, and thereafter ASCO guidelines were to be followed regarding use of GF. The objectives of this study were to determine the frequency of and indications for GF usage and the incidence of FN. GF usage was defined as the use of either GCSF or GMCSF for the purpose of preventing dose reduction/dose delay or as prophylaxis in pts with a prior hospitalization for FN. Of the 546 eligible pts, adequate data was available to report on 528 patients. Among these pts, 75% were >=65 yrs, 41% hemoglobin <12 g/dl, 50% male, 59% elevated LDH and 59% HI/High IPI. 264 of 528 pts (50%) used GF in at least 1 cycle of therapy (GF used in 307 cycles to treat neutropenia). 181 of the 528 pts (34%) used GF per our definition with the 93% using GCSF only in at least 1 cycle of therapy. For these 181 pts, the median number of cycles of GF use was 5 (range 1–8) and the median duration of GF use was 9 d (SD=3). GF was used in 552 of 3256 cycles (17%). Significantly more patients used GF at later cycles of therapy (65/513,13% at cycle 2 vs 98/429, 23% at cycle 6, p<0.001). The use of GF was evaluated by study entry characteristics (age, sex, performance status, IPI score). The only significant difference was that pts age 60–64 yrs were less likely to have received GF than pts >=65 yrs (25% vs 37%,p=0.01). 217 pts (41%, 95% CI [37,45%]) had at least one FN event. FN occurred in 267/3247 (8%) cycles of therapy with 103 (39%, 95% CI [33,45%]) FN events occurring in cycle 1. The median time to FN was d 11 (SD=3) of the cycle. In this older pt population treated with CHOP+/− R therapy for DLBCL, GF was used in 17% of the cycles, with usage more common in later cycles of therapy. FN was most common in the first cycle of therapy occurring mostly within the first two weeks. This early occurrence of FN supports consideration of GF use to prevent FN from the 1st cycle of CHOP-based therapy in older pts (>=60 yrs), in addition to any other usage per ASCO guidelines. Results will be presented on the impact of delivered dose intensity on GF usage and FN.
Reduced Relative Dose Intensity (RDI) in Patients with Aggressive Non-Hodgkin’s Lymphoma (NHL).
Authors: Dale David C. , Goldschmidt Jerome H. , Crawford Jeffrey , Lyman Gary H. ,   for the ANC Study Group
Published: October 2019

Abstract
Introduction: A nationwide survey of oncology practices has previously demonstrated that half of patients with aggressive NHL receive substantial reductions in RDI potentially compromising response rates and long term outcomes. Further study is needed of those factors associated with treatment-related complications and reduced RDI in this population.
Methods: A nationwide survey of 567 oncology practices was undertaken between June 1999 and December 2001 with data extracted from the records of 1,620 adult patients with aggressive NHL treated with CHOP (N=1,367), CHOP-R (N=117) or CNOP (N=136). Outcomes included febrile neutropenia (FN), reduced RDI and disease response to treatment. Multivariate logistic and proportional hazards regression analyses based on common demographic, treatment and disease variables and prophylactic colony-stimulating factor (CSF) provided adjusted odds ratios and hazards ratios, respectively.
Results: FN was reported in 319 (20%) patients of which 80% were hospitalized. The initial episode occurred within the first two cycles of treatment in 60% of patients with FN. Independent predictors of FN risk included age >60 (1.5), female gender (1.5), ECOG >2 (1.9) and liver disease (2.0) with a reduction in risk with prophylactic CSF (0.77). The risk of FN was significantly reduced with prophylactic CSF in patients >60 years of age (HR=.51 [.29,.88]). The overall RDI was 79% with planned and unplanned reductions of 12% and 9%, respectively. RDI <85% of standard dose intensity occurred in 52% of patients including: age >60 (58%), ECOG >2 (56%), stage ≤2 (58%), cardiovascular disease (60%), liver disease (71%), renal disease (58%) and diabetes (59%). Independent predictors of planned reductions in RDI were older age, stage ≤2, heart disease, liver disease, regimen and poor chemotherapy response with less reduction with the addition of prophylactic CSF (R2=0.40; P<.0001). Independent predictors of unplanned reductions in RDI were younger age, diabetes and stage ≤2 with less reduction with the addition of prophylactic CSF (R2=0.13, P<.001).
Conclusions: This practice-based study confirms previous reports of a high level of planned and unplanned reductions in RDI in patients with aggressive NHL. Factors associated with reduced dose intensity include age, comorbid conditions, regimen, stage and no prophylactic CSF.
Role of Allogeneic Stem Cell Transplantation in Lymphoplasmacytic Lymphoma. Analysis of 61 Cases from the European Bone Marrow Registry (EBMT).
Authors: Kyriakou Charalampia A. , Goldstone Anthony H. , Sureda Anna , Yong Kwee , Taghipour Goli , de Elvira Carmen Ruiz , Linch David C. , Mackinnon Stephen , Schmitz Norbert 
Published: October 2019

Abstract
Despite effectiveness of standard chemotherapy regimens, complete response is infrequent in Lymphoplasmacytic Lymphoma (LPL) patients and there is no cure. The role of allogeneic stem cell transplantation (ASCT) has not been explored extensively and the available data are limited. We studied retrospectively LPL patients from 47 European centres who underwent conventional (CT) and non-myeloablative (NMT) allogeneic stem cell transplantation between 1989 and 2003. Sixty-one patients (42 male) of median age at transplant of 41 years (38–57), underwent allogeneic transplantation for LPL. Thirty-two patients were treated with CT and 29 NMT. Thirteen patients received 1, 25 received 2 and 23 more than 2 previous treatment lines. Seven patients were in CR1, 20 in CR2, 19 in PR and 15 with PD. Conditioning used was a combination of TBI and cyclophosphamide or busulfan for the CT and Fludarabine based regimens for the NMT. Twenty-six NMT and 25 CT patients received stem cells from an HLA-identical sibling, while 3 NMT and 7 CT from a matched unrelated donor. For GVHD prophylaxis or treatment cyclosporin A, Methotrexate, ATG, MoAB, T-cell depletion were used. Nine NMT patients received donor lymphocyte infusion for either residual disease or mixed chimera. Median follow up is 7 months (1 to 168). Twenty-nine patients developed a-GVHD (47.5%) [Grade I-II (n=25), Grade III-IV (n=4)] with no statistically significant difference between the 2 groups. Eleven CT patients (34.4%) and 10 NMT (34.5%) patients died from regimen toxicity. Non-relapse mortality was the same for both groups. One CT and 2 NMT patients relapsed and died from disease progression. The progression free survival (PFS) is 51%, at 1 and 41% at 3 years for the entire group and comparison between CT and NMT has not shown a statistical significant difference. Relapse rate at 2 years for CT and NMT is 23% and 34% respectively. Overall survival for CT is 60% at 1 and 55% at 3 years and is similar in the two groups. In conclusion allogeneic stem cell transplantation is safe with moderate non-relapse toxicity and good overall response in this group of advanced and multitreated LPL patients.
The Presence and Number of Activatory KIR (R+D−) Impact the Infection and Survival Status of Patients Transplanted with an HLA Matched Sibling Donor.
Authors: Loiseau Pascale , Chen Chun , Appert Marie-Lorraine , Rocha Vanderson , Busson Marc , Filion Alain , Lepage Virginia , Toubert Antoine , Gluckman Eliane , Charron Dominique 
Published: October 2019

Abstract
Killer immunoglobulin-like receptor (KIR) ligand incompatibilities (=absence on recipient tissues of a ligand for KIRs present in the graft) have been associated with decreased relapse, rejection and acute GVHD, after T cell depleted haplo and unrelated donor Hematopoietic Stem cell transplantation, mainly for myeloid hematopoietic malignancies. The association of donor and recipient KIR genotypes with outcomes, including infections, after HLA genoidentical HSCT has not been studied. We have analysed genotypes for ten KIR genes (2DS1, 2DS2, 2DS3, 2DS4, 2DL1, 2DL2, 2DL3, 3DS1, 3DL1, 3DL2) in 131 donor-recipient pairs from HLA-matched sibling bone marrow transplantations performed for lymphoid (53 cases) and for myeloid malignant diseases (78 cases). We classified the pairs according to KIR-ligand incompatibilities and donor-recipient KIR matching (=concommitant expression of KIRs in donors and recipients). Median age was 29 years. 105 patients were transplanted for a low risk disease, 12 for intermdiate and 14 for high risk disease. Conditioning was myeloablative in all cases and consisted in TBI based (n=63). Cyclosporine and Methotrexate for GVHD prophylaxis was used in 118 cases. Cumulative incidence (competing rsik analysis) of acute GVHD at day 100 and CI of 180 days-bacterial, CMV and fungal infections were 48%, 19%, 34%, 11%, respectively. 5 years overall survival was 70%. We have not found any significant association of “KIR-ligand incompatibilities”, donor KIR genotype, number of activatory KIR genes present in the donor and donor-recipient matching for each KIR with aGVHD, relapse, bacterial, viral or fungal infection and survival, except for KIR2DS2. In fact, donor-recipient mismatching for KIR2DS2 was associated with the incidence of acute GVHD (II-IV p=0.05). Although not significant, we have also observed a trend with decreased survival in patients homozygous for group 2 HLA-C and grafted for myeloid malignant disease with a HLA-matched sibling donor carrying the activatory KIR2DS2 (63 % survival at 20 months (N=6) versus 86% (N=9)). Finally,. the higher is the number of activatory KIRs present in the recipient (R+) and absent from the donor (D−), the higher is the risk of fungal (p=0.03) and CMV infection (p=0.05) and the worse is the survival (at 5 years: 78% survival in case of 0 KIR R+D−, 64% in case of 1 or 2 KIR R+D− and 44% in case of 3 or 4 KIR R+D−, p=0.001). A multivariate analysis for survival confirmed the association of number of R+D− activatory KIR (p = 0.001, HR = 3.13) among other clinical factors such as gender (p=0.03), ABO compatibility (p=0.003), recipient age (p=0.01) and status of the disease (p = 0.0001).
CD45 Defines Signaling Thresholds Critical for Proliferation and Apoptosis in Myeloma Cells.
Authors: Liu Shangqin , Ishikawa Hideaki , Tsuyama Naohiro , Abroun Saeid , Li Fu-Jun , Otsuyama Ken-ichiro , Zheng Xu , Ma Zi , Maki Yasuko , Obata Masanori , Kawano Michio M. 
Published: October 2019

Abstract
Expression of the common leukocyte antigen, CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45+ U266 proliferates in response to a growth factor, interleukin-6 (IL-6). IL-6 as a mitogenic stimulus, activated a src family kinase, Lyn and phospholipase C (PLC)-g2 followed by Ca2+ influxes and protein kinase C (PKC) activation in CD45+ U266. Here we show that compared with CD45− U266, CD45+ U266 was more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress. Both release of apoptosis-inducing factor or cytochrome c and the activation of caspase-9 and caspase-3 were enhanced in CD45+ U266 more than in CD45− U266. Increased susceptibility to the stress-induced apoptosis was also observed in other CD45-expressing myeloma cell lines and the CD45-transfected U266. Reactive oxygen species (ROS) and calcium ion (Ca2+) seem to be involved in the susceptibility to apoptosis of CD45+ U266 because either an anti-oxidant, DTT or a Ca2+ chelating agent, BAPTA blocked the apoptosis. As the oxidative stress-induced Ca2+ influxes and apoptosis of CD45+ U266 were blocked by a src family kinase inhibitor, PP2, CD45 phosphatase regulating the src family kinase activity plays an important role in the augmented apoptosis in CD45+ U266 by oxidative stress. The intracellular accumulation of ROS may activate src associated with CD45, and the activated src kinases accelerate the Ca2+ influxes followed by calicineurin activation, mitochondrial translocation of Bad, and inhibition of Bcl-2 function. These results indicate that the CD45-expression renders myeloma cells competent with not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45+ myeloma cells dependently upon the stimuli. Furthermore, voltage-dependent anion channel (VDAC)-1 was identified as a gene highly expressed in CD45+ U266 by cDNA subtraction. The increased expression of VDAC-1 seemed to augment the sensitivity to the ER-stress because the VDAC-1-transfected CD45− U266 was confirmed to be susceptible to the thapsigargin-induced apoptosis. Thus, CD45 may define the signaling thresholds that are critical for the IL-6-induced proliferation and the oxidative stress-induced apoptosis of myeloma cells, and the CD45 expression accompanied by the increased VDAC-1 expression sensitizes myeloma cells to the various extracellular stimuli triggering apoptosis via the mitochondrial pathways.
The Coexpression of CD11a and CD45bright Is the Hallmark of Proliferating Myeloma Cells.
Authors: Pellat-Deceunynck Catherine , Robillard Nelly , Bataille Regis 
Published: October 2019

Abstract
To identify new potential therapeutical targets in multiple myeloma (MM), we have defined the phenotype of the subset of proliferative myeloma cells (n=66) in comparison with that of normal PC (n=25). Proliferation was evaluated by ex vivo incorporation of BrdU (labeling index, LI). Surface PC phenotype was performed in a four-color assay with CD38, CD45, CD138 and the mAb indicated. For intracellular BrdU staining, cells were first labeled with CD38, CD45 and CD138, fixed and permeabilized before BdrU staining. At least 1000 normal PC and 10000 myeloma cells were analyzed. We show that all bone marrow PC, either malignant or normal, always included a subset of proliferative PC (BrdU+) that was always located within the CD45++subpopulation. Indeed, CD45++ myeloma cells (median 12%) had a labeling index 7.5-fold higher of that of CD45+/− myeloma cells (7.1% versus 0.94%). Actually, in all cases of MM, CD45++ myeloma cells were always the most proliferative myeloma cells. As observed for myeloma cells, LI of normal PC was heterogeneous i.e., higher in the CD45++ population of PC: CD45++ PC (median 65%) had a LI 5.7-fold higher of that of CD45+/− PC. Compared to myeloma cells, LI of PC were higher in both subsets, of 20.5% and 3.6% for CD45++ and CD45+/−, respectively. Non-malignant PC from blood or tonsil were homogeneously CD45++ and did proliferate (LI> 10% and up to 45% for reactive PC). In all PC (normal, reactive, malignant), we found an inverse correlation between CD45 and Bcl-2, confirming a known inverse correlation between proliferation and Bcl-2 expression. Our data suggest that a minor cycling Bcl2lowCD45++ population of myeloma cells differentiate into a no more cycling major Bcl2high CD45+/− population of myelom a cells that accumulates.
We further characterized the phenotype of the CD45++ myeloma cells population: we found that CD11a and to a less extend HLA-DR were expressed by CD45++ myeloma cells only in contrast to CD40 and CXCR4 that were expressed by all myeloma cells. Moreover, all CD45++ myeloma cells coexpressed CD11a. Thus, the-to-be-killed population of myeloma cells could be targeted through CD45 or CD11a.
The Tyrosine Kinase Inhibitor Adaphostin (NSC 680410), but Not Imatinib Mesylate, Inhibits Survival and Src Tyrosine Kinase Family- Triggered Signaling Pathways of MM Cells.
Authors: Podar Klaus , Simoncini Melissa , Tai Yu-Tzu , Sattler Martin , Ishitsuka Kenji , Le Gouill Steven , Hamasaki Makoto , Burger Renate , Raje Noopur , Hideshima Teru C. , Chauhan Dharminder , Anderson Kenneth 
Published: October 2019

Abstract
The tyrosine kinase inhibitor adaphostin is a member of the tyrophostin family of small molecules that interfere with peptide binding rather, than targeting the kinase ATP-binding site. Adaphostin has therefore been examined as an alternative to the 2-phenylaminopyrimidine derivate imatinib mesylate, with remarkable efficacy in the treatment of chronic myeloic leukemia (CML). Previous studies show that adaphostin induces apoptosis: (1) in Bcr/Abl+ cells more rapidly than imatinib mesylate; (2) in imatinib mesylate resistant cells; and (3) in Bcr/ Abl - cells.
Imatinib mesylate has minimal, if any activity in MM; the efficacy of adaphostin in multiple myeloma (MM) is unknown. Here we compare the effects of adaphostin and imatinib mesylate against human MM cells. Our results show concentration-dependent apoptosis in MM.1S, U266, OPM-2, INA-6, RPMI8226 and RPMI-Dox40 MM cells after treatment with adaphostin, but not with imatinib mesylate. Imatinib mesylate induced more than 50% apoptosis in K562 cells using concentrations as low as 1mM, which served as a positive control. Moreover, adaphostin, but not imatinib mesylate, induced caspase-9, caspase-8, and PARP cleavage, as well as downregulation of Mcl-1, in MM cells. Further results demonstrated that adaphostin induces peroxide production and DNA strand breaks after long-term treatment. Importantly MM cell proliferation induced by MM cell binding to BMSCs was abrogated by adaphostin- treatment. IL-6 and IGF-1 signaling and sequelae triggered by these cytokines are important growth, survival, and drug resistance factors in MM; conversely, adaphostin but not imatinib mesylate, inhibited phosphorylation of Src tyrosine kinase family, Akt-1, and ERK. Taken together, our studies in MM cells show that (1) adaphostin- inhibits IGF-1- and IL-6- triggered signaling pathways as well as (2) induces reactive oxygen species and apoptosis. These studies therefore provide the preclinical framework for its clinical evaluation to improve patient outcome in MM.
Bmps(Bone Morphogenetic Proteins) Inhibit Growth in Multiple Myeloma Cells by p53 Activation.
Authors: Sundan Anders , Ro Torstein B. , Bonhorst Janne , Waage Anders , Borset Magne 
Published: October 2019

Abstract
Only a few naturally occurring cytokines are able to inhibit myeloma cell growth, and among them BMP-4 is a potent inhibitor of growth as well as an inductor of apoptosis in myeloma cells. To study the mechanism behind BMP-4-induced growth inhibition, we performed gene expression profiling by microarrays in two human myeloma cell lines after BMP-4 stimulation for 4 hours. We found that BMP-4 upregulated several known p53 target genes like p21/Cip1, Bax, cyclin G, Gadd45 and dual specificity phosphatases, suggesting a role for p53 in BMP-mediated growth inhibition of myeloma cells. p53 is activated by several post-translational modifications, including phosphorylation at several serine/threonine residues. We found that BMP-4 treatment lead to rapid phosphorylation of p53 at Serine 15. Furthermore, we were able to co-precipitate phosphorylated Smad-1/5/8 and p53 from nuclear extracts of cells treated with BMP by applying a p53 binding element from the Gadd45 promoter. Because some myeloma cell lines are resistant for BMP-4-induced growth inhibition, we examined whether this BMP-4 resistance was associated with p53 mutations in the BMP-4-resistant cell lines. We sequenced the p53 cDNA from eight myeloma cell lines, and resistant cells all had mutated or deleted p53. Introduction of normal p53 by adenoviral constructs in the p53 mutated cell lines restored BMP-4 responsiveness to some degree. Furthermore, in a myeloma cell line with a temperature-sensitive p53 mutation, the cells were sensitive towards BMP-induced growth inhibition at the permissive temperature but resistant when p53 was inactive. In conclusion, we show that normal p53 activity is involved in BMP-4-induced growth inhibition of multiple myeloma cells.