bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rituximab-Mediated Antibody-Dependent Cellular Cytotoxicity Is Enhanced by Interleukin-15 or CpG Oligodeoxynucleotides.
Authors: Moga Esther , Briones Javier , Alvarez Eva , Cantó Elisabet , Vidal Silvia , Rodríguez-Sánchez José Luís , Sierra Jordi 
Published: April 2020

Abstract
Introduction
Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism in the clinical activity of rituximab for the treatment of B-cell malignancies. The NK cells, through the activating receptor FcγRIIIa, play a major role in the rituximab-mediated ADCC. We have studied the effect of NK stimulators such IL-15 and CpG oligodeoxynucleotides (ODN) in the enhancement of rituximab-mediated ADCC against B-cell lymphoma.
Methods
ADCC was performed by standard 51Cr release assays using peripheral blood mononuclear cells (PBMC) purified from 4 normal volunteers by Ficoll-Hypaque gradient centrifugation. Cells were cultured for 18 hours in the presence of human recombinant interleukin 15 (rhIL-15; 10 ng/ml) or CpG ODN (2,5 μg/ml). The B-lymphoma cell line Raji was used as target in the presence of rituximab (10 μg/ml) or human IgG1 as control (10 μg/ml) for 30 min at room temperature. Target cells and effector cells were incubated at different ratios ranging from 1:1 to 30:1, for 4 hours at 37°C. The polymorphism at amino acid 158 of the activating FcγRIIIa receptor (FcγRIIIa V→F) was analyzed in effector cells from normal donors with a polymerase chain reaction (PCR)-based allele-specific restriction analysis assay.
Results
Lysis of B lymphoma cells treated with rituximab alone was 40% ± 5% (mean ± SD) at the highest ratio, as compared to 12% ± 7% (p&lt;0.001) in the presence of human IgG1 control. When the effector cells were treated with IL-15, a dramatic increase in the lysis of lymphoma cells was observed (70% ± 8% vs. 40% ± 5%, IL-15 plus rituximab vs. rituximab alone) (p&lt;0.001). Effector cells treated with CpG ODN showed a significant increase in rituximab-mediated cytotoxicity (84% ± 2% vs. 53% ± 16%) (CpG ODN vs. control, respectively; p=0.03). The enhancement of rituximab-mediated ADCC when the effector cells were treated with IL-15 or CpG ODN was similar for both FcγRIIIa-V/V and FcγRIIIa-V/F genotypes on effector cells.
Conclusion
PBMC cells activated in the presence of IL-15 or CpG ODN become strong effectors in rituximab-mediated ADCC against B cell lymphoma. These results may be useful to improve the therapeutic activity of rituximab.
BiovaxID™ Vaccine Therapy of Follicular Lymphoma in First Remission: Long-Term Follow-Up of a Phase II Trial and Status of a Controlled, Randomized Phase III Trial.
Authors: Santos Carlos , Stern Lee , Katz Laura , Watson Thelma , Barry Gause 
Published: April 2020

Abstract
Malignant B-cells in Follicular Non-Hodgkin’s Lymphoma expresses a clonal idiotype immunoglobulin which can serve as the basis for a patient-specific anti-idiotype vaccine. In a previous single-arm Phase II study by Bendandi, et al (Nature Med5:1171–1177, 1999), we evaluated the ability of tumor-specific idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) administered concurrently with granulocyte-monocyte colony-stimulating factor (GM-CSF) adjuvant to induce complete remissions and molecular remissions in treated patients. The vaccine formulation induced a tumor-specific cytotoxic CD8+ and CD4+ T-cell response in patients in first complete remission after standard chemotherapy, as well as achieved molecular remissions in 8 of 11 of these patients. Data available at the time of this abstract for the 20-patient cohort, indicates a median follow-up of 9.167 years. 9 patients (45 %) remain in continuous first CR at their most recent follow-up (either in 2004 or 2005), and overall survival is 95%. The data further indicates the median disease free survival for the cohort is 96.5 months (8.04 years). To date there have been no additional reported mortalities in this cohort. As of August 2005, we report the progress of the Phase III clinical trial for this vaccine, opened in January 2000 by the NCI to evaluate the impact of this hybridoma-based Id vaccine on disease-free survival in a group of up to 375 previously untreated patients who have attained a CR or CRu from PACE [Prednisone, Doxorubicin, Cyclophosphamide, and Etoposide (ProMACE without methotrexate)] chemotherapy, and who are randomized to receive either vaccine or control. To date, 187 patients have been accrued onto the study. Of those patients, 145 (77.5%) achieved a CR or Cru and are being followed in this ongoing clinical trial.
Rituximab Combination with Anthracyclin Based Chemothrapy Significantly Improved the Outcome of Young Patients with Diffuse Large B-Cell Lymphoma in Low as Well in High Risk Subgroups.
Authors: Trneny Marek , Belada David , Vasova Ingrid , Pytlik Robert , Kozak Tomas , Sykorova Alice , Kubackova Katerina , Pirnos Jan , Bolomska Ingrid , Petrova Marketa 
Published: April 2020

Abstract
Background: It has been demonstrated that rituximab with chemotherapy improves the outcome of older pts with DLBCL (Coiffier 2000, 2002, Habermann 2003) regardless risk category as well as the outcome of young patients with low IPI risk (Pfreundschuh, 2004). There is a lack of data on the impact of rituximab in high risk young patients. We have analyzed the outcome of young patients with DLBCL registered in Czech Lymphoma Study Group registry.
Patients: 422 pts with newly diagnosed DLBCL younger than 60y have been registered between Jan 1999- Aug 2004. Pts with primary CNS lymphoma, pts with missing data, without anthracyclin based therapy were excluded from the analysis. Total 376 pts were analyzed. All patients received anthracyclin based therapy, 120 received rituximab (R-CT) and 256 chemotherapy only (CT). There were no significant differences between both group, R-CT and CT resp. Age median was 47.5y and 49y. Advanced CS was found in 73 pts (60.8%) and in 137 (53.5%), higher LDH was in 72 pts (60%) and 133 pts (51.9%), extranodal involvement was found in 76 pts (63.3%) and in 66 (25.8%) pts. The aaIPI risk distribution was as follows (R-CT vs CT): low risk 31 (25.8%) and 96 (31.5%), low-intermed. 34 (28.3%) and 70 (27.3%), intermed.-high 38 (31.7%) and 55 (21.5%), high 17 (14.2%) and 35 (13.7%). CHOP reg was used in 79 (65.8%) and 186 (72.7%) resp., intensified CHOP or CHOP with other combination was used in 36 (30.0%) and 52 (20.3%), other CT was used in 1 (0.8%) and 18 (7.0%). HDT with ASCT was used in 38 (32.2%) and 55 (22.0%) (ns). The median follow up was 22 m for R-CT and 44 m for CT group.
Results: The estimates for 2y PFS was 85.5 % for R-CT and 66.4% for CT group resp. (p 0.0001). The estimates for 2y OS was 90.7% and 77.6% resp. (0.0007). The differences were significant in low risk (L and LI) as well as high risk (IH and H) group. PFS at 2y was 93.4% and 80.2% resp (p 0.005) and OS was 96.9% and 88.8% resp. (0.02) for low risk group. PFS at 2y was 75.8% and 41.8% resp. (0.0003) and OS was 83.4% and 57.0% resp. (0.0007) for high risk group.
Conclusion: We have demonstrated the significance of rituximab combination with CT in young pts with DLBCL in this comparison. Rituximab has significant impact both in low risk pts (consistent with MINT data) as well as in high risk young pts, which has not been described in any prospective trial yet.
Figure Figure
Activity of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in 22 Patients with Relapsed and Refractory Mantle Cell Lymphoma (MCL).
Authors: Younes Anas , Pro Barbara , Rodriguez Maria A. , Romaguera Jorge E. , McLaughlin Peter , Wang Michael , Hagemeister Fredrick B. , Dang Nam H. , Neelapu Sattva , Podoloff Donald 
Published: April 2020

Abstract
Background: The management of MCL is a significant therapeutic challenge, especially in patients with relapsed or refractory disease, who are generally refractory to salvage chemotherapy. Although recent studies have shown the clinical utility of radioimmunotherapy (RIT) in relapsed and transformed indolent B-cell lymphoma, the clinical efficacy of this treatment modality in patients with MCL is unknown. We report the results of an ongoing phase II clinical trial of yttrium 90 ibritumomab tiuxetan (Zevalin®) in patients with relapsed and refractory MCL.
Patients and Methods: Patients with relapsed or refractory MCL with measurable disease, age ≥18 years, and performance status &lt;3 were eligible. Patients were required to have adequate function of the bone marrow (ANC ≥1,500/mm3, platelets ≥100,000/mm3), liver, and kidneys. Patients were excluded if they had prior stem cell transplantation, RIT, CNS lymphoma, HIV infection, pleural effusion, HAMA reactivity, or circulating lymphoma cell count &gt;5000/mm3. Patients with pretreatment platelet counts ≥150,000/mm3 received a dose of Zevalin at 0.4 mCi 90Y/kg (maximum dose 32 mCi), whereas those with platelet counts &lt;150,000/mm3 received 0.3 mCi 90Y/kg.
Results: Twenty-two patients were enrolled and all qualified for evaluation of treatment response and toxicity. The median age was 67 years (range 51–77), and 18 patients were male. All patients had an ECOG performance status of 0 or 1 and had been previously treated with rituximab with or without other chemotherapy. The median number of prior regimens was 3 (range 1–6). Fourteen patients were previously treated with Hyper-CVAD alternating with MTX/Ara-C, 21 previously received rituximab, and 5 previously received bortezomib. Zevalin treatment was generally well tolerated, with the most common toxicities being hematologic. Objective responses were observed in 8 of 22 patients (36%), including 3 CR and 2 CRu. Seven of the eight responding patients were previously treated with 3 or less treatment regimens, and all responding patients did not have bulky disease, with the largest lesion measuring 3 cm or less. Median time to progression for CR/CRu patients was 6 months.
Conclusion: The observed responses to Zevalin in heavily pretreated patients with MCL are promising, but the duration of responses has been short. Furtherinvestigation is warranted after first or second relapse, and in conjunction with front-line therapy.
Rituximab-Mediated ADCC Is Augmented by Concomitant Interference with Inhibitory Self-Recognition by Human NK Cells.
Authors: Binyamin Liat , Alpaugh R. Katherine , Campbell Kerry S. , Borghaei Hossein , Weiner Louis M. 
Published: April 2020

Abstract
The anti-CD20 monoclonal antibody, rituximab is widely used in the treatment of non-Hodgkin lymphomas. However, clinical responses to rituximab are variable. It has been demonstrated that rituximab can lead to tumor cell death by engaging the cellular immune system through antibody dependent cellular cytotoxicity (ADCC). NK cells have been shown to play a critical rule in eliminating rituximab coated B-cells, and the efficiency of killing depends on the interaction between the Fc portion of rituximab and the FcγRIII (CD16) activating receptor on NK cells. NK cell function is regulated by a complex balance of inhibitory and activating signals that enable the cells to survey their surrounding and selectively target and kill targets that do not display a “self” ligand (the “missing self hypothesis”). We hypothesized that interference with inhibitory self-recognition would augment rituximab-induced NK cell-mediated ADCC. Initial studies with the 721.221 B51 (HLA Bw4+) CD20+ cell line and NK92.26.5 cells transduced with human CD16 suggested that interference with KIR3DL1 recognition of Bw4 augmented tumor lysis in the presence of rituximab. To further test this hypothesis we employed human NK cells and autologous EBV transformed B cells from normal volunteers, and blocked the KIR3DL1 inhibitory receptor on NK cells using (Fab′)2 fragments of the DX9 antibody, in conjunction with rituximab exposure. Inhibitory blockade promoted rituximab-mediated cytotoxicity by peripheral blood mononuclear cells in three separate HLABw4+, KIR3DL1+ volunteers. These results suggest that manipulating the balance between inhibitory and activating receptors on NK cells might be applied to improve ADCC and ultimately lead to an improvement in response rates to rituximab and related lymphoma-directed antibodies that mediate ADCC. Supported by R01CA50633.
Targeting the Protein Degradation Pathway in Multiple Myeloma with Synergistic, Selective Small Molecules.
Authors: Bradner James , Shen John Paul , Greenberg Edward , Hideshima Teru , Anderson Kenneth C. , Schreiber Stuart L. 
Published: April 2020

Abstract
The response of refractory multiple myeloma to the proteasome inhibitor bortezomib reveals an intriguing sensitivity of this incurable malignancy to perturbations of protein catabolism. However, an overall clinical response rate of approximately 30% as a single agent suggests the importance of chemoresistance mediated by compensatory mechanisms of protein degradation. With proteasome inhibition, juxtanuclear inclusion bodies accumulate. These “aggresomes” are specific cellular structures comprised of chaperones, misfolded proteins, and proteasome components. The cytoplasmic histone deacetylase inhibitor (HDAC6) is essential for aggresome formation. Recently, we have demonstrated robust cytotoxic synergy in multiple myeloma cells between bortezomib and the carboxy-terminal domain-selective inhibitor of HDAC6, tubacin (1). Tubacin is a hydroxamic acid member of a diversity-oriented synthetic chemical library realized and validated previously by members of our laboratory (2). In our study of bortezomib and tubacin in multiple myeloma, we noted the dose-dependent, significant association between cytotoxicity and the marked accumulation of polyubiquitinated proteins in sensitized cells. With an interest in further interruption of the misfolded protein response, we have explored the cytosolic chaperone protein, hsp90, as an additional target using a chemical biologic approach. 17-AAG is an analog of the benzoquinone ansamycin antibiotic geldanamycin, known to bind to the ADP/ATP pocket of hsp90. 17-AAG stabilizes a conformation of the chaperone favoring targeted degradation of its client proteins via recruitment of the hsp70 co-chaperone complex (3). Further supporting this strategy, collaborators have recently identified that HDAC6 binds to and principally mediates the deacetylation of hsp90 (4). Inhibition with non-selective HDAC inhibitors was shown to augment hsp90 acetylation and inhibit ATP binding, resulting in the promotion of protein degradation by polyubiquitination. With the support of these data, we investigated whether the addition of 17-AAG to bortezomib and tubacin results in increased cytotoxicity in multiple myeloma cells. Indeed, we demonstrate potent cytotoxicity in cultured myeloma cells at low concentrations of each small molecule. Focused study of the MM.1S cell line demonstrates that the addition of 17-AAG to tubacin and bortezomib markedly increases the burden of ubiquitinated, cytosolic cellular protein by 24 hours, correlating with enhanced cell killing. These data further credential the protein degradation pathway in multiple myeloma, demonstrate the contribution of targeted, combined approaches with active small molecules, and provide a blueprint for a rational therapeutic strategy.
Redox Regulation of Retinoic Acid Receptor Function in Myeloid Leukemia Cell Differentiation and Apoptosis.
Authors: Robertson Kent A. , Luo Meihua , Chastain Ashley , Colvin Scott , Reed April , Kelley Mark R. 
Published: April 2020

Abstract
Ape1/ref-1 is a multifunctional base excision DNA repair protein that is involved in the repair of abasic sites in DNA. However, it also has a distinct role in the redox regulation of a variety of cellular proteins, such as Fos, Jun, p53, NFkB, PAX, HIF-1a, HLF, and others. Ape-1/ref-1 maintains these proteins in a reduced state thereby facilitating their DNA binding and transcriptional activation capability. HL-60 cells are known to respond to retinoic acid (RA) with terminal granulocytic differentiation and apoptosis, which is mediated through the RA receptors. Previous experiments suggested that Ape1/ref-1 expression is related to apoptosis. To further define this relationship, we used retroviral gene transduction to over-express HA-tagged Ape1/ref-1 in HL-60 myeloid leukemia cells. We observed that the RA-induced growth inhibition of HL-60 cells over-expressing Ape1/ref-1 was significantly enhanced compared to wild type HL-60 cells. To determine if the growth inhibition was related to enhanced programmed cell death and differentiation, we treated Ape1/ref-1 transduced and vector-only (LXSN) transduced HL-60 cells with RA and evaluated the expression of Ape1/ref-1 and the development of apoptosis and markers of differentiation.
Results: 1) RA induced expression of the retroviral Ape1/ref-1 construct as determined by Western blot resulting in a higher (ie retroviral + endogenous Ape1/ref-1) overall expression of Ape1/ref-1 compared to control cells; 2) analysis of RA-treated cells for apoptosis by propidium iodide, TUNEL, and Annexin V staining as well as morphology, unexpectedly demonstrated enhanced programmed cell death in cells expressing the transduced Ape1/ref-1; 3) Ape-1 over-expression enhanced the retinoid differentiation response by morphology and expression of CD11b. Additional mobility shift experiments demonstrated the redox dependence of retinoic acid receptor binding to retinoid response elements mediated by Ape-1/ref-1. In conclusion, our data supports the contention that Ape1/ref-1 expression may be important for mediating RA-induced myeloid differentiation and programmed cell death.
Rimcazole - A Sigma Receptor Antagonist - As a Potential Novel Therapy for Acute Myeloid Leukemia and Myeloma.
Authors: Upadhye Yogesh , Watt Stephen , Spruce Barbara A. , Bowen David T. 
Published: April 2020

Abstract
The cure rates for most subtypes of acute myeloid leukaemia (AML) have been static for a decade or more. Risk directed therapy is paying dividends for younger patients with AML characterised by balanced translocations, but therapeutic success is more limited for the majority of patients. Although several new therapeutic options are available to prolong survival in myeloma, cure is rarely attainable. Thus novel therapeutic approaches are required for both diseases. Sigma receptors are widely expressed in the cells of the nervous system, and are aberrantly increased in malignant tumour cells, including hematological malignancies. Sigma receptor antagonists have previously been tested in humans as candidiate antipsychotics and also in diagnostic tumour imaging. We have previously shown that sigma receptor antagonists induce apoptotic cell death in a range of cancer cell lines, while sparing normal cells (Spruce et all 2004).
To investigate the potential for sigma receptor ligands in the treatment of hematological malignancies, we studied the effect of rimcazole, a sigma receptor antagonist, in 3 established and well characterized cells lines derived from malignant haemopoetic cells - HL60, K562 and OPM-2. Rimcazole induced dose-dependent cell death in all 3 haemopoetic cell lines.
Figure Figure
Rimcazole induced cell death was shown to be apoptotic, as assessed by FACS analysis using Annexin V and Propidium Iodide staining as markers of apoptosis. Rimcazole also inhibited colony formation by HL60 and K562 cell lines in a standard methycellulose assay in a dose-dependent manner.
Malignant hematological cells are known to have increased NF kappaB activity. Suppression of NF kappaB activity by treatment with a TAT-tagged IkappaB superepressor peptide resulted in attenuation of rimcazole-induced cell death.
Figure Figure
This suggests an NF kappaB-dependent pathway of rimcazole action. We also measured the I kappaB levels in the 3 cell lines after treating them with rimcazole. Decreased concentration of IkappaB was detected by Western Blot method in the samples treated with Rimcazole. Untreated cells were used as control.
We further evaluated in vitro response of primary AML cells stored in the tissue bank from 3 patients diagnosed with AML. The primary AML cells also showed dose dependent death on treatment with Rimcazole. The drug concentrations at which the optimum effect was observed was similar for the 3 primary AML cells as well as established cell lines.
Evaluation of sigma receptor antagonists in other primary leukaemic and myeloma cells is currently in progress.
Stromal Cell IL-8 Production Is Increased in MM and May Impact Both Tumor Cells and the Microenvironment.
Authors: Kline Michael , Donovan Kathleen , Wellik Linda , Lust Christopher , Jin Wendy , Moon-Tasson Laurie , Kumar Shaji , Witzig Thomas E. , Rajkumar S. Vincent , Lust John A. 
Published: April 2020

Abstract
Background: Multiple myeloma (MM) is an incurable hematological malignancy characterized by the expansion of a plasma cell clone that localizes to the bone marrow. Stromal cells residing in the bone marrow respond to signals from MM cells and other cell types by producing cytokines and other proteins that stimulate tumor cell growth, survival, adhesion, migration, and drug resistance. We have examined the proteins produced by stromal cells in response to stimulation by bone marrow from patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM. Furthermore, we have begun analyzing the properties of one of these proteins, the pro-angiogenic chemokine IL-8, in MM.
Methods: Bone marrow aspirates from patients with MGUS (n=3), SMM (n=7), and MM (n=6) were cultured for 48 hours, and the culture supernatants were incubated with stromal cells for an additional 48 hours. Protein levels were analyzed using antibody array and ELISA. Microvessel density (MVD) was determined as a measure of angiogenesis in patient bone marrow samples using CD34 staining. Flow cytometry analysis of MM cell lines and patient bone marrow samples was performed using monoclonal antibodies against IL-8 receptors CXCR1 and CXCR2.
Results and Conclusion: We observed a significant increase in stromal cell IL-8 production stimulated by bone marrow cells from patients with active myeloma and a subset of SMM patients (16.67 ± 9.82 ng/ml) in comparison to bone marrow of patients with MGUS and all other SMM patients (0.55 ± 0.17 ng/ml; P=0.0004). Use of an IL-1 inhibitor and recombinant IL-1β demonstrated that IL-8 production was dependent upon IL-1β signaling. Increased BM microvessel density correlated with stimulation of stromal cell IL-8 production (P=0.0005). Furthermore, the majority of MM cell lines (7/9) and MM patient plasma cells were found to express IL-8 receptors CXCR1 and CXCR2. In addition to its function as a pro-angiogenic factor, IL-8 may directly influence MM cells through its CXCR1 and CXCR2 receptors. We conclude that stromal cell IL-8 production parallels MM disease activity, is IL-1β induced, correlates with bone marrow angiogenesis, and may influence MM disease via impact upon both the microenvironment and tumor cells.