bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of Rituximab Combined with Cladribine and Mitoxantrone in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma
Authors: Ota Shuichi , Tanaka Junji , Nakata Masanobu , Imai Kiyotoshi , Ogasawara Masahiro , Kiyama Yoshio , Irie Tatsuro , Morioka Masanobu , Umehara Shintaro , Iwasaki Hiroshi , Chiba Koji , Kakinoki Yasutaka , Fukuhara Takashi , Kasai Masaharu , Imamura Masahiro 
Published: April 2020

Abstract
BACKGROUND. Synergistic or additive activities for rituximab and cladribine have been shown in preclinical studies. Indolent Non-Hodgkin’s lymphoma (I-NHL) tends to recur with shortening intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Therefore, we evaluated the feasibility, efficacy, and toxicity of combined regimen that consisted of rituximab plus cladribine plus mitoxantrone (the RCM regimen) in the treatment of patients with relapsed or refractory I-NHL.
METHODS. The RCM protocol consisted of rituximab at a dose of 375 mg/m2 on Day 1, cladribine at a dose of 0.09 mg/kg per day on Days 2 through 6, and intravenous mitoxantrone at a dose of 6 mg or 10 mg/m2 per day on Day 2. The RCM courses were repeated at 4-week intervals, for up to 4 cycles.
RESULTS. Fourteen patients with I-NHL and one patient with mantle cell lymphoma entered in the study. The median age was 60 (range 47–77) and 8 were females. Histology was small lymphocytic lymphoma (n=1), follicular lymphoma (n=13), mantle cell lymphoma (n=1). Median time from diagnosis to RCM treatment was 3.6 (range 0.2–8.1) years and median number of prior treatment regimen was 2 (range 1–4). Twelve patients (80%) had recurrent disease after prior therapy including high dose therapy with autologous stem cell transplant, and 3 patients (20%) had refractory disease. Thirteen patients were treated on the RCM regimen, and 8 patients (61.5%) achieved a complete response, 3 patients (23.1%) achieved a partial response. Therefore, the overall response rate was 92.3%. Median time to response was 2.8 months (range 1.0–6.7). Median progression free survival of responders was 16.5 (range 1.3–25.5) months. The treatment revealed tolerability, with episodes of severe neutropenia (grade 3 and 4) observed in 12 patients (85.7%), episodes of grade 3 and 4 thrombocytopenia observed in 2 patients (15.4%). However, severe infections were not observed in any patients.
CONCLUSIONS. The RCM regimen is highly effective and well tolerated modalities of treatment in heavily pretreated and relapsed or refractory patients with I-NHL.
Cladribine in the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
Authors: Noguchi Emi , Okamoto Rumiko , Shimoyama Tatsu , Sasaki Eisaku , Omuro Yasushi , Maeda Yoshiharu , Sakamaki Hisashi , Sasaki Tsuneo 
Published: April 2020

Abstract
BACKGROUND: The treatment of relapsed or refractory Non-Hodgkin lymphoma (NHL) depends on the number of drugs of choice, and additional treatments can achieve remission for many patients. Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a purine nucleoside analogue, and generally approved for indolent NHL relapsed after or refractory to previous chemotherapy. We conducted this analysis to determine efficacy and toxicity of 2-CdA in the treatment of relapsed or refractory NHL.
PATIENTS AND METHODS: 29 relapsed or refractory NHL patients treated with cladribine in a single institution from 2002 to 2007 were entered in a retrospective analysis.
RESULTS: The median age was 64 years. Seventeen patients (59%) were male, twenty (69%) with indolent lymphoma consisting mainly of follicular lymphoma and mantle cell lymphoma, and twenty-eight (97%) previously treated with 1 to 10 regimens (mean 2.7). Cladribine was administrated 24% as a monotherapy and 22% with other chemotherapeutic agents. The dose and duration of administration were variable among the patients, however, most common regimen was 0.9mg/kg/day for seven consecutive days, for 1 to 6 cycles, depending on response. Response rate was 72% (CR and PR were 31%, 41%, respectively). Median overall survival was of 2.9 years. Patients showed improved survival rate in performance status 0 or 1 (Willcoxon: P&lt;0.0001, Log-rank: P&lt;0.0001), more than 3 cycles of cladribine (Willcoxon: P&lt;0.028, Log-rank: P=0.126), or combination chemotherapy (Willcoxon: P=0.042, Log-rank: P=0.040). Main reason for death was disease progression. Myelosuppression was the most common adverse effect. Eight patients (28%) experienced CTCAE grade 4 neutropenia, fourteen (48%) lymphocytopenia, and three (10%) thrombocytopenia, respectively. Two episodes (6.9%) of grade 3–4 infections were observed. There was no treatment related mortality.
CONCLUSIONS: Cladribine is effective even in heavily pretreated patients with NHL. It also has favorable safety, and can be considered as a good alternative treatment for relapsed or refractory NHL.
Proteomic Analysis of Pkc-Beta Inhibitor Enzastaurin-Treated Mantle Cell Lymphoma
Authors: Weinkauf Marc , Rieken Malte , Pastore Alessandro , Hiddemann Wolfgang , Dreyling Martin H. 
Published: April 2020

Abstract
Background: Activation of the PI3K/AKT pathway is involved in pathogenesis of MCL and accordingly, protein kinase C beta (PKCbeta), a pivotal enzyme in B-cell signalling and survival, is over- expressed in most cases of mantle cell lymphoma (MCL). Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signalling through PKCbeta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Recently, a phase II study showed that enzastaurin is able to prolong the progression-free survival in a subset of relapsed MCL (Morschhauser et al, Ann Oncol 2008).
Methods: Four MCL cell lines (GRANTA 519, HBL-2, Jeko-1, Rec-1) were treated with Enzastaurin at a proliferation inhibiting dose of 10μM, defined in previous pilot experiments. After 2–8h of treatment, cells were harvested and a two-dimensional polyacrylamide gel-electrophoresis (2D-PAGE)-based protein screening was performed.
Results: Already 1h after treatment, distinct alterations of the protein pattern were recognized in the 2D-PAGE gels of all cell lines. 115 (12%) of 977 concurrent protein spots exhibited significantly (&gt;3fold) altered protein levels after 4h of enzastaurin exposure, i.e. increased (57 spots; 5,8%) or decreased (58 spots; 5,9%) protein expression, and after 8h the percentage of affected protein spots further increased up to 22% of all concurrent protein spots, due to decreased protein levels. Based on previously defined selection criteria (Weinkauf et al, Electrophoresis 2007) 62 differentially expressed protein spots at 4h (increased/decreased expression: 39/23 spots) were chosen for mass spectrometric identification. Mass spectrometry identified 108 different candidate proteins with significant identification confidence (p&lt;0.05). 29 candidate proteins were detected in multiple protein spots, while 79 candidate proteins were identified in only single protein spots. The identified candidate proteins could be classified in distinct cell programs, including DNA repair and cell division, cytoskeleton (centrosome and spindle), apoptosis, signal transduction and transcription factors. Interestingly, some of the identified candidates had been also previously identified after proteasome inhibition by bortezomib, e.g. ENOA, TOP1, CE290, SMC1A, HSP60 (CH60), ATPB, KAD5 and TPIS.
Conclusion: The identified candidate proteins are currently confirmed in MCL patient samples. Characterization of essential signal pathways after Enzastaurin exposure will not only expand the understanding of the molecular pathogenesis of MCL, but also hint towards promising targets for new molecular therapies.
TLR-9 Activated Lymphoma B Cells Induce Anti-Tumor Immunity in a Murine Model
Authors: Goldstein Matthew J. , Brody Joshua , Levy Ronald 
Published: April 2020

Abstract
Background: Tumor vaccines typically combine unique, tumor antigens with immune stimulants in an effort to elicit a tumor-specific immune response. In prior work we have described a vaccination maneuver that combines cytotoxic chemotherapy to release tumor antigens with intra-tumor injection of a Toll-like Receptor 9 (TLR9) ligand, CpG oligonucleotide (Li and Levy, J. Immunology, 2007). In this therapy, CpG can activate both host antigen presenting cells as well as the tumor itself. Stimulation of tumor B cells through TLR9 induces up-regulation of immune co-stimulatory molecules including CD80, CD86, and CD40 as well as increasing expression of MHC Class I and II. We have now developed an alternative vaccination approach in which B cell lymphoma tumor cells are stimulated with CpG ex vivo and administered as a whole-cell vaccine.
Methods: A20 B cell lymphoma tumor cells were incubated with CpG for 72 hours, irradiated, and administered to naïve Balb/C mice. The complete vaccination regimen included six doses of 1×106 cells administered daily at a sub-cutaneous (s.c.) site. Vaccine-induced immune responses were assessed by measuring IFN-γ expression of peripheral blood lymphocytes (PBLs) in response to co-culture with A20 tumor cells. Tumor protection studies were conducted by challenging vaccinated mice with a lethal dose of 10×106 A20 tumor cells. Anti-tumor immunity generated by vaccination was also tested in adoptive cell transfer studies.
Results: Sub-cutaneous vaccination with CpG-stimulated, whole-cell vaccine induces robust anti-tumor T cell immunity comparable to that induced by intra-tumor vaccination with CpG. This immunizing effect was dependent on tumor cell activation, since native tumor cells were less efficient at inducing anti-tumor immune responses. Both CD4+ and CD8+ T cells participated in this response. Mice vaccinated with this regimen were protected against tumor challenge. Splenocytes from vaccine-primed donors were adoptively transferred into irradiated, syngeneic recipients. These ‘immunotransplanted’ recipients had even greater immune protection against tumor challenge than the directly vaccinated donor mice.
Conclusions: We have developed a vaccination approach that takes advantage of the antigen presentation capability of malignant B cells. Vaccination with CpG-activated lymphoma cells induced anti-tumor immune responses that were further enhanced by adoptive transfer of immune cells into lymphodepleted recipients. These vaccine maneuvers are directly translatable into therapeutic, human clinical trials.
Forodesine (Immucillin H, BCX-1777) Shows Activity on Mantle Cell Lymphoma Primary Cells
Authors: Rinaldi Andrea , Ceresa Emilia , Rossi Davide , Gaidano Gianluca , Bantia Shanta , Manz Chantal Y. , Catapano Carlo , Zucca Emanuele , Bertoni Francesco 
Published: April 2020

Abstract
Mantle cell lymphoma (MCL) represents a subtype of B-cell lymphoma associated with a very unfavourable clinical outcome. Currently no therapy can be considered as standard, and new therapeutic approaches are needed. Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP), whose major role is to catalyze the cleavage of inosine, deoxyinosine guanosine, and deoxyguanosine (dGuo) to their corresponding base and sugar 1-phosphate by phosphorolysis. In the presence of deoxycytidine kinase, PNP inhibition leads to an increase in the concentration of dGuo triphosphate (dGTP), followed by inhibition of DNA synthesis and cell death by apoptosis. When combined with dGuo, forodesine has been shown to have in vitro cytotoxic activity on T-cell (T-ALL, T-PLL) and on B-cell malignancies (CLL, B-ALL), and Phase I/II trials are on going in CLL and CTCL patients. Here, we report the first data on in vitro activity of forodesine in MCL. Primary MCL cells, derived from six patients, were exposed to forodesine (0, 2, 20 μM) in combination with dGuo (0, 10, 20 μM), for 48 hrs. Cells were cultured in X-VIVO 10 medium (Cambrex) with 10% FBS. Cell viability was assessed by flow cytometry with the Annexin V - propidium iodide assay. Four patient samples (67%) showed an increase in the number of Annexin V positive cells ranging from 1.9 to 5.3 times compared to untreated cells. The effect was larger for 20 μM forodesine compared with 2 μM. There was no effect of dGuo alone and only a minimal effect of increasing dGuo concentration from 10 μM to 20 μM. Cell lines did not appear to be ideal models to evaluate the efficacy of forodesine in vitro. Three established MCL cell lines (Granta-519, Rec, JeKo1) were treated with escalating doses of forodesine, but the results were not reproducible, while the same cells showed expected IC50 values between 25–30 μM when exposed to bendamustine for 72 hrs. In conclusion, the in vitro data reported here with 4/6 MCL patients primary samples sensitive to forodesine and the results from various groups on other T- and B-cell malignancies suggest that clinical trials of forodesine in MCL may be warranted.
A Therapeutic Approach for Acute Leukemias: Glycolysis Inhibition Revisited
Authors: Akers Lauren J. , Levy Alejandro G. , Franklin Anna R. , Fang Wendy , Huang Peng , Zweidler-McKay Patrick 
Published: April 2020

Abstract
Background: Recent evidence suggests that myeloid and lymphoid leukemia cells are dependent on aerobic glycolysis for ATP production, known as the Warburg effect. Early glycolysis inhibitors were effective but only at high mM concentrations. The novel third generation glycolysis inhibitor, 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), has shown efficacy in models of neuroblastoma, glioblastoma, colon carcinoma, and lymphoma in the mcM range and has improved oral bioavailability and biodistribution. We proposed that potent inhibition of glycolysis would lead to ATP depletion and induce growth arrest and cell death in acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) cells. Objective: To determine the feasibility and effect of 3-BrOP on human AML, precursor-B, and T cell leukemia cell lines and patient samples.
Design/Methods: A panel of fifteen human pre-B ALL, T-ALL, and AML cell lines were treated with 3-BrOP to determine IC50s via cell counts, cell cycle, and Alamarblue. In addition, western blots and ATP assays were performed to determine caspase activation and ATP depletion.
Results: All cell lines demonstrate growth arrest, decreased alamar blue metabolism and significant apoptosis when treated with 3-BrOP. The five human precursor-B ALL cell lines had IC50s between 10–30mcM, while the T ALL cell lines had IC50s between 15–30mcM. The human AML cell line panel had IC50s between 20–40mcM. In addition, patient samples representing ALL (IC50 15 mcM) and AML (IC50 30mcM) were sensitive to 3-BrOP mediated cell death. Of note, caspase-3 cleavage was detected by 2 hours of exposure, and was nearly complete by 6 hours in both pre-B and T-ALL suggesting a potent an early pro-apoptotic signal. Overall, cell cycle analysis at 48 hours of treatment, showed the majority of cells had died (83–97%, p&lt;0.001). The remaining cells were apoptotic with &gt;80% of Nalm6 (pre-B ALL) and 72% of U937 (AML) cells having sub-G0 DNA content (p&lt;0.001). As expected, exposure to 3-BrOP reduced intracellular ATP concentrations in a dose and time dependent manner. In Nalm6 cells (pre-B ALL), by 48 hours of exposure, the ATP levels were 50% of control at a dose of 15 mcM. At a dose of 22.5 mcM, the ATP level was 13% of control, and by 30 mcM there was no detectable ATP. Importantly, at higher doses (&gt;30mcM) ATP levels were reduced significantly within 24 hours. These effects on ATP levels correlate with dose and time dependent viability.
Conclusions: These data demonstrate that a broad range of acute leukemia cell lines and patient samples appear to be dependent on glycolysis for ATP production and survival. The novel 3rd generation glycolysis inhibitor, 3-BrOP, induces cell death across all subtypes of human acute leukemia cell lines. Glycolysis inhibition via 3-BrOP represents a novel and clinically feasible therapeutic approach for acute leukemias and warrants further pre-clinical evaluation.
Proteome Analysis of the Proteins Associated with All-Trans Retinoic Acid Resistance in Acute Promyelocytic Leukemia Cells
Authors: He Pengcheng , Zhang Mei , Qi Jun , Wang Xiaoning , Xi Jieying , Wang Huaiyu , Li Jing , Wu Di , Wei Kaihua , Liu Feng , Wang Hongli 
Published: April 2020

Abstract
Although 90% patients with untreated acute promyelocytic leukemia(APL) obtain complete remission because of the usage of all-trans retinoic acid(ATRA), patients with ATRA-resistance are increased gradually. ATRA-resistance has become one of the main causes which affect the long-term therapeutic efficacy of APL. The mechanisms of ATRA-resistance are complex, which probably involve the metabolism of ATRA, abnormal expression of cellular retinoic acid binding protein(CRABP) and P-glycoprotein(P-gp), mutation of RARα and aberration translocation of APL. However, in these previous researches, it was one or a few proteins but not the entirety proteins that were emphasized on the mechanisms of ATRA-resistance. Comparative proteomics can analyze the entire protein expression in cells in whole and has the superiority in screening the drug-resistance proteins differentially expressed. In order to investigate the mechanisms of ATRA-resistance in APL in whole, we compared and analyzed the protein expression profiles between MR2 cells(APL cell line with ATRA-resistance) and NB4 cells(APL cell line with ATRA-sensitiveness) by comparative proteomics. After the total proteins of MR2 cells and NB4 cells were extracted respectively, they were separated by two-dimensional electrophoresis(2-DE). The differences in proteome profile between MR2 cells and NB4 cells analyzed by ImageMaster™ 2D Platinum software. The average protein spots in 2-DE maps of MR2 and NB4 cells were 1160±51 and 1068±33 respectively. 8 protein spots were selected to be identified by Matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS), in which the quantity of the protein differentially expressed was more than two times(≥2 or ≤0.5) between MR2 and NB4 cells’ 2-DE map. They were all successfully identified and their definite information was obtained. Among them, 6 proteins were probably involved in the mechanisms of ATRA-resistance in APL and they were Cofilin-1, Elongation factor 1-beta (EF-1β), Tropomyosin isoform(TM), High mobility group protein B1(HMGB1), Ran-specific GTPase-activating protein (RanGAP1) and Galectin-1. Moreover, so far there was no related report on the roles of HMGB1, RanGAP1 and Galectin-1 in the mechanisms of ATRA-resistance in APL. These differential proteins identified provide the new clues for us to further elucidate the mechanisms of ATRA-resistance from multiple factor.
Differential Protein Expressions Between Leukemia HL-60 and Adriamycin-Resistant HL-60 Cell Lines by Comparative Preteomic Analysis
Authors: Hu Jian Da , Lin Min-Hui , Chen Xin-Ji , Liu Ting-Bo , Lv Lian-Huang 
Published: April 2020

Abstract
Resistance is a major problem of chemotherapy failure in acute leukemia. Although multi-drug resistance is an important factor, the exact mechanisms of resistance remain to be clarified. With the aim of better understanding the protein involvement in development of resistance mechanisms, a comparative proteomic analysis——two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) was used to compare differential protein expression profiles in adriamycin-resistant acute myeloid leukemia (AML) HL-60/ADR and sensitive HL-60 cell line. Total cellular proteins extracted from HL-60 and adriamycin- resistant HL-60 cells were separated by 2-D gel electrophoresis.Differential expressed proteins were analyzed by mass spectrometry (MALDI-TOF/TOF) and database searching. 16 significantly differentially expressed protein spots were identified, among which 13 protein spots were identified as up-regulated and 3 as down-regulated. The identified proteins were categorized into: (±)metabolic enzymes; (II)proteins related with signal transduction;(III)cell cycle regulators; and(‡W)cellular proliferation and apoptosis proteins. Some of these differential protein expression were confirmed by western blot. In addition, we investigated the expression of distinct proteins in the primary leukemia cells. The results revealed that nucleolar phosphoprotein (B23) over-expressed in the relapsed patients with acute monocytic leukemia (M5). It suggests that B23 might be a useful indicator of prognosis of M5, but the exact role in resistant mechanism is still to be investigated. 2-D DIGE is a useful approach to investigate differential protein expression related treatment resistance.
Magnetic Nanoparticle of Fe3O4 Loaded with Daunorubicin Reverse Leukemia Multidrug Resistance in Vivo
Authors: Chen Bao-An , Lai Bin-bin , Cheng Jian , Gao Feng , Xu Wen-lin , Shen Hui-lin , Ding Jia-hua , Gao Chong , Sun Yun-yu , Wang Jun , Zhao Gang , Song Hui-hui , Bao Wen , Sun Xin-chen , Cheng Hong-yan , Deng Yu-xia , Li Guo-hong , Liu Li-jie , Chen Wen-ji , Shao Ze-ye , Xia Guo-hua , Wang Jue-qiong , Yuan Peng , Pei Xiao-ping , Chen Ning-na , Li Qin-ning , Wang Xue-mei 
Published: April 2020

Abstract
Object: To the effect of Fe3O4-magnetic nanoparticle loaded with DNR on In order to study the multidrug-resistant reversal effect of Fe3O4-magnetic nanoparticle loaded with DNR in vivo.
Methods: K562-n,a leukemia cell line with high tumorigenicity in nude mice and its multidrug-resistant counterpart K562-n/VCR cells were inoculated subcutaneously into each groins of nude mice (5×106 cells/each) to establish a human leukemia xenograft model. The mice were randomly divided into group A receiving normal saline, group B receiving anti-tumor drugs daunorubicin (DNR), group C receiving Fe3O4-magnetic nanoparticle, group D receiving Fe3O4-magnetic nanoparticle loaded with DNR, and group E receiving Fe3O4-magnetic nanoparticle containing DNR with a magnetic field built on the surface of tumor tissues. After 20 days treatments, mice were killed and tumor tissues were isolated for pathological observation. The volume and weight of tumors were measured, then tumor suppression rate was calculated. The side effects of DNR loaded Fe3O4-magnetic nanoparticle were also evaluated.
Results: The results showed that DNR loaded Fe3O4-magnetic nanoparticle can significantly suppress the growth of K562-n/VCR tumor in vivo, DNR alone can greatly suppress the growth of K562-n, Fe3O4-magnetic nanoparticle loaded with DNR can not further inhibit the K562-n tumor.
Conclusion: In conclusion, Fe3O4-magnetic nanoparticle loaded with DNR can reverse the leukemia multidrug resistance in vivo.