bluuebunny/crossref_metadata_2025_split huggingface dataset:
The BLyS Survival Pathway in NHL-B Cells: Constitutive NF-kB and NFAT Lead to Activation.
Authors: Fu Lingchen , Archito Tamayo , Lin-Lee Yen-Chiu , Pham Lan , Yoshimura Linda , Ford Richard J. 
Published: October 2019

Abstract
B-cell non-Hodgkin’s Lymphomas (NHL-B), neoplasms of the immune system have shown a significant increase in incidence in the USA over the last three decades. While the pathophysiology of the NHL-B is still unclear, the need to identify the relevant genes and critical signaling pathways, and their involvement in the disease processes in NHL-B have begun to be elucidated. Recently, B Lymphocyte Stimulator (BLyS) has been described as a relatively new member of the TNF ligand family, as a potent cell survival factor that is expressed in many hematopoietic cells, including neoplastic B cells. BLyS can bind to three receptors: TACI, BCMA, BAFF-R, and plays a critical role in B cell maturation, differentiation and proliferation. Relatively high levels of BLyS has been found in the serum of NHL-B patients as well as of the patients with autoimmune disease. The mechanisms of BLyS gene expression and regulation is still unclear, but we have recently found that BLyS is constitutively expressed in several NHL-B cell lines and patient tumor samples by RT-PCR, confocal microscopy, realtime PCR and flow cytometry (FCM). We detected high levels and differential expression of BLyS receptors (TACI, BCMA, BAFF-R) in several NHL-B cell lines by flow cytometry, RT-PCR and realtime PCR in both NHL-B cell lines and patient tumor samples. We have identified a single binding site for NF-kB and two binding sites for NFAT in the BLyS promoter. We also show in aggressive lymphoma B cells that constitutive NF-kB and NFAT binds to the BLyS promoter constitutively. Inhibiting NF-kB/NFAT activity levels, using the NF-kB inhibitors, BAY-11 or Velcade (PS-341), can decrease NF-kB binding activity in the BLyS promotor by EMSA. These inhibitors also decrease BLyS and BAFF-R mRNA and protein levels by realtime PCR and flow cytometry. Similarly, when NHL-B cells were transfected with dominant negative NFAT or NF-kB constructs, there is a 50% decrease in BLyS and BAFF-R expressions, demonstrating that both the ligand (BLyS) and the receptor (BAFF-R) expression are regulated by NFAT and NF-kB. Interestingly, follicular (low grade) lymphoma cells do not express constitutive NF-kB/NFAT activation, and barely detectable mRNA and protein levels of BlyS, but can be activated with exogenous CD154/anti IgM in vitro, activating NF-kB/NFAT and promoting binding to the BLyS promoter by EMSA. This results in a significant increase of BLyS protein level by flow cytometry. Our studies indicate that constitutive NF-kB and NFAT are critical transcriptional regulators of the BLyS survival pathway in malignant B cells that may provide a future therapeutic target in the aggressive NHL-B.
Dihydroflavonol BB-1, an Extract of Natural Plant Blumea Balsamifera, Abrogates TRAIL Resistance in Adult T-Cell Leukemia/Lymphoma.
Authors: Hasegawa Hiroo , Yamada Yasuaki , Hayashi Masahiko , Ishibashi Masami , Komiyama Kanki , Murata Ken , Masuda Masato , Takasu Nobuyuki , Tomonaga Masao , Kamihira Shimeru 
Published: October 2019

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells but not in normal cells, hence TRAIL has recently emerged as a novel anti-cancer agent. Adult T-cell Leukemia/Lymphoma (ATLL) is a neoplasm of T-lymphocyte origin etiologically associated with HTLV-I, and is known to be resistant to standard anti-cancer therapies. In a previous study, we showed that although most ATLL cells express TRAIL-death receptors DR4 and/or DR5, they are resistant to TRAIL. To overcome this resistance, we tried to find natural materials that increase the sensitivity to TRAIL in the present study. Here, we report for the first time that dihydroflavonol from a plant increases TRAIL sensitivity by enhancing death receptor expression.
Materials and methods: We used a TRAIL-resistant ATLL cell line, KOB, for screening, and peripheral blood mononuclear cells (PBMCs) from normal healthy donors. The cell surface expression of DR4, DR5, and decoy-receptors DcR1 and DcR2 was examined using flow cytometry (FCM). Cell viability was assessed by MTS assay after incubation with various combinations of natural extracts and TRAIL for 48 hours. Apoptosis was evaluated by Annexin V binding and propidium iodide (PI) staining. We also analyzed caspase−8, − 9 and −3 activation and pro- and anti-apoptotic proteins by Western blot.
Results and Discussion: We screened more than 500 natural products. Among them, the most striking synergism with TRAIL was observed in a dihydroflavonol that was extracted from the Blumea Balsamifera, a family of chrysanthemum from Thailand. It was a methyldihydroquercetin (molecular weight, 318), and we named it BB-1. The viability of KOB cells treated with either TRAIL or BB-1 was 98% and 97%, respectively, and decreased to 60% with concurrent treatment. Interestingly, sequential treatment, pre-treatment with BB-1 followed by TRAIL, further augmented the synergism, and the viability decreased to 38%. Using Annexin V and PI, we confirmed that these are the results of apoptosis. Although it has been reported that anti-apoptotic proteins FLIP, Bcl-2, Bcl-xL and XIAP play key roles in TRAIL resistance, we did not find any change in these factors in the BB-1-treated cells. Instead, we found that BB-1 increased DR5 expression. Subsequent activation of caspase−8, −9 and −3 was observed in a time-dependent manner in the sequentially treated cells, but not in cells treated with BB-1 or TRAIL alone. More importantly, BB1 did not induce DR5 expression or enhance TRAIL sensitivity in PBMCs. Thus, BB-1 augmented TRAIL-induced apoptosis by up-regulating DR5 expression without any cytotoxic activity on normal PBMCs. These results suggest that combined treatment with BB-1 and TRAIL can be a new strategy for cancer immunotherapy against TRAIL-resistant cells.
Proteome Changes Induced by Rituximab: Significance for Monoclonal Antibody Therapy of B-Cell Lymphoproliferative Disorders.
Authors: Everton Kathryn L. , Abbott David R. , Crockett David K. , Elenitoba-Johnson Kojo S.J. , Lim Megan S. 
Published: October 2019

Abstract
Rituximab is a human chimeric monoclonal antibody that targets the CD20 receptor uniquely expressed on normal and malignant B-cells. While it is particularly useful for follicular lymphoma, Rituximab has recently been used for other types of B-cell proliferative disorders. Four major mechanisms have been proposed to account for the activity of Rituximab in B-cell lymphoproliferative disorders: 1) apoptosis and proliferation inhibition via intracellular signaling, 2) increased sensitivity to other chemotherapeutic drugs, 3) complement-dependent cytotoxicity (CDC), and 4) antibody-dependent cellular cytotoxicity (ADCC). A combination of all four mechanisms has also been proposed as the mechanism of action. However, the intracellular events that occur in B-cells in response to Rituximab are largely unknown.
We have employed a global quantitative proteomic profiling approach to study the effects of Rituximab on a t(14;18)+ B cell lymphoma (SUDHL-4). A decrease in viability of 31.3 ± 2.9% was observed after treatment with 10μg/mL of Rituximab for 48 hours. We used isotope-coded affinity tagging (ICAT™) in combination with microcapillary liquid chromatography and tandem mass spectrometry (μLC-MS/MS) to quantitatively determine the proteomic differences between equal amounts of untreated and treated total cell lystates. Protein lysates were labeled with either heavy or light cleavable ICAT™ reagents, digested with trypsin, and purified using avidin affinity chromatography. The labeled peptides were then fractionated using off-line strong cation exchange (SCX) and each fraction was subjected to μLC-MS/MS analysis. Several proteins previously unknown to be expressed in B-cells were identified using this approach. Of the 123 positively identified proteins, 59 proteins were differentially expressed by greater than or less than 1.5 fold (25 upregulated, 34 downregulated). Analysis of differentially expressed proteins identified several functional groups, including integral membrane proteins (Integrin alpha-7 precursor), transcription factors (Zinc finger proteins 445 and 20), proteins involved in migration and adhesion (Astrotactin1), proteins associated with degradation and turnover (26S proteasome non-ATPase regulatory subunit 9), proteins affecting calcium-induced signaling (Tumor-associated calcium signal transducer 1 precursor), proteins associated with lipid rafts (Gemin7), and components of the phosphoinositol (PI4K-alpha) and NF-κB pathways (IKK-E). Our studies reveal the proteomic consequences of Rituximab administration to neoplastic B-cells, and provide novel insights into the mechanism of the drug’s efficacy in the treatment of susceptible B-cell lymphoproliferative disorders.
Syngeneic Hematopoietic Stem Cell Transplantation in Acute Leukaemia. A Report of the Acute Leukaemia Working Party of the EBMT.
Authors: Fouillard Loic , Labopin Myriam , Gluckman Eliane , Gratwohl Alois , Frassoni Francesco , Gorin Norbert Claude , Rocha Vanderson 
Published: October 2019

Abstract
Syngeneic haematopoietic stem cell transplantation (HSCT) is a rare situation and is usually characterised by a high relapse rate because of the absence of graft versus leukaemia effect.
We report results of syngeneic HSCT reported to the EBMT registry from 1975 to 2003. One hundred and 24 acute myeloid leukaemia (AML) and 104 acute lymphoblastic leukaemia (ALL) were reported comprising 150 adults and 78 children, 133 males and 95 females. The number of patients in first complete remission (CR1) was 137, comprising 93 AML (72 adults and 21 children) and 44 ALL (33 adults and 11 children). The number of patients in second complete remission (CR2) was 52 comprising 12 AML (9 adults and 3 children) and 40 ALL (11 adults and 29 children). The number of patients in more advanced disease (AD) was 39 comprising 19 AML (16 adults and 3 children) and 20 ALL (9 adults and 11 children). Total body irradiation was given to 36% of patients. Prophylaxis of graft versus host disease was given to 10% of patients. Source of stem cells was bone marrow for 81% of patients, peripheral blood for 18% and both for 1%.
Outcome at 5 years showed for adult patients with AML in CR1 (n=72) a leukaemia free survival (LFS) of 56+/−7%, a relapse incidence (RI) of 37+/−7% and a non relapse mortality (NMR) of 11+/−5%. For adult patients with ALL in CR1 (n=33), LFS was 60+/−10%, RI 38+/−10% and NRM 3+/−3%.
Outcome at 5 years showed for children with AML in CR1 (n=21) a LFS of 61+/−11%, a RI of 39+/−11% and a NMR of 0%. For children with ALL in CR2 (n=29), LFS was 46+/−10%, RI 52+/−10% and NRM 5+/−5%. Acute graft versus host disease (GVHD) was diagnosed in 12% of patients, 7% grade 1 and 5% grade ≥ 2. Chronic GVHD was observed in 2% of patients.
These retrospective study indicates that syngeneic HSCT can lead to a high LFS in patients with acute leukaemia in CR1 and that GVHD is not a rare event. A graft versus leukemia effect is highly probable in syngeneic HSCT.
Results of Intensive Chemotherapy in 998 Patients Aged 65 Years or Older with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome - Predictive Prognostic Models for Outcome.
Authors: Jabbour Elias , Kantarjian Hagop , O’Brien Susan , Cortes Jorge , Giles Francis , Faderl Stefan , Garcia-Manero Guillermo , Wierda William , Pierce Sherry , Shan Jianqin , Estey Elihu 
Published: October 2019

Background. Elderly patients (age ≥ 65 years) with acute myeloid leukemia (AML) have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, phase I–II studies, low intensity regimens, or “targeted” therapies. Baseline expectations for outcomes of elderly AML with “standard” AML-type therapy are not well defined.
Study Aims. To develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which define expectations with standard AML type therapy.
Patients and Methods. 998 patients age ≥ 65 years with AML or high-risk myelodysplastic syndrome (≥ 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors used standard methods.
Results. The overall CR rate was 45% and induction mortality 29%. Multivariate analyses identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age ≥ 75 years, unfavorable karyotypes (often complex), poor performance (3–4 ECOG), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates below 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25% to 30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%.
Conclusions. Prognostic models were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions.
Proteasome Inhibitors Restore to Normal the Decreased Levels of Protein Expression and Nucleolar Localization of Various Mutant Ribosomal S19 Proteins Identified in DBA Patients.
Authors: Cretien Aurore , Proust Alexis , Gazda Hanna , Meerpohl Jorg , Niemeyer Charlotte Marie , Delaunay Jean , Tchernia Gil , Narla Mohandas , Da Costa Lydie 
Published: October 2019

Abstract
Mutations in ribosomal protein S19 (RPS19) gene have been found in 25% of patients affected with Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. We have previously shown that several RPS19 mutant proteins (V15F, InsAG36, W33stop, Y48stop, R56stop, M75stop, R94stop, 274del31, InsG238, G127Q and L131P) exhibit decreased levels of protein expression and do not localize to the nucleolus like the wild type protein in transfected Cos-7 cells. In contrast, other mutants (W52C, T55M, R56Q, R62W, 24Del18, G120S) exhibit normal levels of protein expression and normal nucleolar localization. We hypothesized that decreased levels of expression of mutant proteins such as V15F, G127Q, and L131P may be due to proteosomal degradation. In order to validate our hypothesis, we analyzed the effects of two proteasome inhibitors (MG132 and lactacystin) on mutant RPS19 protein expression levels and their subcellular localization. Following treatment with proteosome inhibitors, the mutant proteins with missense mutations (V15F, G127Q and L131P) were expressed at levels similar to that of wild type protein and localized in the nucleolus. Similarly, proteasome inhibitors also restored the expression levels and normal subcellular localization to RPS19 with non-sense mutations (InsG238, R94stop, and 274del31) that resulted in the translation of RPS19 protein with at least 80 aminoacids. In marked contrast, proteosome inhibitors failed to restore the expression levels of RPS19 with the non-sense mutants that led to synthesis of shortened proteins (InsAG36, W33stop, Y48stop, R56stop, M75stop). Even in the presence of proteosome inhibitors we noted a dramatic decrease in the levels of expression of these mutant proteins and proteins expressed were localized in the cytoplasm. Our findings imply an important role for proteosomal degradation pathway in regulating the expression levels of RPS19. They further suggest that proteasome inhibitors could be considered as a potential treatment for some steroid resistant DBA affected individuals with specific RPS19 mutations.
High-Dose Mitoxantrone-Based Induction Therapy in Newly-Diagnosed AML. Results of 171 Patients Treated at NYMC between 1991–2003.
Authors: Seiter Karen , Liu Delong , Feldman Eric , Shi Qiuhu , Baskind Paul , Arshad Muhammad , Qureshi Anila , Ahmed Tauseef 
Published: October 2019

Abstract
We developed a high dose mitoxantrone-based induction regimen based on the steep dose-response curve for mitoxantrone. Currently we report long-term results of the treatment of patients with newly-diagnosed AML with a single high dose of mitoxantrone combined with once daily cytarabine. One-hundred sixty-five patients treated on four studies of high-dose mitoxantrone-based induction therapy are included.
Study 1: Phase II study, age <60.
Induction: mitoxantrone 80 mg/m2 x 1, ara-C 3 gm/m2/d x 5, VP-16 150 mg/m2/d qod x 3. Consolidation: 5 mos ara-C x 4d with mitoxantrone 20 mg/m2 months 3 + 5, and with VP-16 150 mg/m2 x 2 months 4 + 6.
Study 2: randomized study of high vs standard dose mitoxantrone with ara-C in pts ≥ 60 yrs. Pts did not receive consolidation. Only pts with high dose mitoxantrone are included here.
Study 3: Same as study 1 except pts received ATRA 45 mg/m2 x 3 doses. Pts < 60 received consolidation as in study 1. Pts ≥ 60 did not receive consolidation.
Study 4: Pts ≥ 60 yrs, same as study 2 + temozolomide postremission therapy. In each study, pts with prior antecedent hematologic disorder (AHD) or secondary AML were included. Median age: 59 (21–88); M/F: 91/80; cytogenetics(SWOG): good:13%, intermediate:50%, poor:26%, indeterminate:5%, IM:6%; Prior AHD: 32% of pts. The median follow up time is 65.9 months (95% CI: 55.7–86.2 months). The overall complete remission rate was 64%, with responses in 78% of patients less than 60 years of age and 52% of patients 60 years of age or older. The median duration of response is 21.2 months and 8.0 months, and overall survival is 15.4 months and 7.6 months, respectively. For a subset of patients who would be eligible for most US trials, the complete remission rate was 84% in younger patients and 60% in older patients. The median duration of response was 39.0 months and 8.2 months, and the median overall survival was 19.4 months and 7.6 months, respectively. Prospective analysis of secondary cytogenetic abnormalities showed such changes in 9 patients. Three of these were at the time of relapse, 3 had spontaneous resolution of these abnormalities, and 3 had MDS that evolved to AML. Two of the latter patients had Neurofibromatosis Type-1. Asymptomatic decreases in ejection fraction were common, however only 2 patients developed clinically significant cardiac dysfunction. The efficacy of these regimens compared favorably to results reported with standard “3+7” regimens. Use of a once-daily cytarabine regimen resulted in almost no neurotoxicity and allowed for administration of consolidation in the outpatient setting.
Pharmacological Profile of DZ-697b, a Novel Anti-Platelet Agent -Selective Inhibitor of vWF- and Collagen-Induced Platelet Aggregation.
Authors: Ogihara Yoshiyasu , Muramatsu Sumie , Kaneda Yuki , Iijima Takako , Shibutani Tomoko , Shibano Toshiro 
Published: October 2019

Abstract
Introduction: Bleeding risk accompanied with anti-platelet drugs is an ultimate dilemma in the treatment of thrombosis patient. Under high shear condition of blood flow, vWF- and collagen-induced signaling pathways are likely to trigger the platelet adhesion to the injured endothelium, which leads to the activation of platelets and arterial thrombus formation. Thus, the recent studies suggest that the selective inhibitor of these pathways is a new target of anti-platelet drugs with lower bleeding risk. We report here a pharmacological profile of DZ-697b, which selectively inhibits platelet aggregation evoked by ristocetin and collagen in vitro and ex vivo.
Materials and methods: Human volunteers blood was processed platelet rich plasma (PRP) or washed platelets. PRP aggregation was induced by ristocetin and collagen. To reveal the selectivity, effect of DZ-697b on U46619 (TXA2 analogue), ADP, thrombin and TRAP induced aggregation in the washed platelets were examined. In guinea pigs and cynomolgus monkeys, effects of DZ-697b given orally were also examined on ex vivo PRP aggregation induced by collagen. To investigate the underlying mechanisms of DZ-697b, changes in phosphorylation of FcR γ chain, a common signaling pathway of both vWF- and collagen-induced platelet aggregation, were studied.
Results: DZ-697b potently inhibited both ristocetin- and collagen-induced human PRP aggregation, the IC50 being 0.74 μM and 0.55 μM, respectively. In contrast, DZ-697b even at 50 μM did not show any influences on U46619, ADP, thrombin and TRAP induced platelet aggregation. DZ-697b did not affect ovine COX-1 and COX-2 activities at up to 300 μM. The bioavailability of this compound was more than 80% in monkeys. Oral administration of DZ-697b at 1–3 mg/kg significantly and persistently inhibited collagen induced PRP aggregation in monkeys and guinea pigs. Application of ristocetin, vWF, and collagen significantly increased the intensity of phosphorylation of FcR γ chain in washed platelets, which were inhibited by DZ-697b.
Conclusion: DZ-697b is an orally active compound which selectively inhibits ristocetin- and collagen-induced platelet aggregation and seems to be promising as novel anti-platelet drug.
Biochemical and Pharmacologic Profiling of a Novel Dual Acting Antithrombin Agent with Antiprotease and Antiplatelet Actions. Hematologic Implications.
Authors: Fareed Jawed , Hoppensteadt D. , Haque W. , Diakur J. , Jeske W. , Florian-Kujawski M. , Maddineni J. , Baltasar F. , Neville B. , Walenga J. M. 
Published: October 2019

Abstract
Background: The pathogenesis of thrombosis involves both cellular and humoral processes. Most antithrombotic drugs exhibit either anti-protease or anti-platelet effects. A combination of anti-protease and anti-platelet drugs provides better efficacy in the management of thrombotic disorders. A series of synthetic low molecular weight serine protease inhibitors with varying anti-platelet effects (Medicure Inc.) are being assessed for antithrombotic properties.
Materials and Methods: This investigation reports on a compound with low antithrombin/high anti-platelet activity MC 45301 (A) and a compound with high antithrombin/low anti-platelet activity MC 45308 (B) activity in in-vitro and in-vivo settings used to profile antithrombotic drugs.
Results: A exhibited strong anti-platelet actions as measured using ADP as an agonist (IC50=1.1 g/ml), whereas B had a higher IC50 (9.4 g/ml). In the antithrombin titration assay A (>100 μg/ml) showed a relatively higher IC50 than B (45 μg/ml). In the global anticoagulant assays, A exhibited somewhat weaker effects than B. In the Xa generation assay, both compounds exhibited similar effects. However, in the thrombin generation assays B exhibited stronger effects. In whole blood assays both compounds produced anticoagulant and anti-platelet effects. Intravenous administration of these compounds to rabbits over a dose range of 50–500 g/kg produced strong dose dependent antithrombotic actions. In comparison to direct antithrombin agents such as argatroban, at a comparable dose, B produced identical antithrombotic actions, which were disproportional to the systemic anticoagulant effects. A produced modest antithrombotic actions with minimal ex vivo clotting effects. This data is highly suggestive that compounds with dual targets are able to produce stronger antithrombotic actions relative to monotherapeutic agents. Additional studies in arterial thrombosis may provide newer insights into the antithrombotic actions of compounds with dual sites of action. Moreover, these agents may be more effective in thrombotic conditions where both platelets and the coagulation system are involved.