bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pegfilgrastim Compared to Granulocyte Colony Stimulating Factor (G-CSF) with Hyper-CVAD Chemotherapy Regimen for Aggressive Lymphoid Malignancy.
Authors: Lane Steven W. , Crawford Julie , Kenealy Melita , Cull Gavin , Seymour John F. , Prince Miles , Marlton Paula , Gill Devinder , Mollee Peter N. 
Published: April 2020

Abstract
Aim
Pegfilgrastim (Neulasta®) has proven efficacy as supportive therapy in a variety of chemotherapy regimens, but has not been studied in dose intensive, rapidly cycling regimens such as hyper-CVAD. We examined whether pegfilgrastim leads to similar kinetics of neutrophil recovery as daily G-CSF.
Methods
Using retrospective analysis, patients receiving pegfilgrastim were matched with controls (G-CSF) for cycle of chemotherapy, prior chemotherapy, dose of cytarabine received, age (&lt;60 or &gt;60), diagnosis (ALL or NHL) and bone marrow involvement. The primary endpoint was duration of grade IV neutropenia (ANC &lt;500/ul). Secondary endpoints included time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures and delay in subsequent chemotherapy.
Results
Between 01/1999 – 06/2005 we identified 124 pegfilgrastim supported cycles in 43 patients. Cases were successfully matched to 124 G-CSF supported cycles from 38 controls. There were no significant differences between cases and controls with regards to prior chemotherapy, age, sex, cytarabine dose, diagnosis or bone marrow involvement. The median duration of grade IV neutropenia was 4 days in both groups (p =0.55).
Pegfilgrastim (95% CI) G-CSF controls (95% CI) P value Grade IV neutropenia - All cycles 4 days (0–11) 4 days (0–10) 0.55 - A cycles 2 days (0–7) 2 days (0–6) 0.65 - B cycles 6 days (2–12) 6 days (0–10) 0.70 Time to ANC &gt;500/ul 13 days (10–19) 14 days (8–18) 0.75 Time to ANC &gt;2000/ul 14 days (11–29) 14.5 days (9–22) 0.27 Febrile Neutropenia 29% 38% 0.16 Positive Blood Cultures 11% 12% 0.85 Delay in next cycle 44% 47% 0.75
Conclusions
A single dose of pegfilgrastim is as effective as daily G-CSF for supporting the hyper-CVAD chemotherapy regimen.
Motexafin Gadolinium Upregulates pAkt Levels and Synergizes with Inhibitors of Akt Phosphorylation.
Authors: Ramos Jason , Sirisawad Mint , Miller Richard A. , Naumovski Louie 
Published: April 2020

Abstract
Motexafin gadolinium (MGd, Xcytrin®) is a tumor-selective expanded porphyrin that targets oxidative stress related proteins. MGd treatment of the follicular lymphoma-derived cell line HF-1 resulted in growth suppression and apoptosis, whereas MGd treatment of the Burkitt’s lymphoma-derived cell line Ramos resulted in growth suppression but not apoptosis. Since phosphorylation status of Akt/PKB kinase is regulated by oxidative stress, we monitored total and phosphorylated Akt (pAkt) in MGd treated HF-1 and Ramos cells. Levels of total and pAkt increased within 30 min after MGd treatment of HF-1 but within 4 hrs began to show a progressive decline to below baseline levels prior to cells undergoing apoptosis. Levels of total Akt did not increase in MGd treated Ramos cells but pAkt increased about 2 fold within 8 h and remained persistently elevated. Since pAkt activates survival pathways, we determined if MGd-induced cell death could be enhanced by inhibiting phosphorylation of Akt. The addition of specific inhibitors of Akt phosphorylation (SH-5 or Akt inhibitor 1) reduced pAkt levels in MGd treated HF-1 and Ramos cells and synergistically enhanced MGd-induced cell death. MGd was also evaluated in combination with celecoxib, an inhibitor of Akt phosphorylation, or docetaxel, a microtubule inhibitor which can decrease Akt phosphorylation. The combination of MGd/celecoxib or MGd/docetaxel resulted in decreased Akt phosphorylation and in synergistic cytotoxicity compared to either agent alone. These data point to a potential protective role for pAkt in MGd-induced apoptosis and suggest that MGd activity may be enhanced by combining it with agents that inhibit Akt phosphorylation.
Efficacy and Safety of Epoetin beta 30 000 IU Once Weekly in Anemic Patients with Non-Myeloid Malignancies Receiving Chemotherapy.
Authors: Damaj Gandhi , Garidi Reda , Rodon Philippe , Bordessoule Dominique , Spaeth Dominique , Fiorentini Paola , Bergougnoux Loïc 
Published: April 2020

Abstract
Background: Once weekly (QW) epoetin beta (NeoRecormon®) 30 000 IU rapidly increases hemoglobin (Hb) levels and prevents transfusions in patients with lymphoid malignancies (Cazzola et al 2003). The aim of this study was to evaluate the efficacy and safety of epoetin beta 30 000 IU QW in patients with non-myeloid malignancies.
Methods: Adult anemic patients (Hb 8–12 g/dl) with non-myeloid malignancies, WHO performance status 0–2 and who were scheduled to receive chemotherapy (CT) entered into this multicenter, open-label, single-arm study. Patients received epoetin beta 30 000 IU QW for 16 weeks. Primary efficacy endpoint was the % of Hb responders during epoetin beta therapy. Hb response was defined to account for the Hb level at baseline: Hb level of 13 g/dl achieved in patients with baseline Hb 11–12 g/dl or Hb increase of 2 g/dl and/or Hb level of 12 g/dl achieved in those with baseline Hb &lt; 11g/dl.
Results: This analysis reports data of the first 98 patients (mean age 63.4 ± 12.4 years; 61% solid; 39% hematological malignancies). Overall, 67% of patients responded to epoetin beta treatment, with a greater number of patients with hematological malignancies (78.9%) obtaining a Hb response. Median time to response was 43 days. Mean Hb level at baseline was 10.1 ±1.04 g/dl. Hb levels increased to a mean of 12.8 ±1.75 g/dl over a median treatment period of 14 weeks with epoetin beta. Median Hb increase of 1.5 g/dl and 2 g/dl at 7 and 10 weeks, respectively, were recorded. A greater number of patients receiving non-platinum (Pt)-based CT responded (73.5%) than those receiving Pt-based CT (51.7%). At least one thromboembolic event (TEE) was observed in 5% of the patients. Only one TEE was considered to be related to the study treatment.
Conclusions: Epoetin beta 30 000 IU QW is an effective and safe treatment of anemia in patients with non-myeloid malignancies, regardless of CT type and appears particularly effective in patients not receiving Pt-based CT or with hematological malignancies.
siRNA Knock down of MPL Receptor in Mouse Hematopoietic Progenitors.
Authors: Souyri Michele , Fleury Maud , Cocault Laurence 
Published: April 2020

Abstract
We recently showed that the expression of the thrombopoietin (TPO) receptor, MPL, could have different impacts on the generation and the expansion of hematopoietic stem cells (HSC) during establishment of definitive hematopoiesis in the mouse embryo. In order to investigate further MPL/TPO signaling pathways involved in the emergence or in the amplification and maturation of HSCs as well as their downstream targets, we set up RNA interference to knock down Mpl expression in hematopoietic progenitors and HSCs. We used the retrovirus pSUPERretro for stable and efficient delivery of siRNAs in primary cells. Three siRNAs were first tested in a model of rat fibroblast overexpressing Mpl (FREmpl) which get transformed in the presence of TPO. This transformation requires pathways involved in TPO-induced proliferation and differentiation of hematopoietic cell lines (Challiet et al., Oncogene19:2033, 2000). Transduced cells were selected and amplified. Northern blot analysis indicated that the 3 siRNAs were able to knock down Mpl expression (65 to 72% inhibition). However, decrease of the protein level and inhibition of TPO mediated transformation was observed only with 2 out of the 3 siRNAs. Inhibition of transformation was accompanied with an inhibition of Stat5 nuclear translocation.
We next introduced these siRNAs in bone marrow cells from 5-FU treated adult C57Bl6 mice, and showed that they were also able to inactivate Mpl expression in primary hematopoietic progenitors after culture of the cells for 7 days in the presence of SCF, Flt3 ligand, IL-3, IL-6 and TPO (1,1% of MPL+ cells instead of 23% in the control population). Further molecular analysis as well as in vivo an in vitro study of these cells is under current investigation and will be presented.
Cyclin D1 Mediates Resistance towards p53-Independent and -Dependent Apoptosis through Anti-Apoptotic Factors and Molecular Chaperones.
Authors: Roue Gael , Pichereau Vianney , Lincet Hubert , Troussard Xavier , Sola Brigitte 
Published: April 2020

Abstract
Cyclin D1 is a key regulator of the G1 to S transition of the cell cycle, physiologically absent in normal lymphocytes, but overexpressed in some lymphoproliferative disorders such as mantle cell lymphoma or multiple myeloma. While cyclin D1 has also been shown to control other aspects of the cellular fate, such as cellular senescence, apoptosis or tumorigenesis, its precise role in the pathogenesis of B-cell lymphomas and leukemias is still unclear. In this context, using various cell lines derived from the pre-B murine cell line BaF3 and conditionally expressing cyclin D1, we have previously reported that when expressed at a level comparable to the one detected in tumoral cells, cyclin D1 impairs cell proliferation mainly by inducing apoptosis. We now report that the BaF3-derived cell line BD1-A21, which constitutively expresses a low but notable level of cyclin D1, presents a recurrent resistance towards various apoptotic stimuli involving different signaling pathways, such as cytokine withdrawal, etoposide treatment and staurosporine-mediated kinases inhibition, when compared to the parental BaF3 cells. This lack of sensitivity towards apoptosis was correlated in cyclin D1-expressing cells with an increase in the basal levels of several antiapoptotic factors such as IAPs (c-IAP1, c-IAP2, XIAP and survivin) or the death receptors pathway inhibitor cFLIP, and the relative maintenance of these factors in IL-3-starved cells. 2D-PAGE analysis also pointed out in cyclin D1 expressing cells the accumulation of a series of molecular chaperones, which the most overexpressed is hsp70, concording with previous works describing the cyclin D1-dependent synthesis of hsp70 in lymphoid cells. Consistently with a protective role of hsp70 in cyclin D1-expressing cells, its pharmacological inhibition by the mean of the flavonoid quercetin allowed to re-sensitize BD1-A21 cells to the apoptotic stimulus evoked by IL-3 starvation. Hsp70 protective efect appeared to act upstream of mitochondrion, as determined by mesurement of mitochondrial membrane potential and western-blot or FACS analysis of the main Bcl-2 family members. The relationship between cyclin D1 constitutive expression, antiapoptotic factors and chaperones accumulation, and resistance to apoptosis is currently under investigation.
Growth Inhibition or Apoptosis after Treatment with Motexafin Gadolinium and Celecoxib Is Cell Line Dependent and Correlates with p27 Levels.
Authors: Ramos Jason , Sirisawad Mint , Chen Jun , Miller Richard A. , Naumovski Louie 
Published: April 2020

Abstract
Motexafin gadolinium (MGd, Xcytrin®) is a tumor selective expanded porphyrin belonging to the class of compounds known as texaphyrins. MGd is a redox mediator that may be directly cytotoxic or growth inhibitory to various tumor cells and can potentiate the effects of chemotherapeutic agents and radiation therapy. Initial promising activity has been seen in an ongoing phase II study of MGd as a single agent in patients with lymphoma. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to induce apoptosis and growth inhibition and potentiate the effects of chemotherapeutic agents. To determine potential synergistic effects of MGd and celecoxib, we treated lymphoma cell lines HF-1, Ramos, DHL-4 and Raji with MGd, celecoxib or the combination. Apoptosis was a prominent feature in two of the cell lines (HF-1 and Ramos) treated with MGd/celecoxib, whereas, growth inhibition was more prominent in the other two (DHL-4 and Raji). In Ramos cells, MGd/celecoxib treatment was synergistic in inducing apoptosis and resulted in activation of a caspase cascade as demonstrated by cleavage of caspases-9, -8, -3 and cleavage of substrates Bid and PARP. Two other specific COX-2 inhibitors, rofecoxib and valdecoxib did not synergize with MGd to induce apoptosis in Ramos cells, suggesting that celecoxib potentiation of MGd is a COX-2-independent activity of celecoxib. MGd/celecoxib-induced apoptosis of HF-1 and Ramos correlated with a decrease in p27Kip1 levels whereas MGd/celecoxib-induced growth inhibition of DHL-4 and Raji correlated with increased p27Kip1 levels. Cell cycle profiles of MGd/celecoxib treated Ramos and Raji cells revealed G1 accumulation only in Raji cells, consistent with elevated levels of active p27Kip1. Our pre-clinical data suggest that celecoxib enhances the efficacy of MGd and indicates a role for p27 in the response of cells to MGd and celecoxib.
Preliminary Study of Inducing Differentiation and Apoptosis in a Novel Human Acute Monocytic Leukemic Cell Line SHI-1.
Authors: Chen Suning , Xue Yongquan , Wu Yafang , Pan Jinlan , Wu De Pei 
Published: April 2020

Abstract
Objective
To explore the inducing differentiation and apoptosis in a novel human acute monocytic leukemic cell line SHI-1.
Methods
Cell morphological analysis, NBT reduction test, the expression of CD11b and CD14, cell cycle analysis and binding of annexinV tested by FCM, DNA electrophoresis were performed to evaluate whether tributyrin (TB), arsenic trioxide (As2O3), and 12-O-tetradecanoyl-phorbol-13 acetate (TPA) could induce the differentiation and apoptosis in the SHI-1 cell line.
Results
The results of morphological analysis, NBT reduction test, and FCM assay showed that TB could induce differentiation of SHI-1 cells. The SHI-1 cell line presented typical apoptotic evidences including morphology features, DNA ladders and the increased apoptotic rate determined by FCM. Moreover, the SHI-1 cell line presented typical apoptotic morphology after being treated with As2O3. The apoptotic rate of the SHI-1 cell line treated with As2O3 was increased determined by FCM. The expression level of CD14 was upregulated while that of CD11b was unchanged in the SHI-1 cell line. Most of the SHI-1 cells adhered to the flask after being treated with TPA for 24 hours.
Conclusions
TB may produce dual effects of differentiation and apoptosis. The cell line could be induced to differentiation partially or apoptosis after being treated with 0.5μM, 1.0μM, and 2.0μM As2O3. TPA could induce differentiation and adhesion of the SHI-1 cell line.
Cell Penetrating Mechanism of Bax Inhibiting Peptides.
Authors: Gomez Jose A. , Yoshida Tomoyuki , Lam Minh , Distelhorst Clark W. , Matsuyama Shigemi 
Published: April 2020

Abstract
Plasma membrane is known to have a high degree of selectivity for molecular trafficking, and it does not allow the penetration of peptides larger than 3 amino acids. Previously known exceptions of large peptides that penetrate the plasma membrane are the Arginine rich peptides such as human immunodeficiency virus (HIV)-tat peptides. However, the mechanism of cell penetration of these peptides is largely unknown. Bax Inhibiting Peptides (BIP) are penta-peptides derived from the Bax binding domain of Ku70. At present, three types of BIP have been developed. Those are: VPMLK, VPTLK, and VPALR. All of these three BIPs directly bind Bax and inhibit Bax-mediated cell death in cultured cells as well as in animal study. Surprisingly, BIPs are cell permeable and autonomously enter the cytoplasm of the cells within 1 hr. Therefore BIPs are recognized as new members of cell penetration peptides. In this study, we investigated the mechanism of cell penetration of BIPs. DAMI cells (a human megakaryocyte cell line) and HeLa cells were used to investigate the detailed mechanism of cell penetration of BIPs. To detect the cell entry of BIPs, fluorescent dyes (fluorescein or tetramethylrodhamine) were conjugated to the N-terminus of BIPs and the cytoplasmic localization of BIPs was confirmed by confocal microscopy. Cell Penetration activities of BIPs were detected at 1 uM concentration in the culture medium. The significant accumulation of BIPs in the cytoplasm were detected within 1 hour of incubation both at 4 °C and 37 °C, suggesting that ATP-independent mechanism of cell penetration of BIP exists. However, cellular uptake of BIPs reaches plateau at 100 uM at 4 °C, whereas it increases in a dose dependent manner up to 1 mM at 37 °C without any sign of cytotoxicity. These results suggest that there are at least two mechanisms contributing to the cell penetration of BIPs that are, “ATP-independent (4 °C)” and “ATP-dependent (37 °C)” mechanisms. In addition to BIPs, we generated a series of mutated BIPs that do not bind Bax but retain cell-penetrating activities. We performed competition assay using fluorescence dye-labeled and non-labeled BIP (and the mutant BIPs), and the preliminary results suggest that there is a specific receptor for each peptide for its delivery into the cells. Our data also indicates that BIPs can deliver a cargo molecule (e.g. fluorescent dye) with at least the same molecular weight. Unlike other cell penetrating peptides, BIP has minimum toxicity due to its nature to inhibit Bax-mediated cell death. Along with the new data showing that BIP protects cells from pathological damages in cell culture and animal model, we will discuss the potential application of BIPs as a new type of drug delivery tool.
Expression of the Smad3 Transgene Restores Radiosensitivity and Migratory Capacity to a Smad3−/− Clonal Bone Marrow Stromal Cell Line.
Authors: Epperly Michael W. , Cao Shaonan , Zhang Xichen , Greenberger Emily E. , Goff Julie , Wang Hong , Bahnson Al , Shields Donna , Franicola Darcy , Greenberger Joel S. 
Published: April 2020

Abstract
An intact Smad3 gene product is critical for a functioning signal transduction pathway following TGF binding to the TGF-β receptor. We have previously established Smad3−/− and Smad3+/+ long term bone marrow cultures (LTBMCs) and isolated clonal bone marrow stromal cell lines from each. The Smad3−/− cells were smaller in size but had a faster cell doubling time (24 hours compared to 48 hours) and increased saturation density compared to +/+ cells (15.3 ± 1.0 x 105 cells/25 mm2 flask compared to 3.8 ± 0.1 x 105, p = 0.003). The plating efficiency of the lines was similar (18.3 ± 2.7 compared to 15.5 ± 1.7, p = 0.417). We transfected the Smad3−/− cell line with a retrovirus containing the Smad3 transgene, and selected a subclone expressing the transgene mRNA, designated Smad3−/−(3). Smad3−/−(3) cells were increased in size to that of Smad3+/+ cells, and showed decreased cell saturation density. Using the Cytoworks computer controlled cell tracking Bioreactor, we measured the migration of each clonal line. Tissue culture wells of 100 cells per well were followed for 5 days tracking each cell in quadruplicate wells per cell line. Smad3+/+ cells migrated significantly faster over 5 days in culture compared to Smad3−/− cells. (The average velocities were 0.62 μm/min for Smad3+/+ and 0.36 μm/min for Smad3−/−, p&lt;0.0001). Over 5 days, the average velocities for Smad3+/+ cells were 0.51, 0.51, 0.52, 0.72, 0.91 μm/min, and for Smad3−/− cells were 0.28, 0.38, 0.41, 0.37, 0.35 μm/min. The 5 p-values comparing these cell lines were all &lt;0.0001. The 7 day clonagenic irradiation survival curve showed that Smad3+/+ and Smad3−/−(3) cells were significantly more sensitive (D0 = 1.75 ± 0.03 and 1.51 ± 0.07 Gy, respectively) compared to the Smad3−/− cell line (D0 = 2.43 ± 0.06 Gy, p=0.0016 and 0.0103). These results demonstrate a concordance of radioresistance and decreased migratory capacity in bone marrow stromal cells devoid of a functioning Smad3 gene product, and restoration of both properties following overexpression of the transgene product. These data may help explain the decreased radiation fibrosis observed in Smad3−/− mice.
Expression of Cadherins in Bone Marrow Stromal Cells Affects Capacity Supporting Expansion of CD34+ Cord Blood Cells.
Authors: Liu Jin-Hwang , Liu Chin-Cheng , Yang Ming-Jie 
Published: April 2020

Abstract
Ex vivo expansion of hematopoietic progenitor cells (HPCs) has been used to circumvent the limitation of umbilical cord blood applied on adult HPC transplantation and may facilitate ex vivo gene manipulation. Nonetheless, the nature of these signals provided by the stromal microenvironment and mechanisms by which stromal cells regulate the growth of stem cells remain to be defined. With the help of retrovirally-expressing human telomerase reverse transcriptase (hTERT) in marrow stromal cells, we isolated 16 human bone marrow stromal cell lines. After a 7-day short stromal cells-dependent co-culture, the cord blood CD34+ cells were 1.0- to 14.5-fold expanded. Among the adhesion molecules in stromal cells examined, expression of N-cadherin and P-cadherin in stromal cells were found to correlate with capacities of stromal cells to support cord blood HPC expansion and be predictive of HPC-expanding capacities.
Immunosupressive Property of Mesenchymal Stem Cells (MSCs) in Mixed Lymphocyte Reactions In Vitro.
Authors: Li Jianyong , Meng Lijuan , Zhu Yu , Lu Hua , Ruan Changgeng 
Published: April 2020

Abstract
Meesnchymal stem cells (MSCs) were successfully used in the prevention and treatment of graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. To further explore the immunosuppressive property of human bone marrow (MSCs) in alloantigen-induced mixed lymphocyte reactions (MLRs) in vitro, human bone marrow MSCs and lymphocytes were prepared from healthy volunteers. MSCs were expanded in vitro in Mesencult serum free media. MSCs were cocultured with one-way MLRs and bidirectional MLRs, responder cells were labeled with carboxyfluorescein diacetate- succinimidyl ester (CFSE) in bidirectional MLRs. Cell Counting Kit-8(CCK-8)kit was used in cell proliferation detection, T-cell subsets were analyzed by flow cytometry (FCM). The results showed that MSCs were positive for CD105, CD73, CD13, CD90 and were negative for hematopoietic cell markers. In one-way MLRs, MSCs down-regulated alloantigen-induced lymphocyte expansion in a dose-dependent and MHC-independend manner. In two-way MLRs, MSCs suppressed proliferation of CFSE positive cells. T cell subsets were changed: Th2 and Tc2 were down-regulated. Th2 was reduced from 1.70% to 0.65%, and Tc2 reduced from 1.10% to 0.47%, while Th1 and Tc1 were unaffected. T cells that became CD69+, which was an early activation marker, were significantly up-regulated from 7.14% to 26.12% and CD4+CD25+T regulatory cells (CD4+CD25+Tr) were up-regulated from 4.04% to 6.19%, which indicating that suppression did not interfere with activation phase of T cells and might be mediated by CD4+CD25+Tr partly. We conclede that MSCs down-regulated alloantigen-induced lymphocyte expansion. The immunosupressive effect might involve in post-activation phase of T cells. CD4+CD25+Tr might contribute to the suppressory activity of MSCs.