bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase
Authors: Gardembas Martine , Rousselot Philippe , Tulliez Michel , Vigier Magda , Buzyn Agnès , Rigal-Huguet Françoise , Legros Laurence , Michallet Mauricette , Berthou Christian , Cheron Nathalie , Maloisel Frederic , Mahon François-Xavier , Facon Thierry , Berthaud Patrice , Guilhot Joëlle , Guilhot François ,   for the CML French Group (FIϕLMC)
Published: August 2003

AbstractIn chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response. (Blood. 2003;102:4298-4305)
Selective targeted delivery of TNFα to tumor blood vessels
Authors: Borsi Laura , Balza Enrica , Carnemolla Barbara , Sassi Francesca , Castellani Patrizia , Berndt Alexander , Kosmehl Hartwig , Birò Attila , Siri Annalisa , Orecchia Paola , Grassi Jessica , Neri Dario , Zardi Luciano 
Published: August 2003

AbstractWe sought to enhance the selective toxicity of tumor necrosis factor α (TNFα) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFα) composed of mouse TNFα and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFα was expressed in mammalian cells, purified, and characterized. L19mTNFα was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFα selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFα showed a greater anticancer therapeutic activity than both mTNFα and TN11mTNFα, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFα allows concentrating therapeutically active doses of TNFα at the tumor level, thus opening new possibilities for the systemic use of TNFα in cancer therapy. (Blood. 2003;102:4384-4392)
In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl–positive cell lines
Authors: La Rosée Paul , Johnson Kara , Corbin Amie S. , Stoffregen Eric P. , Moseson Erika M. , Willis Stephanie , Mauro Michael M. , Melo Junia V. , Deininger Michael W. , Druker Brian J. 
Published: August 2003

AbstractImatinib mesylate (Gleevec, formerly STI571) is an effective therapy for all stages of chronic myelogenous leukemia (CML). While responses in chronic-phase CML are generally durable, resistance develops in many patients with advanced disease. We evaluated novel antileukemic agents for their potential to overcome resistance in various imatinib-resistant cell lines. Using cell proliferation assays, we investigated whether different mechanisms of resistance to imatinib would alter the efficacy of arsenic trioxide (As2O3) or 5-aza-2-deoxycytidine (decitabine) alone and in combination with imatinib. Our results indicate that resistance to imatinib induced by Bcr-Abl overexpression or by engineered expression of clinically relevant Bcr-Abl mutants does not induce cross-resistance to As2O3 or decitabine. Combined treatment with these agents and imatinib is beneficial in cell lines that have residual sensitivity to imatinib monotherapy, with synergistic growth inhibition achieved only at doses of imatinib that overcome resistance. In some imatinib-resistant cell lines, combination treatments that use low doses of imatinib lead to antagonism. Apoptosis studies suggest that this can be explained in part by the reduced proapoptotic activity of imatinib in resistant cell lines. These data underline the importance of resistance testing and provide a rational approach for dose-adjusted administration of imatinib when combined with other agents.
Correction of a mouse model of sickle cell disease: lentiviral/antisickling β-globin gene transduction of unmobilized, purified hematopoietic stem cells
Authors: Levasseur Dana N. , Ryan Thomas M. , Pawlik Kevin M. , Townes Tim M. 
Published: August 2003

AbstractAlthough sickle cell anemia was the first hereditary disease to be understood at the molecular level, there is still no adequate long-term treatment. Allogeneic bone marrow transplantation is the only available cure, but this procedure is limited to a minority of patients with an available, histocompatible donor. Autologous transplantation of bone marrow stem cells that are transduced with a stably expressed, antisickling globin gene would benefit a majority of patients with sickle cell disease. Therefore, the development of a gene therapy protocol that corrects the disease in an animal model and is directly translatable to human patients is critical. A method is described in which unmobilized, highly purified bone marrow stem cells are transduced with a minimum amount of self-inactivating (SIN) lentiviral vector containing a potent antisickling β-globin gene. These cells, which were transduced in the absence of cytokine stimulation, fully reconstitute irradiated recipients and correct the hemolytic anemia and organ pathology that characterize the disease in humans. The mean increase of hemoglobin concentration was 46 g/L (4.6 g/dL) and the average lentiviral copy number was 2.2; therefore, a 21-g/L /vector copy increase (2.1-g/dL) was achieved. This transduction protocol may be directly translatable to patients with sickle cell disease who cannot tolerate current bone marrow mobilization procedures and may not safely be exposed to large viral loads. (Blood. 2003;102:4312-4319)
Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index
Authors: Chim Chor-Sang , Ma Shing-Yan , Au Wing-Yan , Choy Carolyn , Lie Albert K. W. , Liang Raymond , Yau Chun-Chung , Kwong Yok-Lam 
Published: August 2003

Abstract
Nasal natural killer (NK) cell lymphoma is rare, so that its optimal therapy, long-term outcome, and prognostic factors are unclear. Data on 52 men and 15 women with well-characterized nasal NK cell lymphomas were analyzed retrospectively to define the impact of primary therapy on remission and long-term outcome and the validity of the International Prognostic Index (IPI). Most (84%) had stage I/II disease with an IPI score of 1 or less (52%). Seven patients received radiotherapy only; 47 patients received anthracycline-containing chemotherapy plus consolidation radiotherapy; and 12 patients received nonanthracycline-containing chemotherapy plus radiotherapy. The overall complete remission (CR) rate was 64.2%; the 20-year overall survival (OS) and disease-free survival (DFS) rates were 37.1% and 33.5%, respectively. Front-line radiotherapy was apparently better than chemotherapy for CR (100% versus 59%, P = .04) and OS (83.3% versus 32.0%, P = .03). Relapses occurred in 4 radiotherapy-treated (all local) and 14 chemotherapy-treated patients (9 local, 4 systemic). Among these, 5 late relapses (4 local, 1 systemic) occurred at 170 months (range, 92-348 months) from CR. The IPI score was of prognostic significance for the whole group (IPI ≤ 1 superior to IPI ≥ 2 for 20-year OS: 57.4% versus 27.6%, P = 0.012), as well as for patients treated with chemotherapy/radiotherapy (IPI ≤ 1 superior to IPI ≥ 2 for CR: 76.7% versus 35.7%, P = .017; and 10-year OS: 63.8% versus 26.8%, P = .003).
Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages
Authors: Koseki-Kuno Shiori , Yamakawa Mitsunori , Dickneite Gerhard , Ichinose Akitada 
Published: August 2003

AbstractTo understand the molecular pathology of factor XIII (FXIII) deficiency in vivo, its A subunit (FXIIIA)-knockout (KO) mice were functionally analyzed. Although homozygous FXIIIA female KO mice were capable of becoming pregnant, most of them died due to excessive vaginal bleeding during gestation. Abdominal incisions revealed that the uteri of the dead mice were filled with blood and that some embryos were much smaller than others within a single uterus. A series of histologic examinations of the pregnant animals suggested that massive placental hemorrhage and subsequent necrosis developed in the uteri of the FXIIIA KO mice on day 10 of gestation. This was true regardless of the genotypes of fetuses. These results are reminiscent of spontaneous miscarriage in pregnant humans with FXIII deficiency and indicate that maternal FXIII plays a critical role in uterine hemostasis and maintenance of the placenta during gestation. (Blood. 2003;102:4410-4412)
Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs
Authors: Russell Karen E. , Olsen Eva H. N. , Raymer Robin A. , Merricks Elizabeth P. , Bellinger Dwight A. , Read Marjorie S. , Rup Bonita J. , Keith James C. , McCarthy Kyle P. , Schaub Robert G. , Nichols Timothy C. 
Published: August 2003

AbstractIntravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P &lt; .001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P = .0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B. (Blood. 2003;102:4393-4398)
ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1
Authors: Tadros Amir , Hughes David P. , Dunmore Benjamin J. , Brindle Nicholas P. J. 
Published: August 2003

AbstractA20 binding inhibitor of NF-κB activation-2, ABIN-2, is a newly identified intracellular protein that interacts with the zinc finger protein A20. ABIN-2 inhibits nuclear factor-κB (NF-κB) activity and is a possible effector of A20 regulation of NF-κB. Although A20 is a potent inhibitor of endothelial apoptosis, the effect of ABIN-2 on apoptosis is not known. ABIN-2 also interacts with the endothelial receptor Tie2. This receptor is essential for blood vessel formation and promotes endothelial survival. Here we examine the effects of ABIN-2 on endothelial cell apoptosis and its potential involvement in Tie2-mediated endothelial survival. ABIN-2 was found to inhibit endothelial apoptosis and rescue cells from death following growth factor deprivation. The inhibitors of phosphatidylinositol-3 kinase, wortmannin and LY294002, suppressed ABIN-2 inhibition of endothelial cell death. Deletion of the carboxy-terminus of ABIN-2 removed its ability to inhibit apoptosis. Expression of truncated ABIN-2 prevented the Tie2-activating ligand angiopoietin-1 from inhibiting endothelial cell death. (Blood. 2003;102:4407-4409)
HIV-1 preferentially binds receptors copatched with cell-surface elastase
Authors: Bristow Cynthia L. , Mercatante Danielle R. , Kole Ryszard 
Published: August 2003

AbstractHuman leukocyte elastase (HLE) interacts with HIV-1 glycoprotein (gp)41, suggesting a nonenzymatic receptor function for HLE in the context of HIV-1. HLE is found localized to the cell surface, but not granules in HIV permissive clones, and to granules, but not the cell surface of HIV nonpermissive clones. Inducing cell-surface HLE expression on HLE null, HIV nonpermissive clones permits HIV infectivity. HIV binding and infectivity diminish in proportion to HLE RNA subtraction. HIV binding and infectivity show dose dependence for the natural HLE ligand α1 proteinase inhibitor (α1antitrypsin, α1PI). Chemokines prevent, whereas α1PI promotes, copatching of HLE with the canonical HIV receptors. Recent demonstration that decreased viral RNA is significantly correlated with decreased circulating α1PI in HIV seropositive individuals is consistent with a model in which HLE and α1PI can serve as HIV coreceptor and cofactor, respectively, and potentially participate in the pathophysiology of HIV disease progression. (Blood. 2003;102:4479-4486)
Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells
Authors: Fonteneau Jean Francois , Kavanagh Daniel G. , Lirvall Margareta , Sanders Catherine , Cover Timothy L. , Bhardwaj Nina , Larsson Marie 
Published: August 2003

AbstractMajor histocompatibility complex (MHC) class I presentation of exogenous antigens is the mechanism enabling professional antigen-presenting cells (APCs) to induce CD8+ T-cell responses against viruses and tumors that do not have access to the classical MHC class I pathway. We have characterized the uptake, processing, and MHC class I cross-presentation by human dendritic cells (DCs) of cell-associated antigens derived from physiologically relevant sources, namely, vaccinia virus-infected apoptotic and necrotic cells. We show that cross-presentation is a rapid process, detectable within 2 to 4 hours after uptake of dead cells, and that proteolysis by cathepsin D in an acidic endosomal compartment is essential for cross-presentation. The presentation is abolished when the phagocytic or macropinocytic functions of the cells are inhibited and is dependent on transporter associated with antigen processing, sensitive to brefeldin A, and requires functional proteasomes. Altogether, these data suggest that antigens derived from apoptotic and necrotic cells require access to the cytosol to intersect with the conventional MHC class I pathway for presentation of cytosolic proteins. (Blood. 2003;102:4448-4455)
Two-signal requirement for activation and effector function of natural killer cell response to allogeneic tumor cells
Authors: Gao Jian-Xin , Liu Xingluo , Wen Jing , Caligiuri Michael A. , Stroynowski Iwona , Zheng Pan , Liu Yang 
Published: August 2003

AbstractOptimal activation of T cells requires delivery of both antigenic and costimulatory signals. It is unclear, however, if the function of the natural killer (NK) cells is also modulated by these 2 signals. Here we report that efficient control of solid allogeneic tumors by NK cells depends on codelivery of both B7-1 and major histocompatibility complex (MHC) class I on the tumor cells. The codelivery is required for optimal expansion and effector function of NK cells in response to both melanoma and plasmocytoma that expressed allogeneic MHC class I. Our results demonstrate that the 2 signals required for T-cell function also can regulate NK immunity and reveal an important similarity between the innate NK response and the adaptive T-cell response. (Blood. 2003;102:4456-4463)
Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways
Authors: Ichinose M. , Sugiura H. , Yamagata S. , Koarai A. , Tomaki M. , Ogawa H. , Komaki Y. , Barnes P.J. , Shirato K. , Hattori T. 
Published: August 2003

Reactive nitrogen species (RNS) have been reported to be involved in the inflammatory process in chronic obstructive pulmonary disease (COPD). However, there are no studies on the modulation of RNS in COPD. It was hypothesised that inhibition of xanthine oxidase (XO) might decrease RNS production in COPD airways through the suppression of superoxide anion production.Ten COPD and six healthy subjects participated in the study. The XO inhibitor allopurinol (300 mg·day−1p.o.for 4 weeks) was administered to COPD patients. RNS production in the airway was assessed by 3‐nitrotyrosine immunoreactivity and enzymic activity of XO in induced sputum as well as by exhaled nitric oxide (eNO) concentration.XO activity in the airway was significantly elevated in COPD compared with healthy subjects. Allopurinol administration to COPD subjects significantly decreased XO activity and nitrotyrosine formation. In contrast, eNO concentration was significantly increased by allopurinol administration.These results suggest that oral administration of the xanthine oxidase inhibitor allopurinol reduces airway reactive nitrogen species production in chronic obstructive pulmonary disease subjects. This intervention may be useful in the future management of chronic obstructive pulmonary disease.
Long-Term Neurologic and Neurosensory Sequelae in Adult Survivors of a Childhood Brain Tumor: Childhood Cancer Survivor Study
Authors: Packer Roger J. , Gurney James G. , Punyko Judy A. , Donaldson Sarah S. , Inskip Peter D. , Stovall Marilyn , Yasui Yutaka , Mertens Ann C. , Sklar Charles A. , Nicholson H. Stacy , Zeltzer Lonnie K. , Neglia Joseph P. , Robison Leslie L. 
Published: August 2003

Purpose: To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits. Patients and Methods: Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume. Results: Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = < .0001), legal blindness in one or both eyes (RR, 14.8; P = < .0001), cataracts (RR, 11.9; P = < .0001), and double vision (RR, 8.8; P = < .0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P < .05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder. Conclusion: Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.
Steroid Receptor Coactivator 1 Links the Steroid and Interferon γ Response Pathways
Authors: Tzortzakaki Eleni , Spilianakis Charalambos , Zika Eleni , Kretsovali Androniki , Papamatheakis Joseph 
Published: August 2003

AbstractWe show here that steroid receptor coactivator 1 (SRC-1) is a coactivator of MHC class II genes that stimulates their interferon γ (IFNγ) and class II transactivator (CIITA)-mediated expression. SRC-1 interacts physically with the N-terminal activation domain of CIITA through two regions: one central [extending from amino acids (aa) 360–839] that contains the nuclear receptors binding region and one C-terminal (aa 1138–1441) that contains the activation domain 2. Using chromatin immunoprecipitation assays we show that SRC-1 recruitment on the class II promoter is enhanced upon IFNγ stimulation. Most importantly, SRC-1 relieves the inhibitory action of estrogens on the IFNγ-mediated induction of class II genes in transient transfection assays. We provide evidence that inhibition by estradiol is due to multiple events such as slightly reduced recruitment of CIITA and SRC-1 and severely inhibited assembly of the preinitiation complex.
The Cyclin-Dependent Kinase Inhibitor p27 (Kip1) Regulates Both DNA Synthesis and Apoptosis in Mammary Epithelium But Is Not Required for Its Functional Development during Pregnancy
Authors: Davison Elizabeth A. , Lee Christine S. L. , Naylor Matthew J. , Oakes Samantha R. , Sutherland Robert L. , Hennighausen Lothar , Ormandy Christopher J. , Musgrove Elizabeth A. 
Published: August 2003

AbstractDecreased expression of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is common in breast cancer and is associated with poor prognosis. p27 is also an important mediator of steroidal regulation of cell cycle progression. We have therefore investigated the role of p27 in mammary epithelial cell proliferation. Examination of the two major functions of p27, assembly of cyclin D1-Cdk4 complexes and inhibition of Cdk2 activity, revealed that cyclin D1-Cdk4 complex formation was not impaired in p27−/− mammary epithelial cells in primary culture. However, cyclin E-Cdk2 activity was increased approximately 3-fold, indicating that the CDK inhibitory function of p27 is important in mammary epithelial cells. Increased epithelial DNA synthesis was observed during pregnancy in p27−/− mammary gland transplants, but this was paralleled by increased apoptosis. During pregnancy and at parturition, development and differentiation of p27+/+ and p27−/− mammary tissue were indistinguishable. These results demonstrate a role for p27 in both the proliferation and survival of mammary epithelial cells. However, the absence of morphological and cellular defects in p27−/− mammary tissue during pregnancy raises the possibility that loss of p27 in breast cancer may not confer an overall growth advantage unless apoptosis is also impaired.
Stacking Phenomenon of Self-assembled Monolayers and Bilayers of Thioalkyl-substituted Tetrathiafulvalene
Authors: Lu Jun , Zeng Qing-dao , Wang Chen , Wan Li-jun , Bai Chun-li 
Published: August 2003

Abstract
The self-assembled monolayer and bilayer of tetrakis (octadecylthio)tetrathiafulvalene (TODT-TTF) on highly orientated pyrolytic graphite (HOPG) surface were studied by scanning tunneling microscope (STM). Direct observation of the dimer of TODT-TTF formed by π-π interaction was achieved.