bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group
Authors: Rowe Jacob M. , Neuberg Donna , Friedenberg William , Bennett John M. , Paietta Elisabeth , Makary Adel Z. , Liesveld Jane L. , Abboud Camille N. , Dewald Gordon , Hayes F. Ann , Tallman Martin S. , Wiernik Peter H. 
Published: September 2003

AbstractThe optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P = .03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.
Identification of the earliest prethymic T-cell progenitors in murine fetal blood
Authors: Ikawa Tomokatsu , Masuda Kyoko , Lu Min , Minato Nagahiro , Katsura Yoshimoto , Kawamoto Hiroshi 
Published: September 2003

AbstractDuring murine fetal development, hemato-poietic progenitors start to colonize the thymic anlage at day 11 of gestation via blood stream. The present study aims at identifying the earliest prethymic progenitors in circulation. Here, we show that the interleukin-7 receptor–positive (IL-7R+) cells in Lin– c-kit+ population are circulating exclusively between days 11 and 14 of fetal age. Clonal analysis revealed that these IL-7R+ cells mostly contain T-cell lineage–restricted progenitors (p-Ts). The proportion of circulating p-Ts reaches 30% of the total p-Ts during these fetal ages, whereas virtually all B-cell lineage–restricted progenitors stay in the fetal liver, suggesting that the p-Ts are selectively released to the circulation. The circulating p-Ts retain the potential to generate natural killer cells and dendritic cells and exhibit extensive proliferation before the occurrence of T-cell receptor β (TCRβ) chain gene rearrangement. We propose that the wave of p-Ts in fetal blood disclosed by this study represents the ontogenically earliest thymic immigrants.
Tracking angiogenesis induced by skin wounding and contact hypersensitivity using a Vegfr2-luciferase transgenic mouse
Authors: Zhang Ning , Fang Zuxu , Contag Pamela R. , Purchio Anthony F. , West David B. 
Published: September 2003

AbstractThe vascular endothelial growth factor-2 (VEGFR2) gene is transcriptionally regulated during angiogenesis. The ability to monitor and quantify VEGFR2 expression in vivo may facilitate a better understanding of the role of VEGFR2 in different states. Here we describe a transgenic mouse, Vegfr2-luc, in which a luciferase reporter is under control of the murine VEGFR2 promoter. In adult mice, luciferase activity was highest in lung and uterus, intermediate in heart, skin, and kidney, and lower in other tissues. Luciferase expression in these tissues correlated with endogenous VEGFR2 mRNA expression. In a cutaneous wound-healing model, Vegfr2-luc expression was induced in the wound tissue. Histologic and immunohistochemical studies showed significant macrophage infiltration into the wound and induction of Vegfr2-luc expression in endothelial and stromal cells. Dexamethasone significantly suppressed Vegfr2-luc expression and macrophage infiltration into the wound, resulting in delayed healing and impaired angiogenesis. In a skin hypersensitivity reaction produced by treatment with oxazolone, Vegfr2-luc expression was induced in the ear. Treatment by dexamethasone markedly suppressed Vegfr2-luc expression and leukocyte infiltration in the ear and was correlated with reduced dermal edema and epidermal hyperplasia. The Vegfr2-luc model will be valuable in monitoring the ability of drugs to affect angiogenesis in vivo.
Alphastatin, a 24–amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo
Authors: Staton Carolyn A. , Brown Nicola J. , Rodgers Gary R. , Corke Kevin P. , Tazzyman Simon , Underwood James C. E. , Lewis Claire E. 
Published: September 2003

Abstract
Angiogenesis, the development of new blood vessels from existing vasculature, is crucial for the development and metastasis of solid tumors. Here, we show for the first time that a 24–amino acid peptide derived from the amino terminus of the alpha chain of human fibrinogen (termed “alphastatin”) has potent antiangiogenic properties, inhibiting both the migration and tubule formation of human dermal microvascular endothelial cells in response to vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in vitro. Moreover, alphastatin markedly inhibits the growth of tumors in a syngeneic murine model. Tumors from mice receiving daily injections of alphastatin for 12 days exhibited large areas of intravascular disruption and thrombosis with substantial cellular necrosis. Importantly, alphastatin administration had no detectable effect on vessels in such normal tissues as liver, lungs, and kidney. Taken together, these data indicate that alphastatin is a potent new antiangiogenic agent in vitro and antivascular agent in vivo.
Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin
Authors: Eichler Petra , Lubenow Norbert , Strobel Ulrike , Greinacher Andreas 
Published: September 2003

Abstract
Bivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody–positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.
Unique CD18 mutations involving a deletion in the extracellular stalk region and a major truncation of the cytoplasmic domain in a patient with leukocyte adhesion deficiency type 1
Authors: Hixson Patricia , Smith C. Wayne , Shurin Susan B. , Tosi Michael F. 
Published: September 2003

AbstractTwo novel CD18 mutations were identified in a patient who was a compound heterozygote with type 1 leukocyte adhesion deficiency and whose phenotype was typical except that he exhibited hypertrophic scarring. A deletion of 36 nucleotides in exon 12 (1622del36) predicted the net loss of 12 amino acid (aa) residues in the third cysteine-rich repeat of the extracellular stalk region (mut-1). A nonsense mutation in exon 15 (2200G&gt;T), predicted a 36-aa truncation of the cytoplasmic domain (mut-2). Lymphocyte function-associated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) containing the mut-1 β2 subunit were expressed at very low levels compared with wild-type (wt) β2. Mac-1 and LFA-1 expression with the mut-2 β2 subunit were equivalent to results with wt β2. Binding function of Mac-1 with mut-2 β2 was equivalent to that with wt β2. However, binding function of LFA-1 with the mut-2 β2 subunit was reduced by 50% versus wt β2. It was concluded that (1) the portion of the CD18 stalk region deleted in mut-1 is critical for β2 integrin heterodimer expression but the portion of the cytoplasmic domain truncated in mut-2 is not; and (2) the mut-2 cytoplasmic domain truncation impairs binding function of LFA-1 but not of Mac-1. Studies with the patient's neutrophils (PMNs) were consistent with functional impairment of LFA-1 but not of Mac-1. (Blood. 2004;103:1105-1113)
Transregulation of memory CD8 T-cell proliferation by IL-15Rα+ bone marrow–derived cells
Authors: Schluns Kimberly S. , Klonowski Kimberly D. , Lefrançois Leo 
Published: September 2003

AbstractInterleukin 15 (IL-15) and the IL-15 receptor α (IL-15Rα) chain are both required for the basal proliferation of memory CD8 T cells, but which cell types are required to express IL-15 or IL-15Rα to mediate this proliferation is not known. Using bone marrow (BM) chimeras, we showed that virus-specific CD8 memory T-cell proliferation was driven by IL-15 produced by either BM-derived or parenchymal cells. Experiments using mixed BM chimeras showed that IL-15Rα expression by memory CD8 T cells was not required for their division. In addition, wild-type memory CD8 T cells did not divide after transfer into IL-15Rα-/- mice. Further analyses demonstrated that IL-15Rα+ BM-derived cells were crucial in driving memory CD8 T-cell division in the spleen while both parenchymal and BM-derived cells promoted memory cell division in the lung. Proliferation in response to soluble IL-15 in vivo required expression of IL-15Rα by opposing cells and IL-15Rβ by CD8 memory cells, indicating that IL-15 interacted directly with the T cells. These results indicate that transpresentation of IL-15 by IL-15Rα on BM-derived cells mediates the basal proliferation of memory CD8 T cells. (Blood. 2004;103:988-994)
The role of the combination of IL-2 and TGF-β or IL-10 in the generation and function of CD4+ CD25+ and CD8+regulatory T cell subsets
Authors: Horwitz David A , Zheng Song Guo , Gray J Dixon 
Published: September 2003

Abstract
Recently, considerable attention has been focused on thymus-derived CD4+ regulatory T cells that constitutively express CD25 and have a contact-dependent, cytokine-independent mechanism in vitro. However, peripheral CD4+ and CD8+ T cells can also be induced to become regulatory T cells. Here we review our studies using the combination of IL-2 and transforming growth factor β (TGF-β) to generate regulatory T cell subsets ex vivo, and the work of others using IL-10 to induce suppressive activity. Under certain conditions, the autocrine effects of TGF-β and IL-10 induce peripheral T cells to produce immunosuppressive levels of each of these cytokines. This effect of TGF-β is IL-2 dependent. Under other conditions IL-2 and TGF-β can induce CD4+ cells to develop potent contact-dependent, cytokine-independent regulatory activity. At present, there is considerable confusion concerning the mechanism of action of CD4+ CD25+ cells because cytokine-producing regulatory T cells generated in the periphery can express CD25 and other markers displayed by naturally occurring, thymus-derived regulatory T cells. We, therefore, propose a nomenclature that identifies thymus-derived and peripheral regulatory cells, and that also differentiates T regulatory cells from T helper cells. Because T regulatory cells broadly control T helper cell reactivity, the mechanisms that control regulatory cell function are also reviewed. Finally, the potential use of regulatory T cells generated ex vivo as an adoptive immunotherapy for certain autoimmune diseases, to prevent organ graft rejection, or to prevent pathologic host responses to infectious agents is discussed.
Psychosocial treatment for severe personality disorder
Authors: Chiesa Marco , Fonagy Peter 
Published: September 2003

BackgroundIn a previous report a step-down psychosocial programme for severe personality disorders was found to be more effective at expected termination of treatment than a longer in-patient treatment with no planned after-care.AimsTo evaluate the clinical effectiveness of these two psychosocial specialist programmes over a 3-year follow-up period.MethodTwo samples allocated to the in-patienttreatment and to the step-down programme were compared prospectively on symptom severity, social adjustment, global assessment of mental health and other clinical indicators at 6, 12, 24 and 36 months after intake.ResultsImprovements were significantly greater in the step-down programme for social adjustment and global assessment of mental health. Patientsin the programme were found to self-mutilate, attempt suicide and be readmitted significantly less at 24- and 36-month follow-up than patients in the in-patient group.ConclusionsImprovements associated with specialist residential treatment continued 2 years after discharge. A step-down model has significant advantages over a purely in-patient model.
Psychiatric comorbidity and medication use in autism: a community survey
Authors: Morgan Caryl N. , Roy Meera , Chance Patrick 
Published: September 2003

Aims and MethodIndividuals with autism often have complex needs. In this paper, we attempt to establish the prevalence rates of other major psychiatric illnesses in learning disabled adults diagnosed with autism and analyse the use of medication in these individuals. A total of 571 clients with learning disability were screened for autistic spectrum disorder, identifying 164 individuals for study. Psychiatric and medical diagnoses were also reviewed.ResultsOf the individuals with autism, 35% had another comorbid psychiatric disorder. An overall prevalence rate of 10% for hypothyroidism was also identified and 35% of people with autism and no other psychiatric diagnosis were on neuroleptics.Clinical ImplicationsPlanning of services for autism will have to take into account the high comorbidity of autism and other psychiatric conditions. Individuals with autism will also benefit from close monitoring of mental state and the development of hypothyroidism.
Quantification of Free Circulating DNA As a Diagnostic Marker in Lung Cancer
Authors: Sozzi Gabriella , Conte Davide , Leon MariaElena , Cirincione Rosalia , Roz Luca , Ratcliffe Cathy , Roz Elena , Cirenei Nicola , Bellomi Massimo , Pelosi Giuseppe , Pierotti Marco A. , Pastorino Ugo 
Published: September 2003

Purpose: Analysis of circulating DNA in plasma can provide a useful marker for earlier lung cancer detection. This study was designed to assess the sensitivity and specificity of a quantitative molecular assay of circulating DNA to identify patients with lung cancer and monitor their disease. Materials and Methods: The amount of plasma DNA was determined through the use of real-time quantitative polymerase chain reaction (PCR) amplification of the human telomerase reverse transcriptase gene (hTERT) in 100 non–small-cell lung cancer patients and 100 age-, sex-, and smoking-matched controls. Screening performance of the assay was calculated through the receiver operating characteristic (ROC) curve. Odds ratios were calculated using conditional logistic regression analysis. Results: Median concentration of circulating plasma DNA in patients was almost eight times the value detected incontrols (24.3 v 3.1 ng/mL). The area under the ROC curve was 0.94 (95% CI, 0.907 to 0.973). Plasma DNA was a strong risk factor for lung cancer; concentrations in the upper tertile were associated with an 85-fold higher risk than were those in the lowest tertile. Conclusion: This study shows that higher levels of free circulating DNA can be detected in patients with lung cancer compared with disease-free heavy smokers by a PCR assay, and suggests a new, noninvasive approach for early detection of lung cancer. Levels of plasma DNA could also identify higher-risk individuals for lung cancer screening and chemoprevention trials.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies
Authors: Morgan Bruno , Thomas Anne L. , Drevs Joachim , Hennig Juergen , Buchert Martin , Jivan Asvina , Horsfield Mark A. , Mross Klauss , Ball Howard A. , Lee Lucy , Mietlowski William , Fuxius Stefan , Unger Clemens , O’Byrne Ken , Henry Andrew , Cherryman Graham R. , Laurent Dirk , Dugan Margaret , Marmé Dieter , Steward William P. 
Published: September 2003

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development.
Insulin Augmentation of 17α-Hydroxylase Activity Is Mediated by Phosphatidyl Inositol 3-Kinase But Not Extracellular Signal-Regulated Kinase-1/2 in Human Ovarian Theca Cells
Authors: Munir Iqbal , Yen Hui-Wen , Geller David H. , Torbati Donna , Bierden Rebecca M. , Weitsman Stacy R. , Agarwal Sanjay K. , Magoffin Denis A. 
Published: September 2003

AbstractPolycystic ovary syndrome, characterized by hyperandrogenism and chronic anovulation, is frequently associated with insulin resistance. Ample evidence implicates a role for insulin in the genesis of ovarian hyperandrogenism. The objective of this study was to begin to define the intracellular signaling pathway(s) that mediates insulin regulation of 17α-hydroxylase activity in human ovarian theca cells. Third-passage theca cells, isolated from the ovaries of regularly cycling premenopausal women, were used. Insulin alone had no effect on 17α-hydroxylase activity or CYP17 mRNA expression but required costimulation with forskolin. At the insulin concentration used (10 ng/ml), a neutralizing antibody to the insulin receptor (but not an antibody to the type I IGF receptor) blocked the insulin stimulation of 17α-hydroxylase activity, demonstrating that the effects were mediated by the insulin receptor. Insulin stimulated both phosphatidylinositol-3-kinase (PI3-kinase) and extracellular signal-regulated kinase-1/2 (MAPK) pathways. Specific inhibition of MAPK kinase (MEK) with PD98059 or I0126 did not decrease the 17α-hydroxylase activity stimulated by forskolin or forskolin plus insulin. In contrast, the PI3-kinase inhibitor LY294002 completely blocked insulin-stimulated 17α-hydroxylase activity. Our data demonstrate that insulin stimulates PI3-kinase and extracellular signal-regulated kinase-1/2 activities in human theca cells, but only PI3-kinase mediates the insulin augmentation of forskolin-stimulated 17α-hydroxylase activity.
Investigation of the physical properties of spray-dried stabilised lysozyme particles
Authors: Liao Yong-Hong , Brown Marc B , Quader Abdul , Martin Gary P 
Published: September 2003

Abstract
The aim of this study was to investigate the effect of the composition of formulations on the physical properties, including glass-transition temperatures (Tg) and aerodynamic-related characteristics, of spray-dried lysozyme particles. The Tg, as determined by differential scanning calorimetry, of spray-dried lysozyme formulations was found to be dependent upon the type and amount of excipient(s) included in the formulation. In addition, the Tg of sucrose-containing particles appeared to be raised markedly by the inclusion of trehalose, but not by dextran. The surfaces of all spray-dried particles were shown by scanning electron microscopy to be smooth with some containing characteristic dimples, typical of spray-dried material, and the morphology appeared to be independent of variation in excipient composition. However, the volume median diameters (VMD) of spray-dried powders, as determined by laser diffraction, were found to depend upon the amounts of excipients. The fine particle fraction of enzyme delivered to the lower stage of a twin-stage impinger from lysozyme–trehalose 1:1 powders appeared to be greater than that from lysozyme–sucrose 1:1 particles (22.5% vs 15.9%) when dispersed via a Rotahaler although a similar dispersibility of the two formulations (39.6% vs 36.7%) was found from a glass inhaler. In general, spray-drying was demonstrated to be feasible to produce respirable particles of the stabilised model protein, with Tg of the formulations being &gt;30°C higher than room temperature.
Induction of apoptosis of RAW 264.7 cells by the cytostatic macrolide apicularen A
Authors: Hong JangJa , Yamaki Kouya , Ishihara Kenji , Ahn Jong Woong , Zee OkPyo , Ohuchi Kazuo 
Published: September 2003

Abstract
In RAW 264.7 cells, a mouse leukaemic monocyte cell line, apicularen A decreased cell growth and survival as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in a concentration-dependent manner at 10–1000 nM. Apicularen B, an N-acetyl-glucosamine glycoside of apicularen A, was 10–100-fold less effective than apicularen A. Apicularen A induced a DNA ladder, an increase in the percentage of sub-G1 cells and annexin V-binding cells, and promoted the activation of caspase as revealed by the cleavage of poly(ADP-ribose) polymerase, indicating that apicularen A induced apoptosis in RAW 264.7 cells. In addition, apicularen A phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK. The p44/42 MAPK inhibitor PD98059 rescued the cells from apicularen-induced decrease in cell growth and survival as determined by the MTT assay, while the p38 MAPK inhibitor SB203580 augmented the effect of apicularen A. This suggested the activation of p44/42 MAPK to be pro-apoptotic and the activation of p38 MAPK anti-apoptotic in apicularen A-treated RAW 264.7 cells.