bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure
Authors: Abkowitz Janis L. , Robinson Abigail E. , Kale Sujata , Long Michael W. , Chen Jing 
Published: April 2003

AbstractWe created parabiotic mice, joining ROSA26 and PeP3b animals, to study the trafficking of hematopoietic stem cells (HSCs) from marrow to blood and their return to marrow. The transfer of HSCs was assayed by secondary marrow transplantation and was 1.0% to 2.5% after 3, 6, 8, and 12 weeks. Thus, HSC homeostasis is primarily maintained by the retention of stem cells derived from replication events within the marrow, not the homing and engraftment of HSCs from the circulation. Of interest, the phenotypes of marrow progenitors and granulocytes were similar to those for HSCs, implying that the marrow functions as an intact compartment where differentiating cells derive from endogenous HSC. In contrast, 50% of splenic granulocytes and progenitor cells derived from the parabiotic partner, suggesting splenic progenitor cells were in constant equilibrium with progenitors in blood. In additional studies, animals were exposed to granulocyte–colonystimulating factor (G-CSF) and stem cell factor at days 17 to 20 of parabiosis and were studied 3 weeks later; 10.1% of marrow HSCs derived from the parabiotic partner. These data imply that HSCs, mobilized to the blood in response to cytokine exposure, are destined to later return to marrow, an observation that supports the concept that the mobilized peripheral blood stem cells used in clinical transplantation function physiologically.
New insights into the structural basis of integrin activation
Authors: Xiong Jian-Ping , Stehle Thilo , Goodman Simon L. , Arnaout M. Amin 
Published: April 2003

AbstractIntegrins are cell adhesion receptors that communicate biochemical and mechanical signals in a bidirectional manner across the plasma membrane and thus influence most cellular functions. Intracellular signals switch integrins into a ligand-competent state as a result of elicited conformational changes in the integrin ectodomain. Binding of extracellular ligands induces, in turn, structural changes that convey distinct signals to the cell interior. The structural basis of this bidirectional signaling has been the focus of intensive study for the past 3 decades. In this perspective, we develop a new hypothesis for integrin activation based on recent crystallographic, electron microscopic, and biochemical studies.
RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement
Authors: Roscic-Mrkic Branka , Fischer Marek , Leemann Christine , Manrique Amapola , Gordon Cynthia J. , Moore John P. , Proudfoot Amanda E. I. , Trkola Alexandra 
Published: April 2003

AbstractThe CC-chemokine RANTES (regulated on activation normal T-cell expressed and secreted; CCL5) transduces multiple intracellular signals. Like all chemokines, it stimulates G protein–coupled receptor (GPCR) activity through interaction with its cognate chemokine receptor(s), but in addition also activates a GPCR-independent signaling pathway. Here, we show that the latter pathway is mediated by an interaction between RANTES and glycosaminoglycan chains of CD44. We provide evidence that this association, at both low, physiologically relevant, and higher, probably supraphysiologic concentrations of RANTES, induces the formation of a signaling complex composed of CD44, src kinases, and adapter molecules. This triggers the activation of the p44/42 mitogen-activated protein kinase (MAPK) pathway. By specifically reducing CD44 expression using RNA interference we were able to demonstrate that the p44/p42 MAPK activation by RANTES requires a high level of CD44 expression. As well as potently inhibiting the entry of CCR5 using HIV-1 strains, RANTES can enhance HIV-1 infectivity under certain experimental conditions. This enhancement process depends in part on the activation of p44/p42 MAPK. Here we show that silencing of CD44 in HeLa-CD4 cells prevents the activation of p44/p42 MAPK and leads to a substantial reduction in HIV-1 infectivity enhancement by RANTES.
Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen
Authors: Naik Ulhas P. , Naik Meghna U. 
Published: April 2003

AbstractPlatelet spreading on immobilized fibrinogen (Fg) involves progression through a number of morphologic stages that, although distinctive, are not well understood mechanistically. Here we demonstrate that an association between GPIIb/IIIa and calcium- and integrin-binding protein (CIB) is required for the process of platelet spreading. Upon platelet adhesion to immobilized Fg, CIB localizes to the transiently formed filopodia and then redistributes diffusely along the membrane periphery of spread platelets. Immunoprecipitation analyses indicate that CIB and glycoprotein IIb/IIIa (GPIIb/IIIa) interact with each other as platelets adhere to immobilized Fg, and together they associate with the platelet cytoskeleton. Introduction of anti-CIB antibody or GPIIb cytoplasmic peptide into platelets blocks lamellipodia but not filopodia formation. GPIIb peptide–induced inhibition of platelet spreading is recovered by the incorporation of recombinant CIB protein, suggesting that interaction between CIB and GPIIb/IIIa is required for progression from filopodial to spread morphologies. Further, anti-CIB– or GPIIb peptide–induced inhibition of platelet spreading can be overcome by the addition of exogenous adenosine diphosphate (ADP). These data suggest that formation of the CIB-GPIIb/IIIa complex may be necessary for initiation of downstream signaling events, such as ADP secretion, that lead to platelet spreading.
Molecular characterization of Turkish patients with pyrimidine 5′ nucleotidase-I deficiency
Authors: Balta Gunay , Gumruk Fatma , Akarsu Nurten , Gurgey Aytemiz , Altay Cigdem 
Published: April 2003

Abstract
Pyrimidine 5′ nucleotidase-I (P5N-I) deficiency is a rare autosomal recessive disorder associated with hemolytic anemia, marked basophilic stippling, and accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. Recently, the structure and location of the P5N-I gene have been published. This paper presents the results of a study characterizing the molecular pathologies of P5N-I deficiency in a total of 6 Turkish patients from 4 unrelated families of consanguineous marriages. Mutation analysis in the P5N-I gene led to the identification of 3 novel mutations in these patients. In 4 patients from 2 families, a homozygous insertion of double G at position 743 was detected in exon 9 (743-744insGG), leading to premature termination of translation 23 bp downstream. In one family, a homozygous T to G transition at position 543 (543T&gt;G) in exon 8 resulted in the replacement of tyrosine (Tyr) with a stop codon (Tyr181Stop). In another family, a homozygous insertion of a single A in exon 7 (384-385insA) created a stop signal at the codon nearby. In all families, the parents were heterozygous for the relevant mutations. None of these changes was detected in 200 chromosomes from a healthy Turkish population. These mutations were not correlated with any particular phenotype.
Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy
Authors: Ruscito Brian J. , Harrison Neil L. 
Published: April 2003

AbstractLiver failure is often accompanied by cognitive impairment and coma, a syndrome known as hepatic encephalopathy (HE). The administration of flumazenil, a benzodiazepine (BZ) antagonist, is effective in reversing the symptoms of HE in many patients. These clinical observations gave rise to notions of an endogenous BZ-like mechanism in HE, but to date no viable candidate compounds have been characterized. We show here that the hemoglobin (Hb) metabolites hemin and protoporphyrin IX (PPIX) interact with the BZ site on the γ-aminobutyric acid (GABAA) receptor and enhance inhibitory synaptic transmission in a manner similar to diazepam and zolpidem. This finding suggests that hemin and PPIX are neuroactive porphyrins capable of acting as endogenous ligands for the central BZ site. The accumulation of these porphyrins under pathophysiologic conditions provides a potentially novel mechanism for the central manifestations of HE.
Impaired selectin-ligand biosynthesis and reduced inflammatory responses in β-1,4-galactosyltransferase-I–deficient mice
Authors: Asano Masahide , Nakae Susumu , Kotani Norihiro , Shirafuji Naoki , Nambu Aya , Hashimoto Noriyoshi , Kawashima Hiroto , Hirose Mayumi , Miyasaka Masayuki , Takasaki Seiichi , Iwakura Yoichiro 
Published: April 2003

AbstractSelectins recognize ligands containing carbohydrate chains such as sialyl Lewis x (sLex) that are mainly presented at the terminus of N-acetyl lactosamine repeats on core 2 O-glycans. Several glycosyltransferases act successively to extend the N-acetyl lactosamine repeats and to synthesize sLex, and β-1,4-galactosyltransferase (β4GalT) plays a key role in these processes. Recently isolated 6 β4GalT genes are candidates, but their individual roles, including those in selectin-ligand biosynthesis, remain to be elucidated. More than 80% of the core 2 O-glycans on the leukocyte membrane glycoproteins of β4GalT-I–deficient mice lacked galactose residues in β-1,4 linkage, and soluble P-selectin binding to neutrophils and monocytes of these mice was significantly reduced, indicating an impairment of selectin-ligand biosynthesis. β4GalT-I–deficient mice exhibited blood leukocytosis but normal lymphocyte homing to peripheral lymph nodes. Acute and chronic inflammatory responses, including the contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH) responses, were suppressed, and neutrophil infiltration into inflammatory sites was largely reduced in these mice. Our results demonstrate that β4GalT-I is a major galactosyltransferase responsible for selectin-ligand biosynthesis and that inflammatory responses of β4GalT-I–deficient mice are impaired because of the defect in selectin-ligand biosynthesis.
Intensification of Therapy for Children With Lower-Risk Acute Lymphoblastic Leukemia: Long-Term Follow-Up of Patients Treated on Children’s Cancer Group Trial 1881
Authors: Hutchinson Raymond J. , Gaynon Paul S. , Sather Harland , Bertolone Salvatore J. , Cooper Herbert A. , Tannous Raymond , Wells Linda M. , Heerema Nyla A. , Sailer Scott , Trigg Michael E. 
Published: April 2003

Purpose: From December 1988 through December 1992, the Children’s Cancer Group (CCG) conducted a randomized trial (CCG-1881) designed to evaluate the impact of adding a single delayed intensification phase of therapy to standard therapy for patients with newly diagnosed low-risk acute lymphoblastic leukemia (ALL). Patients and Methods: Patients (n = 778) with newly diagnosed ALL, 2 to 9 years of age at diagnosis with an initial WBC count less than 10,000/μL, were eligible for this protocol. All patients received induction, consolidation, and interim maintenance phases of therapy over the first 16 weeks. At week 16, patients remaining in remission were randomly assigned to receive or not receive a single 7-week delayed intensification (DI) phase of therapy. Maintenance therapy was given in lieu of or after DI, with total duration of therapy approximately 3 years for boys and 2 years for girls. Results: Patients randomized to receive DI experienced fewer relapse events in all categories. Kaplan-Meier life-table estimates for continuous complete remission (CCR) at 7 years for the randomized regimens were 77% (SE, 2.4%) for the standard regimen and 83% (SE, 2.7%) for the DI regimen (P = .072). The only prognostic factor of significance postrandomization in this selected low-risk population was the day 14 marrow response (P = .0001). Conclusion: The addition of a single DI phase of therapy was well tolerated and augmented 7-year CCR by 6% (SE of the difference, 3.3%), resulting in 26% fewer adverse events. Overall survival for eligible patients at 7 years is 90% (SE, 1.2%).
Phase I Trial and Pharmacokinetic Study of BMS-247550, an Epothilone B Analog, Administered Intravenously on a Daily Schedule for Five Days
Authors: Abraham Jame , Agrawal Manish , Bakke Susan , Rutt Ann , Edgerly Maureen , Balis Frank M. , Widemann Brigitte , Davis Louis , Damle Bharat , Sonnichsen Daryl , Lebwohl David , Bates Susan , Kotz Herb , Fojo Tito 
Published: April 2003

Purpose: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Patients and Methods: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. Results: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 ± 6.0 hours, the volume of distribution at steady-state was 798 ± 375 L, and the clearance was 712 ± 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. Conclusion: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.
Side Effects of Adjuvant Endocrine Treatment in Premenopausal Breast Cancer Patients: A Prospective Randomized Study
Authors: Nystedt Marianne , Berglund Gunilla , Bolund Christina , Fornander Tommy , Rutqvist Lars Erik 
Published: April 2003

Purpose: To compare the effect of adjuvant endocrine therapies with and without chemotherapy on physical symptoms, anxiety, and depressive symptoms in premenopausal women with breast cancer in a randomized clinical trial (the Zoladex in Premenopausal Patients trial). Patients and Methods: The patients were randomly assigned to goserelin, goserelin plus tamoxifen, tamoxifen alone, or no endocrine therapy. The duration of the endocrine treatment was 2 years. The groups were observed for 3 years after primary treatment (ie, during 2 years of active treatment as well as 1 year after cessation of the adjuvant endocrine therapy). All patients with node-positive disease received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF), which was given concurrently with the endocrine treatment. Results: Patients treated with CMF typically reported higher levels of physical symptoms than did patients who did not receive CMF. It was only among patients who did not receive chemotherapy that the endocrine treatment had differential effects. Goserelin was most burdensome and resulted in similar symptom levels as those of CMF, whereas the side effects of tamoxifen alone were milder. After cessation of the endocrine treatment, the side effects diminished in patients who had not received CMF, whereas patients treated with CMF reported ongoing problems at the 3-year follow-up. In contrast, anxiety and depressive symptoms were not significantly affected by endocrine treatment or chemotherapy during the 3 years of assessment. Conclusion: Goserelin and tamoxifen resulted in menopausal symptoms, but these symptoms were reversible. However, women treated with CMF experienced physical symptoms throughout the whole study period.
Partially T-Cell–Depleted Allogeneic Stem-Cell Transplantation for First-Line Treatment of Multiple Myeloma: A Prospective Evaluation of Patients Treated in the Phase III Study HOVON 24 MM
Authors: Lokhorst Henk M. , Segeren Christine M. , Verdonck Leo F. , van der Holt Bronno , Raymakers Reinier , van Oers Marinus H.J. , Barge Renee M.Y. , Schouten Harry C. , Westveer Petra H.M. , Steijaert Monique M.C. , Cornelissen Jan J. , Sonneveld Pieter 
Published: April 2003

Purpose: To determine in a prospective study the efficacy, toxicity, and long-term outcome of up-front allogeneic stem-cell transplantation (allo-SCT) in multiple myeloma (MM). Patients and Methods: In the prospective phase III study by the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), HOVON 24 MM, 53 patients with an HLA-identical sibling (median age at transplantation, 48 years; range, 31 to 56 years) were allocated to a partial T-cell–depleted allo-SCT after induction therapy. Results: The overall response rate after allo-SCT was 89% (47 of 53 patients), including the 19% of patients (10 of 53 patients) with a complete remission (CR). Five patients achieved a CR only after allo-SCT. Five (71%) of seven primary refractory patients obtained a response to allo-SCT, all of whom had a partial remission. With a median follow-up of 38 months (range, 25 to 61 months), 20 patients are alive since allo-SCT and 33 patients have died (14 from progressive disease, 18 from treatment-related mortality [TRM], and one from another cause). Occurrence of acute graft-versus-host disease grades 2 to 4 predicted for higher TRM in a time-dependent analysis. The median progression-free survival time after allo-SCT was 17 months. Median overall survival time after allo-SCT was 25 months, or 29 months from the start of therapy. Only three patients are in continuing CR, indicating that the potential cure rate of this approach is, at best, 6%. Conclusion: This first prospective evaluation of up-front allo-SCT of MM in a multicenter setting does not support the use of T-cell–depleted myeloablative allo-SCT as part of first-line therapy.
Using the Expected Survival to Explain Differences Between the Results of Randomized Trials: A Case in Advanced Ovarian Cancer
Authors: Buyse Marc , Burzykowski Tomasz , Parmar Mahesh , Torri Valter , Omura George , Colombo Nicoletta , Williams Chris , Conte Pierfranco , Vermorken Jan 
Published: April 2003

Purpose: A meta-analysis of randomized trials in advanced ovarian cancer showed a longer survival with cyclophosphamide, doxorubicin, and cisplatin (CAP) than with cyclophosphamide and cisplatin (CP; P = .009). In contrast, the results of the large International Collaborative Ovarian Neoplasm Study (ICON2) showed no survival difference between CAP and carboplatin (P = .98). In this article, we show how these discrepant results can be reconciled through the estimation of expected survival curves. Materials and Methods: A proportional hazards model, fitted to the meta-analysis data, was used to construct the expected survival curve for each treatment arm of the ICON2 trial. Expected survival curves were compared with observed survival curves in the ICON2 trial at all time points using a nonparametric test. Results: The prognostic model for survival obtained in the meta-analysis included extent of residual disease, age, histologic grade, and International Federation of Gynecology and Obstetrics stage. When this model was applied to the ICON2 data, there was no difference between the expected and observed curves in the CAP arm. In contrast, the observed survival curve for carboplatin was far superior to the expected survival curve for CP (P < .01). Conclusion: These analyses provide indirect evidence that better results are achieved with carboplatin alone at an optimally tolerated dose, compared with the CP combination at a cisplatin dose of 50 to 60 mg/m2. The expected survival may provide valuable insight when direct comparisons between randomized groups yield discrepant results across different studies.
repp86 Expression and Outcome in Patients With Neuroblastoma
Authors: Krams Matthias , Heidebrecht Hans-Juergen , Hero Barbara , Berthold Frank , Harms Dieter , Parwaresch Reza , Rudolph Pierre 
Published: April 2003

Purpose: Given the well-known challenges of neuroblastoma prognosis, we investigated whether the expression of restrictedly expressed proliferation-associated protein of 86 kDa theoretical molecular mass (repp86), a proliferation-associated protein expressed in S, G2, and M phases of the cell cycle, correlates with the clinical outcome in patients with neuroblastoma.Patients and Methods: 161 children with different stages of neuroblastoma were studied; the median follow-up time was 72.8 months. The patients were staged according to the International Neuroblastoma Staging System, and histologic grading of the tumors was performed according to the criteria of Hughes and those of the International Neuroblastoma Pathology Classification. The MYCN gene copy number was determined by Southern blot analysis or fluorescence in situ-hybridization, and repp86 expression was assessed immunohistochemically by means of monoclonal antibody Ki-S2 on paraffin sections from archival tumor samples.Results: A repp86 labeling index (RI) of more than 10% positive tumor cells significantly predicted a shortened disease-free interval and an increased tumor mortality (both P < .0001). Moreover, the RI allowed the identification of patients with favorable and adverse prognosis in subsets defined by stage, grade, age, and MYCN status. In a multivariate analysis, the RI emerged as the most important predictor of event-free and disease-specific survival with hazard ratios of 11.7 and 10.5, respectively (both P < .0001).Conclusion: It seems that repp86 expression is closely associated with the biologic behavior of neuroblastoma. Assessment of the RI might, therefore, considerably refine prognostic models.
Phase III Study of Cyclophosphamide, Doxorubicin, and Fluorouracil (CAF) Plus Leucovorin Versus CAF for Metastatic Breast Cancer: Cancer and Leukemia Group B 9140
Authors: Parnes H.L. , Cirrincione C. , Aisner J. , Berry D.A. , Allen S.L. , Abrams J. , Chuang E. , Cooper M.R. , Perry M.C. , Duggan D.B. , Szatrowski T.P. , Henderson I.C. , Norton L. 
Published: April 2003

Purpose: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. Patients and Methods: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). Results: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. Conclusion: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.