bluuebunny/crossref_metadata_2025_split huggingface dataset:
A gene-deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia
Authors: Ehrhardt Anja , Xu Hui , Dillow Aaron M. , Bellinger Dwight A. , Nichols Timothy C. , Kay Mark A. 
Published: June 2003

Abstract
Many approaches for treating hemophilia via gene transfer have been attempted in large animal models but all have potential drawbacks. Recombinant adenoviral vectors offer high-efficiency transfer of an episomal vector but have been plagued by the cytotoxicity/immunogenicity of early-generation vectors that contain viral genes. In our current study, we have used a nonintegrating helper-dependent (HD) adenoviral vector for liver-directed gene transfer to achieve hemostatic correction in a dog with hemophilia B. We measured plasma canine factor IX (cFIX) concentrations at a therapeutic range for up to 2.5 months and normalization of the whole blood clotting time (WBCT) for about a month. This was followed by a decrease and stabilized partial correction for 4.5 months. Hepatic gene transfer of a slightly lower dose of the HD vector resulted in WBCTs that were close to normal for 2 weeks, suggesting a dose threshold effect in dogs. In sharp contrast to other studies using first- or second-generation adenoviral vectors, we observed no vector-related elevation of liver enzymes, no fall in platelet counts, and normal liver histology. Taken together, this study demonstrates that injection of an adenoviral HD vector results in complete but transient phenotypic correction of FIX deficiency in canine models with no detectable toxicity. (Blood. 2003;102:2403-2411)
Rapid expansion of cytomegalovirus–specific cytotoxic T lymphocytes by artificial antigen-presenting cells expressing a single HLA allele
Authors: Papanicolaou Genovefa A. , Latouche Jean-Baptiste , Tan Cuiwen , Dupont Jakob , Stiles Jeffrey , Pamer Eric G. , Sadelain Michel 
Published: June 2003

AbstractCytomegalovirus (CMV) is a major threat in patients undergoing allogeneic bone marrow transplantation. The adoptive transfer of CMV-specific cytotoxic T lymphocytes (CTLs) expanded from the blood of CMV-seropositive donors has been shown to effectively control CMV infection. However, the requirement for safe and effective antigen-presenting cells (APCs) for each patient precludes broad applicability of this successful form of therapy. Here we analyze the ability of artificial APCs (AAPCs) to activate and expand CMV-specific CTLs from peripheral blood of seropositive HLA A2.1+ donors. We demonstrate that AAPCs expressing the CMV P495 peptide or the full-length pp65 protein stimulate P495-specific CTLs at least as effectively as autologous, peptide-pulsed, peripheral blood mononuclear cells or EBV-transformed B cells. Starting from 100 mL of blood, the AAPCs reliably yield clinically relevant CTL numbers after a single stimulation. CTLs activated on AAPCs effectively kill CMV-infected fibroblasts and have a Tc1 memory effector phenotype identical to that of CTLs generated with autologous APCs. AAPCs thus offer a rapid, controlled, convenient, and highly reproducible system for expanding CMV-specific CTLs. Furthermore, the CTL expansion obtained with AAPCs encoding full-length pp65 indicates that AAPCs may be used to present known as well as unknown CTL epitopes in the context of the AAPC's HLA. (Blood. 2003;102:2498-2505)
AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases
Authors: Schoch Claudia , Schnittger Susanne , Klaus Mirjam , Kern Wolfgang , Hiddemann Wolfgang , Haferlach Torsten 
Published: June 2003

Abstract
Acute myeloid leukemia (AML) cases with 11q23 abnormalities involving the MLL gene comprise one category of recurring genetic abnormalities in the WHO classification. In an unselected series of 1897 AML cases, 54 patients with an 11q23/MLL rearrangement were identified, resulting in an incidence of 2.8%. The incidence of AML with MLL rearrangement was significantly higher in therapy-related AML (t-AML) than in de novo AML (9.4% vs 2.6%, P &lt; .0001). The frequency of MLL rearrangements was significantly higher in patients younger than 60 years (5.3% vs 0.8%, P &lt; .0001). While the incidence of MLL rearrangements in AML M4, M5a, and M5b was 4.7%, 33.3%, and 15.9%, respectively, it was found in only 0.9% of all other French-American-British (FAB) subtypes (P &lt; .0001). Compared with AML with intermediate karyotype, AML with 11q23/MLL rearrangement had a worse outcome, which was rather comparable with AML with unfavorable karyotype. Compared with t-AML, the median overall survival (OS) of de novo AML with MLL rearrangement was significantly better (2.5 vs 10 months, P = .0143). No significant differences in median OS were observed between cases with t(9;11) compared with all other MLL rearrangements (10.0 vs 8.9 months, P = .36). In conclusion, the category AML with 11q23/MLL abnormalities accounts for 2.8% of unselected AML, is closely associated with monocytic differentiation, and has a dismal prognosis. (Blood. 2003;102:2395-2402)
The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma
Authors: Fonseca Rafael , Debes-Marun Carina S. , Picken Elisa B. , Dewald Gordon W. , Bryant Sandra C. , Winkler Jerry M. , Blood Emily , Oken Martin M. , Santana-Dávila Rafael , González-Paz Natalia , Kyle Robert A. , Gertz Morie A. , Dispenzieri Angela , Lacy Martha Q. , Greipp Philip R. 
Published: June 2003

Abstract
Aneuploid is ubiquitous in multiple myeloma (MM), and 4 cytogenetic subcategories are recognized: hypodiploid (associated with a shorter survival), pseudodiploid, hyperdiploid, and near-tetraploid MM. The hypodiploid, pseudodiploid, and near-tetraploid karyotypes can be referred to as the nonhyperdiploid MM. Immunoglobulin heavy-chain (IgH) translocations are seen in 60% of patients. We studied the relation between aneuploidy and IgH translocations in MM. Eighty patients with MM and abnormal metaphases were studied by means of interphase fluorescent in situ hybridization (FISH) to detect IgH translocations. We also studied a second cohort of 199 patients (Eastern Cooperative Oncology Group [ECOG]) for IgH translocations, chromosome 13 monosomy/deletions (Δ13), and ploidy by DNA content. Mayo Clinic patients with abnormal karyotypes and FISH-detected IgH translocation were more likely to be nonhyperdiploid (89% versus 39%, P &lt; .0001). Remarkably, 88% of tested patients with hypodiploidy (16 of 18) and 90% of tested patients with tetraploidy (9 of 10) had an IgH translocation. ECOG patients with IgH translocations were more likely to have nonhyperdiploid MM by DNA content (68% versus 21%, P &lt; .001). This association was seen predominantly in patients with recurrent chromosome partners to the IgH translocation (11q13, 4p16, and 16q23). The classification of MM into hyperdiploidy and nonhyperdiploidy is dictated largely by the recurrent (primary) IgH translocations in the latter. (Blood. 2003;102:2562-2567)
The protein kinase C inhibitor RO318220 potentiates thrombin-stimulated platelet-supported prothrombinase activity
Authors: London Fredda S. 
Published: June 2003

AbstractProthrombinase activity was tested on thrombin- and SFLLRN-activated platelets treated with RO318220, a potent inhibitor of protein kinase C. RO318220 completely inhibited platelet dense and α-granule secretion at a concentration of 20 μM but had no effect on prothrombinase activity in the presence of excess factor Va (20 nM). This indicates that protein kinase C activity and agonist-initiated secretion are not necessary for the development of a procoagulant surface. Treatment with 75 to 150 μM RO318220 potentiated platelet-supported thrombin generation up to 280% of control platelets with no change in Kd appFXa. Treated with increasing concentrations of RO318220, an increasing proportion of thrombin-stimulated platelets bound annexin V with decreasing binding sites per platelet. A lower mean forward scatter (FSC-H) of platelets treated with RO318220 suggested platelet vesiculation as a result of RO318220 treatment; however, 100 μM calpeptin pretreatment eliminated the decrease in FSC-H without affecting either the increase in platelets positive for annexin V binding, the decrease in binding sites per platelet, or the 3-fold increase in prothrombinase activity. Thus, RO318220 appears to increase prothrombinase activity by increasing platelet responsiveness to thrombin rather than by inducing platelet vesiculation. This suggests that RO318220 inhibits a signaling molecule within a negative regulatory pathway that governs platelet procoagulant surface changes. (Blood. 2003;102:2472-2481)
Labile plasma iron in iron overload: redox activity and susceptibility to chelation
Authors: Esposito Breno P. , Breuer William , Sirankapracha Pornpan , Pootrakul Pensri , Hershko Chaim , Cabantchik Z. Ioav 
Published: June 2003

Abstract
Plasma non-transferrin-bound-iron (NTBI) is believed to be responsible for catalyzing the formation of reactive radicals in the circulation of iron overloaded subjects, resulting in accumulation of oxidation products. We assessed the redox active component of NTBI in the plasma of healthy and β-thalassemic patients. The labile plasma iron (LPI) was determined with the fluorogenic dihydrorhodamine 123 by monitoring the generation of reactive radicals prompted by ascorbate but blocked by iron chelators. The assay was LPI specific since it was generated by physiologic concentrations of ascorbate, involved no sample manipulation, and was blocked by iron chelators that bind iron selectively. LPI, essentially absent from sera of healthy individuals, was present in those of β-thalassemia patients at levels (1-16 μM) that correlated significantly with those of NTBI measured as mobilizer-dependent chelatable iron or desferrioxamine chelatable iron. Oral treatment of patients with deferiprone (L1) raised plasma NTBI due to iron mobilization but did not lead to LPI appearance, indicating that L1-chelated iron in plasma was not redox active. Moreover, oral L1 treatment eliminated LPI in patients. The approach enabled the assessment of LPI susceptibility to in vivo or in vitro chelation and the potential of LPI to cause tissue damage, as found in iron overload conditions. (Blood. 2003;102:2670-2677)
Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin
Authors: Miranda Carlos J. , Makui Hortence , Soares Ricardo J. , Bilodeau Marc , Mui Jeannie , Vali Hajatollah , Bertrand Richard , Andrews Nancy C. , Santos Manuela M. 
Published: June 2003

AbstractThe clinical use of doxorubicin (DOX), an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knock-out (Hfe-/-) mice and wild-type mice. DOX-induced iron metabolism changes were intensified in Hfe-/- mice, which accumulated significantly more iron in the heart, liver, and pancreas, but less in the spleen compared with wild-type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe-/- mice and Hfe+/-mice compared with wild-type mice. DOX-treated Hfe-/- mice had a higher degree of mitochondrial damage and iron deposits in the heart than did wild-type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans. (Blood. 2003;102:2574-2580)
Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-γ receptor-1 deficiency
Authors: Horwitz Mitchell E. , Uzel Gulbu , Linton Gilda F. , Miller Judi A. , Brown Margaret R. , Malech Harry L. , Holland Steven M. 
Published: June 2003

AbstractInterferon-γ receptor-1 (IFNγR1) deficiency is a rare inherited immunodeficiency. We performed a nonmyeloablative allogeneic stem cell transplantation on a boy with complete IFNγR1 deficiency and refractory disseminated Myco-bacterium avium infection. Despite the patient's profound immune defect, early donor stem cell engraftment was low. Full donor engraftment was accomplished only following multiple donor lymphocyte infusions. Detection of IFNγR1 expression on peripheral blood monocytes and neutrophils corresponded with establishment of stable, complete donor hematopoietic chimerism. However, expression of, and signaling through IFNγR1 disappeared shortly thereafter. Disseminated Mycobacterium avium infection persisted and the patient died. Coculture of Myco-bacterium avium with normal myeloid cells resulted in an IFNγ signaling defect similar to that observed in vivo. Active disseminated Mycobacterium avium infection may significantly compromise normal immune reconstitution following allogeneic stem cell transplantation. Patients with IFNγR1 deficiency should receive transplants before developing refractory mycobacterial infections. (Blood. 2003;102:2692-2694)
Resolution and outcome of acute circulatory failure does not correlate with hemodynamics
Authors: Suistomaa Matti , Uusaro Ari , Parviainen Ilkka , Ruokonen Esko 
Published: June 2003

Abstract
Introduction
Hemodynamic goals in the treatment of acute circulatory failure (ACF) are controversial. In critical care, organ failures can be assessed using Sequential Organ Failure Assessment and its refinement, total maximal Sequential Organ Failure Assessment (TMS). We studied the associations between resolution of ACF and hemodynamics in the early (< 24 hours) phase of intensive care unit care and their relation to TMS and mortality.

Patients and methods
Eighty-three patients with ACF (defined as arterial lactate > 2 mmol/l and/or base deficit > 4) who had pulmonary artery catheters and stayed for longer than 24 hours in the intensive care unit were included. Hemodynamics, oxygen transport, vasoactive drugs and TMS scores were recorded. Normalisation of hyperlactatemia and metabolic acidosis in less than 24 hours after admission was defined as a positive response to hemodynamic resuscitation.

Results
Fifty-two patients responded to resuscitation. Nonresponders had higher mortality than responders (52% versus 33%, P = 0.044). Hospital mortality was highest (63%) among nonresponders who received vasoactive drugs. The TMS scores of nonresponders (median [interquartile range], 12 [9–16]) were higher than the scores of responders (10 [7–12], P = 0.019). Late accumulation of TMS scores was associated with increasing mortality, and if the TMS score increase occurred > 5 days after admission then the mortality was 77%. Responders had higher mean arterial pressure at 24 hours, but it was no different between survivors and nonsurvivors. No other hemodynamic and oxygen transport variables were associated with the success of resuscitation or with mortality.

Conclusions
Except for the mean arterial pressure at 24 hours, invasively derived hemodynamic and oxygen transport variables are not associated with the response to resuscitation or with mortality. Positive response to resuscitation in ACF is associated with less severe organ failures as judged by TMS scores. Late accumulation of the TMS score predicts poor outcome.
Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial
Authors: Clark Joseph I. , Atkins Michael B. , Urba Walter J. , Creech Steven , Figlin Robert A. , Dutcher Janice P. , Flaherty Larry , Sosman Jeffrey A. , Logan Theodore F. , White Richard , Weiss Geoffrey R. , Redman Bruce G. , Tretter Christopher P.G. , McDermott David , Smith John W. , Gordon Michael S. , Margolin Kim A. 
Published: June 2003

Purpose: This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). Patients and Methods: Eligibility requirements were resected locally advanced (LA; T3b-4 or N1–3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. Results: Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P = .73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P = .38). Analysis including metastasectomy patients made no difference in DFS or overall survival. Conclusion: One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.
Phase I Clinical Trial of Weekly Combretastatin A4 Phosphate: Clinical and Pharmacokinetic Results
Authors: Rustin Gordon J.S. , Galbraith Susan M. , Anderson Helen , Stratford Michael , Folkes Lisa K. , Sena Luiza , Gumbrell Lindsey , Price Patricia M. 
Published: June 2003

Purpose: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors. Patients and Methods: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2. Results: Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 μmol • h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 μmol • h/L compared with 5.8 μmol • h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope and motor neuropathy at 88 mg/m2, and fatal ischemia in previously irradiated bowel at 52 mg/m2. Other drug-related grade 2 or higher toxicities seen in more than one patient were pain, lymphopenia, fatigue, anemia, diarrhea, hypertension, hypotension, vomiting, visual disturbance, and dyspnea. One patient at 68 mg/m2 had improvement in liver metastases of adrenocortical carcinoma. Conclusion: CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.
Assessment of Pharmacodynamic Vascular Response in a Phase I Trial of Combretastatin A4 Phosphate
Authors: Anderson Helen L. , Yap Jeffrey T. , Miller Mathew P. , Robbins Adele , Jones Terry , Price Patricia M. 
Published: June 2003

Purpose: Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume. Patients and Methods: Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)–labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided. Results: PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, −49% at ≥ 52 mg/m2; P = .0010). Significant reductions were also seen in tumor blood volume (mean change, −15% at ≥ 52 mg/m2; P = .0070). Although by 24 hours there was tumor vascular recovery, for doses ≥ 52 mg/m2 the reduction in perfusion remained significant (P = .013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, −35%; P = .018), spleen blood volume (mean change, −18%; P = .022), kidney perfusion (mean change, −6%; P = .026), and kidney blood volume (mean change, −6%; P = .014). No significant changes were seen at 24 hours in spleen or kidney. Conclusion: CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.
Combretastatin A4 Phosphate Has Tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging
Authors: Galbraith Susan M. , Maxwell Ross J. , Lodge Martin A. , Tozer Gillian M. , Wilson John , Taylor N. Jane , Stirling J. James , Sena Luiza , Padhani Anwar R. , Rustin Gordon J.S. 
Published: June 2003

Purpose: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. Materials and Methods: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. Results: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at ≥ 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium–diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. Conclusion: CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.