bluuebunny/crossref_metadata_2025_split huggingface dataset:
MASS MATRICES AND EIGENSTATES FOR SCALARS/PSEUDOSCALARS: INDIRECT CP VIOLATION, MASS HIERARCHIES AND SYMMETRY BREAKING
Authors: MACHET B. 
Published: October 2002

I study indirect CP violation for neutral kaons, and extend it to large values of the CP-violating parameter (taken to be real). I show how and at which condition there can exist a continuous set of basis in which the kinetic and mass terms in the Lagrangian can be diagonalized simultaneously. An ambiguity results for the mass spectrum, which then depends on the basis. In particular, for fixed (positive) (mass)2 of the CP eigenstates [Formula: see text], and for certain ranges of values of the CP-violating parameter, a negative (mass)2 can arise in the CP-violating basis. Under certain conditions, even a small perturbation, lifting the ambiguity, can drastically affect the pattern of masses. These investigations extend in a natural way to indirect CP violation among a set of Higgs-like doublets. The C-odd commutator [Formula: see text], or its equivalent for Higgs multiplets, plays an important role. The condition for its vanishing and its consequences are among the main concerns of this work.
Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors
Authors: Liao Albert T. , Chien May B. , Shenoy Narmada , Mendel Dirk B. , McMahon Gerald , Cherrington Julie M. , London Cheryl A. 
Published: October 2002

Abstract
Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand binding. To identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking the function of mutant Kit, we evaluated 3 indolinones (SU11652, SU11654, and SU11655) that act as competitive inhibitors of adenosine triphosphate binding to several members of the split kinase family of RTKs, including VEGFR, FGFR, PDGFR, and Kit. Mast cell lines expressing either wild-type (WT) Kit, a point mutation in the JM domain, a tandem duplication in the JM domain, or a point mutation in the catalytic domain were used for these studies. All 3 indolinones inhibited phosphorylation of WT Kit in the presence of stem cell factor at concentrations as low as 0.01 μM. Autophosphorylation of both JM mutants was inhibited at 0.01 to 0.1 μM, resulting in cell cycle arrest within 24 hours, whereas autophosphorylation of the catalytic domain mutant was inhibited at 0.25 to 0.5 μM, resulting in cell death within 24 hours. poly(ADP-ribose) polymerase (PARP) cleavage was noted in all Kit mutant lines after indolinone treatment. In summary, SU11652, SU11654, and SU11655 are effective RTK inhibitors capable of disrupting the function of all forms of mutant Kit. Because the concentrations of drug necessary for receptor inhibition are readily achievable and nontoxic in vivo, these compounds may be useful in the treatment of spontaneous cancers expressing Kit mutations.
Pretargeting radioimmunotherapy of a murine model of adult T-cell leukemia with the α-emitting radionuclide, bismuth 213
Authors: Zhang Meili , Yao Zhengsheng , Garmestani Kayhan , Axworthy Donald B. , Zhang Zhuo , Mallett Robert W. , Theodore Louis J. , Goldman Carolyn K. , Brechbiel Martin W. , Carrasquillo Jorge A. , Waldmann Thomas A. 
Published: October 2002

AbstractWe used a pretargeting technique to treat a nonobese diabetic/severe combined immunodeficient murine model of human adult T-cell leukemia with an anti-Tac antibody-streptavidin (HAT-SA) conjugate, which recognizes CD25, followed by bismuth 213 (213Bi)-1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)- biotin. In the 3-step pretargeting radioimmunotherapy protocol, HAT-SA (140 or 400 μg) was administered intravenously (i.v.) to bind to the interleukin 2 receptor α (IL-2Rα; CD25)–expressing tumor cells. After 24 hours, 100 μg of a synthetic clearing agent was administered i.v. to remove unbound circulating HAT-SA conjugate from the circulation. Four hours later,213Bi–DOTA-biotin was administered i.v. for therapy. Tumor growth was significantly inhibited in 3 trials by using 250 μCi (9.25 MBq) of 213Bi–DOTA-biotin with a pretargeting technique as monitored by serum levels of soluble IL-2Rα and/or human β-2-microglobulin (P &lt; .05, t test) and by survival of tumor-bearing mice in the treatment groups (P &lt; .02, log rank test) as compared with the control groups. No prolongation of survival was observed with a nonspecific antibody-SA conjugate or in the absence of the radionuclide. Additionally, no prolongation of survival resulted from administration of 213Bi directly linked to intact HAT. Furthermore, there was no prolongation of survival when the β-emitting radionuclide yttrium 90 instead of the α-emitting radionuclide213Bi was used. The pretargeting approach with213Bi inhibited tumor growth more effectively than did immunotherapy with unmodified HAT. The best results were obtained with combination therapy that involved 213Bi–DOTA-biotin with a pretargeting technique supplemented by 4 weekly doses of HAT. The findings of this study support the use of this combination approach in a clinical trial in patients with IL-2Rα–expressing leukemias.
Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti–tumor necrosis factor-α antibody therapy
Authors: Papadaki Helen A. , Kritikos Heraklis D. , Valatas Vasilis , Boumpas Dimitrios T. , Eliopoulos George D. 
Published: October 2002

Abstract
Circumstantial evidence has implicated tumor necrosis factor α (TNF-α) in the pathogenesis of anemia of chronic disease (ACD) in rheumatoid arthritis (RA). We investigated the role of TNF-α in erythropoiesis of patients with active RA (n = 40) and the effect of anti–TNF-α antibody administration (cA2). Patients with RA had lower numbers of CD34+/CD71+ and CD36−/glycophorin A+ (glycoA+) bone marrow (BM) cells and increased proportions of apoptotic cells within the CD34+/CD71+ and CD36+/glycoA+ cell compartments, compared to healthy controls (n = 24). Erythroid burst-forming units (BFU-Es) obtained by BM mononuclear or purified CD34+ cells were significantly lower in RA patients compared to controls. These abnormalities were more pronounced among patients with ACD. Increased TNF-α levels in patient long-term BM culture supernatants inversely correlated with BFU-Es and hemoglobin levels and positively with the percentage of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells. Following cA2 therapy, a normalization was documented in the number of CD34+/CD71+ and CD36−/glycoA+ cells, the number of BFU-Es, and the proportion of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells, which was associated with a significant increase in hemoglobin levels compared to baseline. Recovery from anemia was more prominent in patients with ACD. The exogenous addition of an anti–TNF-α antibody in the cultures increased BFU-E number in patients prior to cA2 treatment but not after treatment, further substantiating the inhibitory role of TNF-α on patients' erythropoiesis. We conclude that TNF-α–mediated apoptotic depletion of BM erythroid cells may account for ACD in RA and that cA2 administration may ameliorate ACD in these patients by down-regulating the apoptotic mechanisms involved in erythropoiesis.
Heterozygous PU.1 mutations are associated with acute myeloid leukemia
Authors: Mueller Beatrice U. , Pabst Thomas , Osato Motomi , Asou Norio , Johansen Lisa M. , Minden Mark D. , Behre Gerhard , Hiddemann Wolfgang , Ito Yoshiaki , Tenen Daniel G. 
Published: October 2002

AbstractThe transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1−/− mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. We identified 10 mutant alleles of the PU.1 gene in 9 of 126 AML patients. The PU.1 mutations comprised 5 deletions affecting the DNA-binding domain, and 5 point mutations in 1) the DNA-binding domain (2 patients), 2) the PEST domain (2 patients), and 3) the transactivation domain (one patient). DNA binding to and transactivation of the M-CSF receptor promoter, a direct PU.1 target gene, were deficient in the 7 PU.1 mutants that affected the DNA-binding domain. In addition, these mutations decreased the ability of PU.1 to synergize with PU.1-interacting proteins such as AML1 or c-Jun in the activation of PU.1 target genes. This is the first report of mutations in the PU.1 gene in human neoplasia and suggests that disruption of PU.1 function contributes to the block in differentiation found in AML patients.
Association of CD34 cell dose with hematopoietic recovery, infections, and other outcomes after HLA-identical sibling bone marrow transplantation
Authors: Bittencourt Henrique , Rocha Vanderson , Chevret Sylvie , Socié Gérard , Espérou Hélène , Devergie Agnès , Dal Cortivo Liliane , Marolleau Jean-Pierre , Garnier Federico , Ribaud Patricia , Gluckman Eliane 
Published: October 2002

Abstract
Although CD34 cell dose is known to influence outcome of peripheral stem cell– and/or T-cell–depleted transplantation, such data on unmanipulated marrow transplantation are scarce. To study the influence of CD34+ cell dose on hematopoietic reconstitution and incidence of infections after bone marrow transplantation, we retrospectively analyzed 212 patients from January 1994 to August 1999 who received a transplant of an unmanipulated graft from an HLA-identical sibling donor. Median age was 31 years; 176 patients had hematologic malignancies. Acute graft-versus-host disease prophylaxis consisted mainly in cyclosporin associated with methotrexate (n = 174). Median number of bone marrow nucleated cells and CD34+ cells infused were 2.4 × 108/kg and 3.7 × 106/kg, respectively. A CD34+ cell dose of 3 × 106/kg or more significantly influenced neutrophil (hazard ratio [HR] = 1.37, P = .04), monocyte (HR = 1.47, P = .02), lymphocyte (HR = 1.70, P = .003), erythrocyte (HR = 1.77, P = .0002), and platelet (HR = 1.98,P = .00008) recoveries. CD34+ cell dose also influenced the incidence of secondary neutropenia (HR = 0.60,P = .05). Bacterial and viral infections were not influenced by CD34 cell dose, whereas it influenced the incidence of fungal infections (HR = 0.41, P = .008). Estimated 180-day transplantation-related mortality (TRM) and 5-year survival were 25% and 56%, respectively, and both were highly affected by CD34+ cell dose (HR = 0.55, P = .006 and HR = 0.54, P = .03, respectively). Five-year survival and 180-day TRM were, respectively, 64% and 19% for patients receiving a CD34+ cell dose of 3 × 106/kg or more and 40% and 37% for the remainders. In conclusion a CD34+ cell dose of 3 × 106/kg or more improved all hematopoietic recoveries, decreased the incidence of fungal infections and TRM, and improved overall survival.
HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning
Authors: Bergeron Raymond J. , Wiegand Jan , Brittenham Gary M. 
Published: October 2002

AbstractWe have continued the preclinical evaluation of the efficacy and safety of the hexadentate phenolic aminocarboxylate iron chelatorN, N′-bis(2-hydroxybenzyl) ethylenediamine-N, N′-diacetic acid monosodium salt (NaHBED) for the treatment of both chronic transfusional iron overload and acute iron poisoning. We examined the effect of route of administration by giving equimolar amounts of NaHBED and deferoxamine (DFO) to Cebus apella monkeys as either a subcutaneous (SC) bolus or a 20-minute intravenous (IV) infusion. By both routes, NaHBED was consistently about twice as efficient as DFO in producing iron excretion. For both chelators at a dose of 150 μmol/kg, SC was more efficient than IV administration. The biochemical and histopathologic effects of NaHBED administration were assessed. No systemic toxicity was found after either IV administration once daily for 14 days to iron-loaded dogs or after SC administration every other day for 14 days to dogs without iron overload. Evidence of local irritation was found at some SC injection sites. When the NaHBED concentration was reduced to 15% or less in a volume comparable to a clinically useful one, no local irritation was found with SC administration in rats. Because treatment of acute iron poisoning may require rapid chelator infusion, we compared the effects of IV bolus administration of the compounds to normotensive rats. Administration of DFO produced a prompt, prolonged drop in blood pressure and acceleration of heart rate; NaHBED had little effect. NaHBED may provide an alternative to DFO for the treatment of both chronic transfusional iron overload and of acute iron poisoning.
Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission
Authors: Bunin Nancy , Carston Michael , Wall Donna , Adams Roberta , Casper James , Kamani Naynesh , King Roberta ,   the National Marrow Donor Program Working Group
Published: October 2002

Abstract
Allogeneic bone marrow transplantation (BMT) may be curative for more patients than chemotherapy for the child with relapsed acute lymphoblastic leukemia. This study reviewed the outcomes of 363 children with acute lymphoblastic leukemia in second remission who received unrelated donor BMT from 1988 to 2000 in order to define prognostic factors that affect leukemia-free survival (LFS). Median patient age was 9 years (range, 0-19 years), and median follow-up 29 was months (range, 0-125 months). The median duration of first remission was 24 months (range, 0-109 months). Prognostic factors, including age, duration of first remission, HLA matching, and graft-versus-host (GVH) disease, were analyzed using both univariate and multivariate analyses. Overall survival was 38%, and LFS was 36% at 5 years. LFS was significantly worse for patients 15 years or older (log-rank, P = .009). HLA matching was associated with improved LFS. Acute GVH disease developed in 71%, with 29% having grades III-IV. The incidence of chronic GVH disease was 39% for patients who survived more than 80 days and was significantly higher for female patients receiving marrow from female donors (P = .0009). Transplantation-related mortality was 42% and was associated with HLA mismatches, age 15 years and older, and first remission less than 12 months. The 5-year estimate for relapse was 22%, with first remission at least 6 months associated with a lower risk. Results of unrelated donor BMT appear similar to multi-institutional studies of matched related donor BMT, and this approach appears to be curative for many patients. However, innovative approaches are needed for patients with initial remissions of less than 6 months and for older teenagers.
Vitamin C inhibits granulocyte macrophage–colony-stimulating factor–induced signaling pathways
Authors: Cárcamo Juan M. , Bórquez-Ojeda Oriana , Golde David W. 
Published: October 2002

AbstractVitamin C is present in the cytosol as ascorbic acid, functioning primarily as a cofactor for enzymatic reactions and as an antioxidant to scavenge free radicals. Human granulocyte macrophage–colony-stimulating factor (GM-CSF) induces an increase in reactive oxygen species (ROS) and uses ROS for some signaling functions. We therefore investigated the effect of vitamin C on GM-CSF–mediated responses. Loading U937 cells with vitamin C decreased intracellular levels of ROS and inhibited the production of ROS induced by GM-CSF. Vitamin C suppressed GM-CSF–dependent phosphorylation of the signal transducer and activator of transcription 5 (Stat-5) and mitogen-activated protein (MAP) kinase (Erk1 and Erk2) in a dose-dependent manner as was phosphorylation of MAP kinase induced by both interleukin 3 (IL-3) and GM-CSF in HL-60 cells. In 293T cells transfected with alpha and beta GM-CSF receptor subunits (αGMR and βGMR), GM-CSF–induced phosphorylation of βGMR and Jak-2 activation was suppressed by vitamin C loading. GM-CSF–mediated transcriptional activation of a luciferase reporter construct containing STAT-binding sites was also inhibited by vitamin C. These results substantiate the importance of ROS in GM-CSF signaling and indicate a role for vitamin C in downmodulating GM-CSF signaling responses. Our findings point to vitamin C as a regulator of cytokine redox-signal transduction in host defense cells and a possible role in controlling inflammatory responses.
Diagnostic and Prognostic Value of [18F]Fluorodeoxyglucose Positron Emission Tomography for Recurrent Head and Neck Squamous Cell Carcinoma
Authors: Wong R. J. , Lin D. T. , Schöder H. , Patel S. G. , Gonen M. , Wolden S. , Pfister D. G. , Shah J. P. , Larson S. M. , Kraus D. H. 
Published: October 2002

PURPOSE: Patients with recurrent head and neck squamous cell carcinoma (HNSCC) present a diagnostic and therapeutic challenge. We evaluated the diagnostic accuracy and prognostic value of [18F]fluorodeoxyglucose positron emission tomography (PET) in this patient population. PATIENTS AND METHODS: We performed a retrospective review of 143 patients with previously treated HNSCC who underwent 181 PET scans at our institution from May 1996 through April 2001 to detect recurrent disease. Disease recurrence within 6 months was used as the gold standard for assessing true disease status at PET. RESULTS: With equivocal sites considered positive, the sensitivity and specificity of PET for detecting recurrence overall were 96% and 72%, respectively. PET was highly sensitive and specific at regional and distant sites. At local sites, sensitivity was high, but specificity was lower because of false-positive findings. One fifth of all false-positive PET scans occurred at sites of known inflammation or infection. The area under the curve for a receiver operator characteristic curve on the basis of standardized uptake value (SUV) was 0.882 ± 0.025. PET interpretation, SUV, and physical examination were independent predictors of relapse-free and overall survival in a time-dependent, multivariate proportional hazards model. An increase in SUV by one unit increased the relative risk (RR) of relapse by 11% and the RR of death by 14%. A positive PET interpretation increased the RR of relapse by four-fold and the RR of death by seven-fold. CONCLUSION: PET was a highly sensitive method of detecting recurrent HNSCC and provided important prognostic information for relapse-free and overall survival.
Effects on Quality of Life of Combined Trastuzumab and Chemotherapy in Women With Metastatic Breast Cancer
Authors: Osoba David , Slamon Dennis J. , Burchmore Michael , Murphy Maureen 
Published: October 2002

PURPOSE: The study was designed to compare the effects of treatment with a combination of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and chemotherapy versus chemotherapy alone on health-related quality of life (HRQL) in patients with HER-2/neu overexpressing, metastatic breast cancer. PATIENTS AND METHODS: A sample of 400 patients, not previously treated for metastatic disease and randomized to receive either trastuzumab plus chemotherapy (208 patients) or chemotherapy alone (192 patients), completed the European Organization for Research and Treatment Care Quality of Life Questionnaire at baseline and on at least one subsequent occasion at 8, 20, 32, 44, and 56 weeks. HRQL improvement or worsening was defined as a ≥ 10-point change (range, 0 to 100 points) in the scores of six preselected domains (global quality of life [QOL], physical, role, social, and emotional functioning, and fatigue). Stable HRQL was defined as a change of less than 10. A Bonferroni correction was applied for multiple testing. RESULTS: After completion of chemotherapy, patients treated with trastuzumab and chemotherapy reported significant improvement in fatigue (P < .05) as compared with their baseline scores. Higher proportions of patients receiving the combined therapy achieved improvement in global QOL (P < .05) than did patients treated with chemotherapy alone. Higher proportions of the combined therapy group also achieved improvement in physical and role functioning and in fatigue as compared with the chemotherapy group, but the differences were not statistically significant. There were no differences in the proportions of patients in the two groups that reported worsening. CONCLUSION: Statistically significantly higher proportions of patients treated with a combination of trastuzumab and chemotherapy reported improved global QOL than did patients treated by chemotherapy alone.
Oxaliplatin in Combination With Protracted-Infusion Fluorouracil and Radiation: Report of a Clinical Trial for Patients With Esophageal Cancer
Authors: Khushalani Nikhil I. , Leichman Cynthia Gail , Proulx Gary , Nava Hector , Bodnar Lisa , Klippenstein Donald , Litwin Alan , Smith Judy , Nava Enriqueta , Pendyala Lakshmi , Smith Patrick , Greco William , Berdzik Joanne , Douglass Harold , Leichman Lawrence 
Published: October 2002

PURPOSE: To identify a dose and schedule of oxaliplatin (OXP) to be safely administered in combination with protracted-infusion (PI) fluorouracil (5-FU) and external-beam radiation therapy (XRT) for patients with primary esophageal carcinoma (EC). PATIENTS AND METHODS: Eligibility included therapeutically naïve EC patients with clinical disease stages II, III, or IV. Initial doses and schedules for cycle 1 consisted of OXP 85 mg/m2 on days 1, 15, and 29; PI 5-FU 180 mg/m2 for 24 hours for 35 days; and XRT 1.8 Gy in 28 fractions starting on day 8. At completion of cycle 1, eligible patients could undergo an operation or begin cycle 2 without XRT. Postoperative patients were eligible for cycle 2. Stage IV patients were allowed three cycles in the absence of disease progression. OXP and 5-FU increases were based on dose-limiting toxicity (DLT) encountered in cohorts of three consecutive patients. RESULTS: Thirty-eight eligible patients received therapy: 22 noninvasively staged as IV and 16 noninvasively staged as II and III. Thirty-six patients completed cycle 1, 29 patients started cycle 2, and 24 patients completed cycle 2. The combined-modality therapy was well tolerated, but DLT prevented OXP and 5-FU escalation. No grade 4 hematologic toxicity was noted. Eleven grade 3 and two grade 4 clinical toxicities were noted in eight patients. After cycle 1, 29 patients (81%) had no cancer in the esophageal mucosa. Thirteen patients underwent an operation with intent to resect the esophagus; five patients (38%) exhibited pathologic complete responses. CONCLUSION: OXP 85 mg/m2 on days 1, 15, and 29 administered with PI 5-FU and XRT is safe, tolerable, and seems effective against primary EC. The role of OXP in multimodality regimens against EC deserves further evaluation.