bluuebunny/crossref_metadata_2025 huggingface dataset:
ORTHOGONAL DECOMPOSITIONS FOR LÉVY PROCESSES WITH AN APPLICATION TO THE GAMMA, PASCAL, AND MEIXNER PROCESSES
Authors: LYTVYNOV EUGENE
Published: April 2003

It is well known that between all processes with independent increments, essentially only the Brownian motion and the Poisson process possess the chaotic representation property (CRP). Thus, a natural question appears: What is an appropriate analog of the CRP in the case of a general Lévy process. At least three approaches are possible here. The first one, due to Itô, uses the CRP of the Brownian motion and the Poisson process, as well as the representation of a Lévy process through those processes. The second approach, due to Nualart and Schoutens, consists of representing any square-integrable random variable as a sum of multiple stochastic integrals constructed with respect to a family of orthogonalized centered power jumps processes. The third approach, never applied before to the Lévy processes, uses the idea of orthogonalization of polynomials with respect to a probability measure defined on the dual of a nuclear space. The main aims of this paper are to develop the three approaches in the case of a general (ℝ-valued) Lévy process on a Riemannian manifold and (what is more important) to understand a relationship between these approaches. We apply the obtained results to the gamma, Pascal, and Meixner processes, in which case the analysis related to the orthogonalized polynomials becomes essentially simpler and richer than in the general case.
THE CONSTRUCTION OF THE CHAOTIC REPRESENTATION FOR THE GAMMA FIELD
Authors: BEREZANSKY YURIJ M. , MIERZEJEWSKI DMYTRO A.
Published: April 2003

This paper is devoted to the proof of chaotic representation for Gamma field and the corresponding stochastic process. It is known that a direct generalization of the chaotic representation connected with a Gamma process is impossible. Our construction is different from the classical one: for the components of our decomposition we have the representation by a many-dimensional stochastic integral (some of these components have the classical form of the multiple stochastic integral).
FEYNMAN–KAC REPRESENTATION AND MARKOV PROPERTY OF SEMIGROUPS GENERATED BY NONCOMMUTATIVE ELLIPTIC OPERATORS
Authors: BAHN CHANGSOO , PARK YONG MOON
Published: April 2003

We construct Markovian semigroups generated by noncommutative elliptic operators on a von Neumann algebra. We first introduce a general framework of quantum Feynman–Kac formula in terms of unitary evolutions and multipliers, and then apply the general result to our problem. We construct multipliers which are determined by operator valued stochastic differential equations and satisfy cocycle relations with respect to a randomized flow on a von Neumann algebra. Our works are greatly influenced by that of Lindsay and Sinha.10 In order to ensure Markov property of the semigroups, we modify the method employed by Lindsay and Sinha.10
SCALING LIMIT FOR GIBBS STATES OF JOHNSON GRAPHS AND RESULTING MEIXNER CLASSES
Authors: HORA AKIHITO
Published: April 2003

Asymptotic behavior of spectral distribution of the adjacency operator on the Johnson graph with respect to the Gibbs state is discussed in infinite volume and zero temperature limit. The limit picture is drawn on the one-mode interacting Fock space associated with Meixner polynomials.
FRACTIONAL WHITE NOISE CALCULUS AND APPLICATIONS TO FINANCE
Authors: HU YAOZHONG , ØKSENDAL BERNT
Published: April 2003

The purpose of this paper is to develop a fractional white noise calculus and to apply this to markets modeled by (Wick–) Itô type of stochastic differential equations driven by fractional Brownian motion BH(t); 1/2 < H < 1.

We show that if we use an Itô type of stochastic integration with respect to BH(t) (as developed in Ref. 8), then the corresponding Itô fractional Black–Scholes market has no arbitrage, contrary to the situation when the pathwise integration is used. Moreover, we prove that our Itô fractional Black–Scholes market is complete and we compute explicitly the price and replicating portfolio of a European option in this market. The results are compared to the classical results based on standard Brownian motion B(t).
In Vivo Gene Transfer of the O
2
-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats
Authors: Pozeg Zlatko I. , Michelakis Evangelos D. , McMurtry M. Sean , Thébaud Bernard , Wu Xi-Chen , Dyck Jason R.B. , Hashimoto Kyoko , Wang Shaohua , Moudgil Rohit , Harry Gwyneth , Sultanian Richard , Koshal Arvind , Archer Stephen L.
Published: April 2003

Background—

Alveolar hypoxia acutely elicits pulmonary vasoconstriction (HPV). Chronic hypoxia (CH), despite attenuating HPV, causes pulmonary hypertension (CH-PHT). HPV results, in part, from inhibition of O
2
-sensitive, voltage-gated potassium channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). CH decreases Kv channel current/expression and depolarizes and causes Ca
2+
overload in PASMCs. We hypothesize that Kv gene transfer would normalize the pulmonary circulation (restore HPV and reduce CH-PHT), despite ongoing hypoxia.

Methods and Results—

Adult male Sprague-Dawley rats were exposed to normoxia or CH for 3 to 4 weeks and then nebulized orotracheally with saline or adenovirus (Ad5) carrying genes for the reporter, green fluorescent protein reporter±human Kv1.5 (cloned from normal PA). HPV was assessed in isolated lungs. Hemodynamics, including Fick and thermodilution cardiac output, were measured in vivo 3 and 14 days after gene therapy by use of micromanometer-tipped catheters. Transgene expression, measured by quantitative RT-PCR, was confined to the lung, persisted for 2 to 3 weeks, and did not alter endogenous Kv1.5 levels. Ad5-Kv1.5 caused no mortality or morbidity, except for sporadic, mild elevation of liver transaminases. Ad5-Kv1.5 restored the O
2
-sensitive K
+
current of PASMCs, normalized HPV, and reduced pulmonary vascular resistance. Pulmonary vascular resistance decreased at day 2 because of increased cardiac output, and remained reduced at day 14, at which time there was concomitant regression of right ventricular hypertrophy and PA medial hypertrophy.

Conclusions—

Kv1.5 is an important O
2
-sensitive channel and potential therapeutic target in PHT. Kv1.5 gene therapy restores HPV and improves PHT. This is, to the best of our knowledge, the first example of K
+
channel gene therapy for a vascular disease.
Reverse Structural and Gap-Junctional Remodeling After Prolonged Atrial Fibrillation in the Goat
Authors: Ausma Jannie , van der Velden Huub M.W. , Lenders Marie-Hélène , van Ankeren Erwin P. , Jongsma Habo J. , Ramaekers Frans C.S. , Borgers Marcel , Allessie Maurits A.
Published: April 2003

Background—

Prolonged atrial fibrillation (AF) results in electrical, structural, and gap-junctional remodeling. We examined the reversibility of the changes in (ultra)structure and gap junctions.

Methods and Results—

Four groups of goats were used: (1) sinus rhythm (SR), (2) 4 months’ AF (4 mo AF), (3) 2 months’ SR after 4 mo AF (2 mo post-AF), and (4) 4 months’ SR after 4 mo AF (4 mo post-AF). Atria were characterized electrophysiologically, (ultra)structure was studied by light and electron microscopy, and structural and gap-junctional protein expression was studied by immunohistochemistry or Western blotting. The atrial effective refractory period had completely returned to normal values 2 mo post-AF. Induced AF episodes still lasted for minutes at 2 and 4 mo post-AF, compared with seconds in the SR group. Structural abnormalities were still present at 2 and 4 mo post-AF, although to a lesser extent. The increased atrial myocyte diameter was back to normal at 4 mo post-AF. The number of myocytes with severe myolysis had almost normalized 4 mo post-AF, whereas myocytes with mild myolysis remained significantly increased. Extracellular matrix area fraction after 4 mo AF was similar to SR. However, the extracellular matrix fraction per myocyte had increased after 4 mo AF and remained higher post-AF. Changes in expression of structural proteins were partially restored post-AF. The reduction of connexin 40 that was observed during AF was completely reversed at 4 mo post-AF.

Conclusions—

Recovery from structural remodeling after 4 mo AF is a slow process and is still incomplete 4 mo post-AF. Several months post-AF, the duration of AF episodes is still prolonged (minutes).
C-Reactive Protein and the Future Risk of Thromboembolic Stroke in Healthy Men
Authors: Curb J. David , Abbott Robert D. , Rodriguez Beatriz L. , Sakkinen Pamela , Popper Jordan S. , Yano Katsuhiko , Tracy Russell P.
Published: April 2003

Background—

Evidence suggests that C-reactive protein (CRP) is related to thromboembolic (TE) stroke. Whether associations are altered in the presence of other risk factors is unclear. The purpose of this study was to additionally assess the relation between CRP and TE stroke.

Methods and Results—

On the basis of 20 years of follow-up after CRP measurement, 259 cases of TE stroke were identified and compared with 1348 controls. Subjects were aged 48 to 70 years when CRP was measured. Levels of CRP were positively associated with TE stroke throughout the 20 years of follow-up. Although associations were modest within 5 years of CRP measurement, the odds of stroke in the top versus bottom CRP quartile increased over time to a 3.8-fold excess by 10 to 15 years into follow-up (
P
<0.001). For men without hypertension or diabetes, the overall corresponding odds were 1.6 to 1.7 (
P
<0.05). In men ≤55 years of age, the odds increased to a 3-fold excess (
P
=0.006), and in nonsmokers, there was a 5.8-fold excess (
P
<0.001). Associations in past and current smokers, in men >55 years of age, and in those with hypertension or diabetes were not significant.

Conclusions—

Findings suggest that elevated CRP in middle adulthood and in men with healthier risk factor profiles may be important as a risk factor for TE stroke. Use of CRP levels as a clinical screen to identify an increased risk of cardiovascular disease in otherwise healthy men warrants consideration.
Elevated Serum Levels of the CXCR3 Chemokine ITAC Are Associated With the Development of Transplant Coronary Artery Disease
Authors: Kao John , Kobashigawa Jon , Fishbein Michael C. , MacLellan W. Robb , Burdick Marie D. , Belperio John A. , Strieter Robert M.
Published: April 2003

Background—

Human and animal studies of acute allograft rejection have implicated CCR5 and CXCR3 chemokines as causative factors. However these chemokines have not been assessed in transplant coronary artery disease (TCAD).

Methods and Results—

Serum levels of chemokines were measured by ELISA. Levels of ITAC/CXCL11 were found to be elevated in patients with severe TCAD compared with long-term survivors of transplantation without TCAD and with healthy volunteers who had not undergone transplantation (1.476±0.274 ng/mL, 0.926±0.466 ng/mL, and 0.741±0.321 ng/mL, respectively;
P
<0.05 for all comparisons to TCAD group). Immunohistochemical localization confirmed the presence of CXCR3
+
mononuclear cells within lesions and the presence of the ligand, ITAC/CXCL11, on the surface of endothelial cells associated with TCAD.

Conclusions—

Elevated peripheral blood levels of the CXCR3 chemokine ITAC/CXCL11 are associated with severe TCAD and may serve as a marker for patients at increased risk for the development of this disease. Immunohistochemical localization of the CXCR3 chemokine ligand ITAC/CXCL11 on the endothelial surface of TCAD lesions with underlying infiltration of inflammatory mononuclear cells expressing CXCR3 suggests a causative role for this chemokine in the development of TCAD. The present study is one of the first to demonstrate a role for ITAC/CXCL11 in this disease.
Specific transgene expression in human and mouse CD4+cells using lentiviral vectors with regulatory sequences from theCD4 gene
Authors: Marodon Gilles , Mouly Enguerran , Blair Emma J. , Frisen Charlotte , Lemoine François M. , Klatzmann David
Published: April 2003

Achieving cell-specific expression of a therapeutic transgene by gene transfer vectors represents a major goal for gene therapy. To achieve specific expression of a transgene in CD4+ cells, we have generated lentiviral vectors expressing the enhanced green fluorescent protein (eGFP) reporter gene under the control of regulatory sequences derived from theCD4 gene—a minimal promoter and the proximal enhancer, with or without the silencer. Both lentiviral vectors could be produced at high titers (more than 107 infectious particles per milliliter) and were used to transduce healthy murine hematopoietic stem cells (HSCs). On reconstitution of RAG-2–deficient mice with transduced HSCs, the specific vectors were efficiently expressed in T cells, minimally expressed in B cells, and not expressed in immature cells of the bone marrow. Addition of the CD4gene-silencing element in the vector regulatory sequences led to further restriction of eGFP expression into CD4+ T cells in reconstituted mice and in ex vivo–transduced human T cells. Non–T CD4+ dendritic and macrophage cells derived from human CD34+ cells in vitro expressed the transgene of the specific vectors, albeit at lower levels than CD4+ T cells. Altogether, we have generated lentiviral vectors that allow specific targeting of transgene expression to CD4+ cells after differentiation of transduced mice HSCs and human mature T cells. Ultimately, these vectors may prove useful for in situ injections for in vivo gene therapy of HIV infection or genetic immunodeficiencies.
Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia
Authors: Matsushima Takafumi , Handa Hiroshi , Yokohama Akihiko , Nagasaki Jun , Koiso Hiromi , Kin Yoshitora , Tanaka Yoko , Sakura Tohru , Tsukamoto Norifumi , Karasawa Masamitsu , Itoh Katsuhiko , Hirabayashi Hisami , Sawamura Morio , Shinonome Shogo , Shimano Shun-ichi , Miyawaki Shuichi , Nojima Yoshihisa , Murakami Hirokazu
Published: April 2003

By retrospectively analyzing 288 patients with de novo myelodysplastic syndrome (MDS), we sought to determine the prevalence and clinical characteristics of bone marrow eosinophilia and basophilia that were detected at presentation. Bone marrow eosinophilia and basophilia were defined as a differential count of each cell type exceeding 5.0% and 1.0%, respectively. Of 288 patients with MDS, 36 (12.5%) fulfilled this criterion for bone marrow eosinophilia (MDS-Eos); 34 patients (11.8%) showed basophilia (MDS-Bas), and 11 (3.8%) satisfied both criteria (MDS-EosBas). The remaining 229 patients had neither eosinophilia nor basophilia in their bone marrow (MDS−/−) at presentation. Cytogenetic analysis was carried out on unstimulated bone marrow cells obtained from 264 patients. When the cytogenetic categorization of the IPSS (International Prognostic Scoring System) for MDS was applied, significantly higher numbers of MDS-Eos and MDS-Bas patients had chromosomal abnormalities carrying intermediate or poor prognosis, compared with the MDS−/− patients. Specific chromosomal abnormalities and complex karyotypes were associated with MDS-Eos and/or MDS-Bas. In accordance with these results, the overall survival rate was significantly lower, and the evolution to acute myelogenous leukemia (AML) occurred more frequently in the MDS-Eos and MDS-Bas than in the MDS−/− patients. Multivariate analysis demonstrated that bone marrow basophilia was an independent risk factor for evolution to AML. Our study indicates that bone marrow eosinophilia and basophilia in patients with MDS predict a poorer prognosis.
Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies
Authors: Cornely Oliver A. , Ullmann Andrew J. , Karthaus Meinolf
Published: April 2003

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/μL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.
Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-γ1 and Itk activity
Authors: Kang Mi-Ae , Yun Su-Young , Won Jonghwa
Published: April 2003

Rosmarinic acid (RosA) is a hydroxylated compound frequently found in herbal plants and is mostly responsible for anti-inflammatory and antioxidative activity. Previously, we observed that RosA inhibited T-cell antigen receptor (TCR)– induced interleukin 2 (IL-2) expression and subsequent T-cell proliferation in vitro. In this study, we investigated in detail inhibitory mechanism of RosA on TCR signaling, which ultimately activates IL-2 promoter by activating transcription factors, such as nuclear factor of activated T cells (NF-AT) and activating protein-1 (AP-1). Interestingly, RosA inhibited NF-AT activation but not AP-1, suggesting that RosA inhibits Ca2+- dependent signaling pathways only. Signaling events upstream of NF-AT activation, such as the generation of inositol 1,4,5-triphosphate and Ca2+ mobilization, and tyrosine phosphorylation of phospholipase C-γ1 (PLC-γ1) were strongly inhibited by RosA. Tyrosine phosphorylation of PLC-γ1 is largely dependent on 3 kinds of protein tyrosine kinases (PTKs), ie, Lck, ZAP-70, and Itk. We found that RosA efficiently inhibited TCR-induced tyrosine phosphorylation and subsequent activation of Itk but did not inhibit Lck or ZAP-70. ZAP-70–dependent signaling pathways such as the tyrosine phosphorylation of LAT and SLP-76 and serine/threonine phosphorylation of mitogen-activated protein kinases (MAPKs) were intact in the presence of RosA, confirming that RosA suppresses TCR signaling in a ZAP-70–independent manner. Therefore, we conclude that RosA inhibits TCR signaling leading to Ca2+ mobilization and NF-AT activation by blocking membrane-proximal events, specifically, the tyrosine phosphorylation of inducible T cells kinase (Itk) and PLC-γ1.
Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide
Authors: Krampera Mauro , Glennie Sarah , Dyson Julian , Scott Diane , Laylor Ruthline , Simpson Elizabeth , Dazzi Francesco
Published: April 2003

Mesenchymal stem cells (MSCs) have been recently shown to inhibit T-cell proliferation to polyclonal stimuli. We characterized the effect of MSCs of bone marrow origin on the T-cell response of naive and memory T cells to their cognate antigenic epitopes. The immune response to murine male transplantation antigens, HY, was selected because the peptide identity and major histocompatibility complex (MHC) restriction of the immunodominant epitopes are known. C57BL/6 female mice immunized with male cells were the source of memory T cells, whereas C6 mice transgenic for HY-specific T-cell receptor provided naive T cells. Responder cells were stimulated in vitro with male spleen cells or HY peptides in the presence or absence of MSCs. MSCs inhibited HY-specific naive and memory T cells in a dose-dependent fashion and affected cell proliferation, cytotoxicity, and the number of interferon γ (IFN-γ)–producing HY peptide-specific T cells. However, the MSC inhibitory effect did not selectively target antigen-reactive T cells. When MSCs were added to the T-cell cultures in a Transwell system or MSCs were replaced by MSC culture supernatant, the inhibitory activity was abrogated. T-cell reactivity was also restored if MSCs were removed from the cultures. The expression of MHC molecules and the presence in culture of antigen-presenting cells (APCs) or of CD4+/CD25+ regulatory T cells were not required for MSCs to inhibit. We conclude that MSCs inhibit naive and memory T-cell responses to their cognate antigens. Overall our data suggest that MSCs physically hinder T cells from the contact with APCs in a noncognate fashion.
Iron transport by Nramp2/DMT1: pH regulation of transport by 2 histidines in transmembrane domain 6
Authors: Lam-Yuk-Tseung Steven , Govoni Gregory , Forbes John , Gros Philippe
Published: April 2003

Mutations at natural resistance-associated macrophage protein 1(Nramp1) impair phagocyte function and cause susceptibility to infections while mutations at Nramp2 (divalent metal transporter 1 [DMT1]) affect iron homeostasis and cause severe microcytic anemia. Structure-function relationships in the Nramp superfamily were studied by mutagenesis, followed by functional characterization in yeast and in mammalian cells. These studies identify 3 negatively charged and highly conserved residues in transmembrane domains (TM) 1, 4, and 7 as essential for cation transport by Nramp2/DMT1. The introduction of a charged residue (Gly185Arg) in TM4 found in the naturally occurring microcytic anemiamk (mouse) and Belgrade (rat) mutants is shown to cause a partial or complete loss of function in mammalian and yeast cells, respectively. A pair of mutation-sensitive and highly conserved histidines (His267, His272) was identified in TM6. Surprisingly, inactive His267 and His272 mutants could be rescued by lowering the pH of the transport assay. This indicates that His267/His272 are not directly involved in metal binding but, rather, play an important role in pH regulation of metal transport by Nramp proteins.
Relationships and distinctions in iron-regulatory networks responding to interrelated signals
Authors: Muckenthaler Martina , Richter Alexandra , Gunkel Niki , Riedel Dieter , Polycarpou-Schwarz Maria , Hentze Sabine , Falkenhahn Mechthild , Stremmel Wolfgang , Ansorge Wilhelm , Hentze Matthias W.
Published: April 2003

Specialized cDNA-based microarrays (IronChips) were developed to investigate complex physiological gene-regulatory patterns in iron metabolism. Approximately 115 human cDNAs were strategically selected to represent genes involved either in iron metabolism or in interlinked pathways (eg, oxidative stress, nitric oxide [NO] metabolism, or copper metabolism), and were immobilized on glass slides. HeLa cells were treated with iron donors or iron chelators, or were subjected to oxidative stress (H2O2) or NO (sodium nitroprusside). In addition, we generated a stable transgenic HeLa cell line expressing the HFE gene under an inducible promoter. Gene-response patterns were recorded for all of these interrelated experimental stimuli, and analyzed for common and distinct responses that define signal-specific regulatory patterns. The resulting regulatory patterns reveal and define degrees of relationship between distinct signals. Remarkably, the gene responses elicited by the altered expression of the hemochromatosis protein HFE and by pharmacological iron chelation exhibit the highest degree of relatedness, both for iron-regulatory protein (IRP) and non-IRP target genes. This finding suggests that HFE expression directly affects the intracellular chelatable iron pool in the transgenic cell line. Furthermore, cells treated with the iron donors hemin or ferric ammonium citrate display response patterns that permit the identification of the iron-loaded state in both cases, and the discrimination between the sources of iron loading. These findings also demonstrate the broad utility of gene-expression profiling with the IronChip to study iron metabolism and related human diseases.
SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo
Authors: O'Farrell Anne-Marie , Abrams Tinya J. , Yuen Helene A. , Ngai Theresa J. , Louie Sharianne G. , Yee Kevin W. H. , Wong Lily M. , Hong Weiru , Lee Leslie B. , Town Ajia , Smolich Beverly D. , Manning William C. , Murray Lesley J. , Heinrich Michael C. , Cherrington Julie M.
Published: April 2003

FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.
Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation
Authors: Bouscary Didier , Pene Frédéric , Claessens Yann-Erick , Muller Odile , Chrétien Stany , Fontenay-Roupie Michaëla , Gisselbrecht Sylvie , Mayeux Patrick , Lacombe Catherine
Published: April 2003

The production of red blood cells is tightly regulated by erythropoietin (Epo). The phosphoinositide 3–kinase (PI 3-kinase) pathway was previously shown to be activated in response to Epo. We studied the role of this pathway in the control of Epo-induced survival and proliferation of primary human erythroid progenitors. We show that phosphoinositide 3 (PI 3)–kinase associates with 4 tyrosine-phosphorylated proteins in primary human erythroid progenitors, namely insulin receptor substrate–2 (IRS2), Src homology 2 domain–containing inositol 5′-phosphatase (SHIP), Grb2-associated binder–1 (Gab1), and the Epo receptor (EpoR). Using different in vitro systems, we demonstrate that 3 alternative pathways independently lead to Epo-induced activation of PI 3-kinase and phosphorylation of its downstream effectors, Akt, FKHRL1, and P70S6 kinase: through direct association of PI 3-kinase with the last tyrosine residue (Tyr479) of the Epo receptor (EpoR), through recruitment and phosphorylation of Gab proteins via either Tyr343 or Tyr401 of the EpoR, or through phosphorylation of IRS2 adaptor protein. The mitogen-activated protein (MAP) kinase pathway was also activated by Epo in erythroid progenitors, but we found that this process is independent of PI 3-kinase activation. In erythroid progenitors, the functional role of PI 3-kinase was both to prevent apoptosis and to stimulate cell proliferation in response to Epo stimulation. Finally, our results show that PI 3-kinase–mediated proliferation of erythroid progenitors in response to Epo occurs mainly through modulation of the E3 ligase SCFSKP2, which, in turn, down-regulates p27Kip1 cyclin-dependent kinase (CDK) inhibitor via proteasome degradation.
Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies
Authors: Raschi Elena , Testoni Cinzia , Bosisio Daniela , Borghi Maria O. , Koike Takao , Mantovani Alberto , Meroni Pier Luigi
Published: April 2003

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPLs) and recurrent thrombosis or fetal loss. The thrombophilic state has been partially related to the induction of a proinflammatory and procoagulant endothelial cell (EC) phenotype induced by anti–β2-glycoprotein I (β2-GPI) antibodies that bind β2-GPI expressed on the EC surface. Anti–β2-GPI antibody binding has been shown to induce nuclear factor-κB (NF-κB) translocation leading to a proinflammatory EC phenotype similar to that elicited by interaction with microbial products (lipopolysaccharide [LPS]) and proinflammatory cytokines (interleukin 1β [IL-1β], tumor necrosis factor α [TNF-α]). However, the upstream signaling events are not characterized yet. To investigate the endothelial signaling cascade activated by anti–β2-GPI antibodies, we transiently cotransfected immortalized human microvascular endothelial cells (HMEC-1) with dominant-negative constructs of different components of the pathway (ΔTRAF2, ΔTRAF6, ΔMyD88) together with reporter genes (NF-κB luciferase and pCMV-β-galactosidase). Results showed that both human anti–β2-GPI IgM monoclonal antibodies as well as polyclonal affinity-purified anti–β2-GPI IgG display a signaling cascade comparable to that activated by LPS or IL-1. ΔTRAF6 and ΔMyD88 significantly abrogate antibody-induced as well as IL-1– or LPS-induced NF-κB activation, whereas ΔTRAF2 (involved in NF-κB activation by TNF) does not affect it. Moreover, anti– β2-GPI antibodies and LPS followed the same time kinetic of IL-1 receptor–activated kinase (IRAK) phosphorylation, suggesting an involvement of the toll-like receptor (TLR) family. Our findings demonstrate that anti–β2-GPI antibodies react with their antigen likely associated to a member of the TLR/IL-1 receptor family on the EC surface and directly induce activation.
Opposing effects of PML and PML/RARα on STAT3 activity
Authors: Kawasaki Akira , Matsumura Itaru , Kataoka Yoshihisa , Takigawa Eri , Nakajima Koichi , Kanakura Yuzuru
Published: April 2003

Promyelocytic leukemia protein PML acts as a tumor suppressor, whereas its chimeric mutant promyelocytic leukemia/retinoic acid receptorα (PML/RARα) causes acute promyelocytic leukemia (APL). Because PML has been shown to form transcription-regulatory complexes with various molecules, we speculated that PML and/or PML/RARα might affect signal transducer and activator of transcription 3 (STAT3) activity, which plays a crucial role in granulocyte colony-stimulating factor (G-CSF)–induced growth and survival of myeloid cells. In luciferase assays, PML inhibited STAT3 activity in NIH3T3, 293T, HepG2, and 32D cells. PML formed a complex with STAT3 through B-box and COOH terminal regions in vitro and in vivo, thereby inhibiting its DNA binding activity. Although PML/RARα did not interact with STAT3, it dissociated PML from STAT3 and restored its activity suppressed by PML. To assess the biologic significance of these findings, we introduced PML and PML/RARα into interleukin-3 (IL-3)–dependent Ba/F3 cells expressing the chimeric receptor composed of extracellular domain of G-CSF-R and cytoplasmic domain of gp130, in which gp130-mediated growth is essentially dependent on STAT3 activity. Neither PML nor PML/RARα affected IL-3–dependent growth of these clones. By contrast, gp130-mediated growth was abrogated by PML, whereas it was enhanced by PML/RARα. These results reveal new functions of PML and PML/RARα and suggest that dysregulated STAT3 activity by PML/RARα may participate in the pathogenesis of APL.
Mast cells produce interleukin-25 upon FcεRI-mediated activation
Authors: Ikeda Kei , Nakajima Hiroshi , Suzuki Kotaro , Kagami Shin-ichiro , Hirose Koichi , Suto Akira , Saito Yasushi , Iwamoto Itsuo
Published: April 2003

Interleukin-25 (IL-25) is a recently described T helper 2 (TH2) cell–derived cytokine that belongs to the IL-17 family and induces the production of IL-4, IL-5, and IL-13 from an unidentified non–T-cell population. Here, we show that mast cells are also potent IL-25–producing cells. When bone marrow–derived mast cells were stimulated by immunoglobulin E cross-linking, IL-25 mRNA was induced within 30 minutes in a calcineurin-dependent manner, and the levels of IL-25 mRNA were comparable with those of activated TH2 cells. Production of IL-25 by mast cells was also detected at protein levels by immunoblotting. These results suggest that mast cells may enhance TH2-type immune response by producing IL-25.
Marrow frequency of rat long-term repopulating cells: evidence that marrow hematopoietic stem cell concentration may be inversely proportional to species body weight
Authors: McCarthy Kenneth F.
Published: April 2003

As measured by the long-term repopulating cell (LTRC) assay, only a few hematopoietic stem cells (HSCs) or perhaps a single HSC are required to totally repopulate the lymphohematopoietic tissues of lethally irradiated mice, cats, and humans, raising the question as to why large mammals require more marrow cells to either rescue them from lethal irradiation or establish a long-term hematopoietic graft than do small mammals. An explanation might be that HSC marrow frequency across species is not constant, but decreases as species body weight increases. This hypothesis was tested by comparing the LTRC marrow concentration of mice to that of rats. Specifically, histocompatible AKR/J Thy 1.1 marrow was transferred to 7-Gy irradiated C3H/HeN, Thy 1.2 mice, and histocompatible Norway Black marrow (NBr), RT 7.2 marrow was transferred to 7-Gy irradiated RT 7.1 Lewis rats. The recipients were scored for successful grafts 6 to 20 weeks later. By limiting dilution analysis, a value of 1 LTRC/47 700 marrow cells was calculated for mice, but only 1 LTRC/502 000 marrow cells was calculated for rats. Viewed in the context of marrow grafting in larger mammals, these results suggest that species with greater body mass have lower marrow HSC frequency.
Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients
Authors: Blazar Bruce R. , Sharpe Arlene H. , Chen Andy I. , Panoskaltsis-Mortari Angela , Lees Christopher , Akiba Hisaya , Yagita Hideo , Killeen Nigel , Taylor Patricia A.
Published: April 2003

OX40 (CD134) is expressed on activated T cells; its ligand, OX40 ligand (OX40L) is expressed on dendritic cells, B cells, and activated endothelial cells. To determine how OX40-OX40L interaction affects graft-versus-host disease (GVHD), we used antagonistic anti-OX40L monoclonal antibody (mAb) or OX40−/−donor or OX40L−/− recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is up-regulated on both CD4+ and CD8+ T cells isolated during GVHD, the major effects of OX40 ligation were on CD4+ and not CD8+ T-cell–mediated alloresponses as assessed in both GVHD and engraftment model systems. GVHD inhibition by blockade of the OX40/OX40L pathway did not require CD28 signaling. Some studies have indicated OX40 is essential for inducing T-helper type 2 (Th2) responses. However, in vivo blockade of OX40-OX40L interactions reduced GVHD mortality induced by either signal transducer and activator of transcription–6−/− (Stat-6−/−) (Th2-defective) or Stat-4−/− (Th1-defective) major histocompatibility complex (MHC)–disparate splenocytes, indicating that the GVHD-ameliorating effects did not require Stat-4 or Stat-6 signaling. Although OX40L has been reported to be expressed on activated T cells, no effects on GVHD were observed when OX40L−/− versus OX40L+/+ T cells were infused in different models. These data provide insights as to the mechanisms responsible for OX40/OX40L regulation of GVHD.
The quantitative assessment of body iron
Authors: Cook James D. , Flowers Carol H. , Skikne Barry S.
Published: April 2003

Current initiatives to reduce the high prevalence of nutritional iron deficiency have highlighted the need for reliable epidemiologic methods to assess iron status. The present report describes a method for estimating body iron based on the ratio of the serum transferrin receptor to serum ferritin. Analysis showed a single normal distribution of body iron stores in US men aged 20 to 65 years (mean ± 1 SD, 9.82 ± 2.82 mg/kg). A single normal distribution was also observed in pregnant Jamaican women (mean ± 1 SD, 0.09 ± 4.48 mg/kg). Distribution analysis in US women aged 20 to 45 years indicated 2 populations; 93% of women had body iron stores averaging 5.5 ± 3.35 mg/kg (mean ± 1 SD), whereas the remaining 7% of women had a mean tissue iron deficit of 3.87 ± 3.23 mg/kg. Calculations of body iron in trials of iron supplementation in Jamaica and iron fortification in Vietnam demonstrated that the method can be used to calculate absorption of the added iron. Quantitative estimates of body iron greatly enhance the evaluation of iron status and the sensitivity of iron intervention trials in populations in which inflammation is uncommon or has been excluded by laboratory screening. The method is useful clinically for monitoring iron status in those who are highly susceptible to iron deficiency.
Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG
Authors: Song Seng , Crow Andrew R. , Freedman John , Lazarus Alan H.
Published: April 2003

Intravenous immunoglobulin (IVIG) is used to treat immune thrombocytopenia resulting from a variety of autoimmune and nonautoimmune diseases such as idiopathic thrombocytopenic purpura (ITP), heparin-induced thrombocytopenia, and posttransfusion purpura. IVIG is a limited resource and although considered safe, may nevertheless carry some risk of transferring disease. Its high cost makes monoclonal antibodies, capable of mimicking the clinical effects of IVIG, highly desirable. We show here, using a murine model of ITP, that selected monoclonal antibodies can protect against thrombocytopenia. SCID mice were pretreated with 1 of 21 monoclonal antibodies before induction of thrombocytopenia by antiplatelet antibody. Four antibodies reacted with the CD24 antigen on erythrocytes. Two antibodies were of the IgM class, and although one IgM antibody caused a minimal degree of anemia (P < .05), neither antibody ameliorated immune thrombocytopenia. One of 2 anti-CD24 antibodies of the IgG class ameliorated immune thrombocytopenia and blocked reticuloendothelial system function at the same doses that protected against thrombocytopenia. Some antibodies reactive with other circulating cell types also protected against immune-mediated thrombocytopenia while no antibody without a distinct target antigen in the mice was protective. Protective monoclonal antibodies significantly prevented thrombocytopenia at down to a 1000-fold lower dose (200 μg/kg) as compared with standard IVIG treatment (2 g/kg). It is concluded that monoclonal IgG with specificity for a circulating cellular target antigen may provide an alternative therapeutic approach to treating immune thrombocytopenia.
Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders
Authors: Pardanani Animesh , Reeder Terra , Porrata Luis F. , Li Chin-Yang , Tazelaar Henry D. , Baxter E. Joanna , Witzig Thomas E. , Cross Nicholas C. P. , Tefferi Ayalew
Published: April 2003

Imatinib mesylate (Gleevec), a small molecule inhibitor of abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we sought to confirm the preliminary observations in HES as well as evaluate the therapeutic value of imatinib in eos-CMD that is not associated with t(5;12)(q33;p13). Five patients with HES (all men, median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of 100 to 400 mg/day. Cytogenetic studies showed no evidence of either the bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFRβ (exons 2-23) and c-kit (exons 1-21) in 6 patients demonstrated mostly previously known polymorphisms. At a median follow-up of 17 weeks (range, 10-33 weeks), 2 patients with HES and 1 with eos-CMD have achieved complete clinical remission and 1 additional patient with HES has achieved a partial remission. In contrast to previous observations, all 4 responding patients had elevated serum interleukin-5 levels. Although the drug was well tolerated in most patients, a previously unrecognized treatment toxicity of acute left ventricular dysfunction occurred in a responding patient with HES within the first week of treatment. Myocardial biopsy revealed eosinophilic infiltration and degranulation, and the cardiogenic shock was reversed with the prompt institution of corticosteroid therapy.
Hydroxyurea can eliminate transfusion requirements in children with severe β-thalassemia
Authors: Bradai Mohamed , Abad Mohand Tayeb , Pissard Serge , Lamraoui Fatima , Skopinski Laurent , de Montalembert Mariane
Published: April 2003

Hydroxyurea (HU) enhances fetal hemoglobin (Hb) production. An increase in total Hb level has been repeatedly reported during HU treatment in patients with sickle cell disease and in several patients with β-thalassemia intermedia. Effects in patients with β-thalassemia major are controversial. We now report a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent β-thalassemia. The median follow-up was 19 ± 3 months (range, 13-21 months). We conclude that HU can eliminate transfusional needs in children with β-thalassemia major, which could be particularly useful in countries such as Algeria, where supplies of blood or chelating agents are limited.
Gassmann fluid substitutions: A tutorial
Authors: Smith Tad M. , Sondergeld Carl H. , Rai Chandra S.
Published: April 2003

Fluid substitution is an important part of seismic attribute work, because it provides the interpreter with a tool for modeling and quantifying the various fluid scenarios which might give rise to an observed amplitude variation with offset (AVO) or 4D response. The most commonly used technique for doing this involves the application of Gassmann's equations.

Modeling the changes from one fluid type to another requires that the effects of the starting fluid first be removed prior to modeling the new fluid. In practice, the rock is drained of its initial pore fluid, and the moduli (bulk and shear) and bulk density of the porous frame are calculated. Once the porous frame properties are properly determined, the rock is saturated with the new pore fluid, and the new effective bulk modulus and density are calculated.

A direct result of Gassmann's equations is that the shear modulus for an isotropic material is independent of pore fluid, and therefore remains constant during the fluid substitution process. In the case of disconnected or cracklike pores, however, this assumption may be violated. Once the values for the new effective bulk modulus and bulk density are calculated, it is possible to calculate the compressional and shear velocities for the new fluid conditions.

There are other approaches to fluid substitution (empirical and heuristic) which avoid the porous frame calculations but, as described in this tutorial, often do not yield reliable results. This tutorial provides the reader with a recipe for performing fluid substitutions, as well as insight into why and when the approach may fail.
Hydraulic stimulation of natural fractures as revealed by induced microearthquakes, Carthage Cotton Valley gas field, east Texas
Authors: Rutledge James T. , Phillips W. Scott
Published: April 2003

We produced a high‐resolution microseismic image of a hydraulic fracture stimulation in the Carthage Cotton Valley gas field of east Texas. We improved the precision of microseismic event locations four‐fold over initial locations by manually repicking the traveltimes in a spatial sequence, allowing us to visually correlate waveforms of adjacent sources. The new locations show vertical containment within individual, targeted sands, suggesting little or no hydraulic communication between the discrete perforation intervals simultaneously treated within an 80‐m section. Treatment (i.e., fracture‐zone) lengths inferred from event locations are about 200 m greater at the shallow perforation intervals than at the deeper intervals. The highest quality locations indicate fracture‐zone widths as narrow as 6 m. Similarity of adjacent‐source waveforms, along with systematic changes of phase amplitude ratios and polarities, indicate fairly uniform source mechanisms (fracture plane orientation and sense of slip) over the treatment length. Composite focal mechanisms indicate both left‐ and right‐lateral strike‐slip faulting along near‐vertical fractures that strike subparallel to maximum horizontal stress. The focal mechanisms and event locations are consistent with activation of the reservoir's prevalent natural fractures, fractures that are isolated within individual sands and trend subparallel to the expected hydraulic fracture orientation (maximum horizontal stress direction). Shear activation of these fractures indicates a stronger correlation of induced seismicity with low‐impedance flow paths than is normally found or assumed during injection stimulation.
Effects of single vertical fluid‐filled fractures on full waveform dipole sonic logs
Authors: Xu Pei‐Cheng , Parra Jorge O.
Published: April 2003

We conducted a parametric study of the effects of single, finite‐width, adjacent, vertical, fluid‐filled fractures on full‐wave borehole dipole logs using the transformed boundary integral equation method. We found that a fracture has significant effects on dipole response if it is within half the wavelength, or two to three times the borehole diameter, from the borehole center. Dual flexural waves and a leaky fracture mode resulted from the waveguide composed of the borehole and fracture. The first flexural wave was controlled by both the borehole and fracture, whereas the second flexural wave was controlled primarily by the borehole but influenced by the fracture. The separation of these two flexural waves increased and the strength of the first one decreased when the distance between the fracture and the borehole increased. The leaky fracture mode was represented by a sharp minimum in the amplitude spectrum, and energy leakage to the fracture reached a maximum when the fracture intersected the borehole. These two unique characteristics distinguish a single fracture from anisotropy. We also estimated location, orientation, and aperture of the fracture through waveform and spectral analyses.