bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents
Authors: Cragg Mark S. , Glennie Martin J. 
Published: October 2003

AbstractDespite the success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about their mechanism(s) of action. Here, we show that certain of these reagents (rituximab and 1F5), which redistribute CD20 into membrane rafts, are bound efficiently by C1q, deposit C3b, and result in complement-dependent cytotoxicity (CDC). This activity is important in vivo, because complement depletion using cobra venom factor (CVF) markedly reduced the efficacy of rituximab and 1F5 in 2 lymphoma xenograft models. However, complement depletion had no effect on the potent therapeutic activity of B1, a mAb that does not redistribute CD20 into membrane rafts, bind C1q, or cause efficient CDC. Equivalent immunotherapy also occurred in the presence or absence of natural killer (NK) cells. Perhaps most surprising was the observation that F(ab′)2 fragments of B1 but not 1F5 were able to provide substantial immunotherapy, indicating that non-Fc-dependent mechanisms are involved with B1. In accordance with this, B1 was shown to induce much higher levels of apoptosis than rituximab and 1F5. Thus, although complement is important for the action of rituximab and 1F5, this is not so for B1, which more likely functions through its ability to signal apoptosis. (Blood. 2004;103:2738-2743)
Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein
Authors: Yam Judy Wai Ping , Jin Dong-Yan , So Chi Wai , Chan Li Chong 
Published: October 2003

AbstractThe chimeric MLL-EEN fusion protein is created as a result of chromosomal translocation t(11;19)(q23;p13). EEN, an Src homology 3 (SH3) domain–containing protein in the endophilin family, has been implicated in endocytosis, although little is known about its role in leukemogenesis mediated by the MLL-EEN fusion protein. In this study, we have identified and characterized EBP, a novel EEN binding protein that interacts with the SH3 domain of EEN through a proline-rich motif PPERP. EBP is a ubiquitous protein that is normally expressed in the cytoplasm but is recruited to the nucleus by MLL-EEN with a punctate localization pattern characteristic of the MLL chimeric proteins. EBP interacts simultaneously with EEN and Sos, a guanine-nucleotide exchange factor for Ras. Coexpressoin of EBP with EEN leads to suppression of Ras-induced cellular transformation and Ras-mediated activation of Elk-1. Taken together, our findings suggest a new mechanism for MLL-EEN–mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction.
LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds
Authors: Kinashi Tatsuo , Aker Memet , Sokolovsky-Eisenberg Maya , Grabovsky Valentin , Tanaka Chisato , Shamri Revital , Feigelson Sara , Etzioni Amos , Alon Ronen 
Published: October 2003

AbstractRecently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins.1 We now report that the small GTPase, Rap1, a key regulator of inside-out integrin activation is abnormally regulated in LAD Epstein-Barr virus (EBV) lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out an LAD defect in Rap1 guanosine triphosphate (GTP) loading. The very late antigen 4 (VLA-4) integrin abnormally tethered LAD EBV lymphocytes to its ligand vascular cell adhesion molecule 1 (VCAM-1) under shear flow due to impaired generation of high-avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 monoclonal antibody (mAb). Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high-avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it “LAD-III.” (Blood. 2004;103:1033-1036)
A novel SHP-1/Grb2–dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling
Authors: Minoo Parham , Zadeh Maryam Mohsen , Rottapel Robert , Lebrun Jean-Jacques , Ali Suhad 
Published: October 2003

AbstractSHP-1, an src homology 2 (SH2) domain containing protein tyrosine phosphatase, functions as a negative regulator of signaling downstream of cytokine receptors, receptor tyrosine kinases and receptor complexes of the immune system. Dephosphorylation of receptors and/or receptor-associated kinases has been described as the mechanism for the function of SHP-1. Here we demonstrate a novel mechanism by which SHP-1 down-regulates the Janus kinase–2 (Jak2)/signal transducer and activator of transcription-5 (Stat5) pathway downstream of the prolactin receptor (PRLR) and the erythropoietin receptor (EPOR) in a catalytic activity–independent manner. Structural/functional analysis of SHP-1 defined the C-terminal tyrosine residues (Y278, Y303, Y538, Y566) within growth factor receptor–bound protein 2 (Grb-2) binding motif to be responsible for delivering the inhibitory effects. Our results further indicate that these tyrosine residues, via recruitment of the adaptor protein Grb-2, are required for targeting the inhibitory protein suppressor of cytokine signaling–1 (SOCS-1) to Jak2 kinase. Finally, loss of SOCS-1 expression in SOCS-1–/– mouse embryonic fibroblast (MEF) cells led to attenuation in SHP-1 function to down-regulate PRL-induced Stat5 activation. All together, our results indicate that SHP-1 inhibits PRLR and EPOR signaling by recruitment and targeting of SOCS-1 to Jak2, highlighting a new mechanism of SHP-1 regulation of cytokine-receptor signaling.
Identification of critical amino-acid residues on the erythroid intercellular adhesion molecule-4 (ICAM-4) mediating adhesion to αV integrins
Authors: Mankelow Tosti J. , Spring Frances A. , Parsons Stephen F. , Brady R. Leo , Mohandas Narla , Chasis Joel A. , Anstee David J. 
Published: October 2003

AbstractIntercellular adhesion molecule-4 (ICAM-4, syn. LW glycoprotein) interacts with the integrins αLβ2, αMβ2, A4β1, the αV family, and αIIbβ3. Systematic mutagenesis of surface-exposed residues conserved between human and murine ICAM-4 defined 12 single amino-acid changes that affect the interaction of ICAM-4 with αV integrins. Mutation of 10 of these residues, 8 of which are spatially close on the surface of the molecule, led to a reduction in adhesion. Moreover, peptides corresponding to regions of ICAM-4 involved in its interaction with αV integrins inhibited these interactions. The other 2 mutations increased the extent of interaction of ICAM-4 with αV integrins. These mutations appear to prevent glycosylation of N160, suggesting that changes in glycosylation may modulate ICAM-4–αV integrin interactions. The region of ICAM-4 identified as the binding site for αV integrins is adjacent to the binding sites for αLβ2 and αMβ2. Selective binding of ICAM-4 to different integrins may be important for a variety of normal red cell functions and also relevant to the pathology of thrombotic disorders and vasoocclusive events in sickle cell disease. Our findings suggest the feasibility of developing selective inhibitors of ICAM-4–integrin adhesion of therapeutic value in these diseases.
Ghrelin and Des-Octanoyl Ghrelin Promote Adipogenesis Directly in Vivo by a Mechanism Independent of the Type 1a Growth Hormone Secretagogue Receptor
Authors: Thompson Nichola M. , Gill Dave A. S. , Davies Rhos , Loveridge Nigel , Houston Pamela A. , Robinson Iain C. A. F. , Wells Timothy 
Published: October 2003

Abstract
Ghrelin promotes fat accumulation, despite potent stimulation of the lipolytic hormone, GH. The function of the major circulating isoform of ghrelin, des-octanoyl ghrelin, is unclear, because it does not activate the GH secretagogue receptor (GHS-R1a) and lacks the endocrine activities of ghrelin. We have now addressed these issues by infusing ghrelin, des-octanoyl ghrelin, or synthetic GHS-R1a agonists into three rat models with moderate, severe, or total GH deficiency. We show that in the context of significant GH secretion, the adipogenic effect of systemic ghrelin infusion is pattern dependent. However, this adipogenic action is not mediated by the pituitary hormones. Using a novel unilateral local infusion strategy, we demonstrate that ghrelin promotes bone marrow adipogenesis in vivo by a direct peripheral action. Surprisingly, this effect was also observed with des-octanoyl ghrelin, whereas a potent synthetic GHS-R1a agonist was ineffective. Thus, these adipogenic effects are mediated by a receptor other than GHS-R1a. This is the first in vivo demonstration of a direct adipogenic effect of des-octanoyl ghrelin, a major circulating form of ghrelin that lacks GH-releasing activity. We suggest that the ratio of ghrelin and des-octanoyl ghrelin production could help regulate the balance between adipogenesis and lipolysis in response to nutritional status.
The influence of morphine on the absorption of paracetamol from various formulations in subjects in the supine position, as assessed by TDx measurement of salivary paracetamol concentrations
Authors: Kennedy Julia M , Tyers Nicola M , Davey Andrew K 
Published: October 2003

Abstract
The aim of this study was to determine the influence of the type of paracetamol formulation on the rate of absorption when subjects are in the supine position, with or without taking concomitant morphine. Two groups of healthy volunteers were used, who were in the fasting state and remained in the supine position during the study. One group took 1500 mg of paracetamol on three occasions as conventional tablets, dispersible tablets or a suspension in a randomized crossover design. Seventeen saliva samples per subject were obtained (time zero to 360 min post-dose), which were then centrifuged and kept at −20°C prior to analysis. The second group repeated the study following four doses of morphine syrup (10 mg 4 hourly) in the 12 h preceding paracetamol ingestion. In this phase of the study, paracetamol absorption from suspension was not investigated. A TDx assay was used to determine salivary paracetamol concentrations. The tmax for conventional tablets when taken concomitantly with morphine was 160 (+81) min compared to 51 (+58) min for subjects not taking morphine. For dispersible tablets the tmax in the morphine group was 14 (+9) min compared to 15 (+12) min without morphine. The results suggest that patients who are confined to bed and taking morphine will have an unacceptably long delay between taking conventional paracetamol tablets and the paracetamol reaching therapeutic plasma concentrations. Conversely, there is little effect on the absorption of dispersible paracetamol under the same conditions.
Peroxynitrite scavenging activity of lithospermate B from Salvia miltiorrhiza
Authors: Soung Do You , Rhee Sook Hee , Kim Jung Sun , Lee Ji Young , Yang Hee-Sun , Choi Jae Sue , Yokozawa Takako , Han Yong Nam , Chung Hae Young 
Published: October 2003

Abstract
Peroxynitrite (ONOO−) is produced by the reaction of superoxide (O2−) with nitric oxide. ONOO− damages proteins through nitration or oxidation. For protection from ONOO− induced protein modifications, ONOO− scavengers should be supplemented. Evidence was obtained that lithospermate B extracted from Salvia miltiorrhiza showed the strongest scavenging activity among its constituents. Its ONOO− scavenging activity is via an electron donation mechanism. A dihydroxyl group and a double bond seem to be essential structure requirements. The data from the experiments further confirmed a protective effect of lithospermate B on bovine serum albumin and low-density lipoprotein against ONOO−. This study demonstrated that lithospermate B with hydroxyl groups and double bonds exerts an anti-nitration effect by scavenging ONOO−.
Examinations of the antioxidative properties of the topically administered drug bufexamac reveal new insights into its mechanism of action
Authors: Trommer Hagen , Plätzer Manuela , Raith Klaus , Wohlrab Wolfgang , Podhaisky Hans-Peter , Neubert Reinhard H H 
Published: October 2003

Abstract
The effect of bufexamac on UV-irradiation-induced lipid peroxidation was investigated. Linolenic acid was used as a model lipid. Bufexamac was shown to be capable of reducing the amount of lipid peroxidation. The quantification was carried out by the thiobarbituric acid assay. Irradiation experiments were also performed using HaCaT keratinocytes as a model system. The oxidative changes were quantified by DNA synthesis measurements and cell viability determinations. Bufexamac was found to act antioxidatively again. To investigate free radical involvement, electron paramagnetic resonance studies were carried out. The influence of bufexamac on the concentration of hydroxyl radicals generated by the Fenton system was examined using the spin trapping technique. Moreover, the hydroxamic acid's ability to react with stable radicals was checked. The quantification assay of 2,2-diphenyl-1-picrylhydrazyl hydrate showed no concentration changes of the stable radical caused by bufexamac. In the Fenton assay antioxidative effects were measured after the addition of the drug. The qualitative changes after irradiating bufexamac were studied at a molecular level by electrospray mass spectrometry. Multiple-stage mass spectrometry experiments enabled the establishment of fragmentation schemes. Phenolic degradation products were detected. The results suggest a new interpretation of the controversially debated mechanism of action of bufexamac and indicate possible reasons for its eczema provoking potential.
Hydrothermal Synthesis of A New Mo–V–O Complex Metal Oxide and Its Catalytic Activity for The Oxidation of Propane
Authors: Katou Tomokazu , Vitry Damien , Ueda Wataru 
Published: October 2003

Abstract
Preparation of a new orthorhombic Mo–V–O catalyst was succeeded by hydrothermal synthesis for the first time. This orthorhombic structure showed high activity for propane oxidation. Selectivity to acrylic acid dramatically increased by the introduction of Te into the orthorhombic Mo–V–O catalyst.
Organogel Formation of Optically Active 1,6-di-O-TIPDS-myo-inositol
Authors: Hosoda Asao , Miyake Yasuhito , Nomura Eisaku , Taniguchi Hisaji 
Published: October 2003

Abstract
Two novel optically active myo-inositol derivatives having a bulky alkyl–silyl group as a hydrophobic part were synthesized. These compounds acted as a gelator toward nonpolar hydrophobic solvents such as n-hexane, cyclohexane, and toluene via the formation of an intermolecular OH···O hydrogen bonding network.
Wavelets in state space models
Authors: Zandonade Eliana , Morettin Pedro A. 
Published: October 2003

AbstractIn this paper, we consider the utilization of wavelets in conjunction with state space models. Specifically, the parameters in the system matrix are expanded in wavelet series and estimated via the Kalman Filter and the EM algorithm. In particular this approach is used for switching models. Two applications are given, one to the problem of detecting the paths of targets using an array of sensors, and the other to a series of daily spreads between two Brazilian bonds. Copyright © 2003 John Wiley & Sons, Ltd.
A wavelet solution to the spurious regression of fractionally differenced processes
Authors: Fan Yanqin , Whitcher Brandon 
Published: October 2003

AbstractIn this paper we propose to overcome the problem of spurious regression between fractionally differenced processes by applying the discrete wavelet transform (DWT) to both processes and then estimating the regression in the wavelet domain. The DWT is known to approximately decorrelate heavily autocorrelated processes and, unlike applying a first difference filter, involves a recursive two‐step filtering and downsampling procedure. We prove the asymptotic normality of the proposed estimator and demonstrate via simulation its efficacy in finite samples. Copyright © 2003 John Wiley & Sons, Ltd.
Unusual origin of the flexor digiti minimi brevis muscle
Authors: Wingerter S. , Gupta S. , Le S. , Shamasunder S. , Bernstein R. , Rabitaille W. , Kukuyeva Y. , Downie S. 
Published: October 2003

AbstractAn unusual origin of the flexor digiti minimi brevis muscle of the right hand was discovered during cadaveric dissection. The muscle originated from the anterior aspect of the transverse fibers of the distal antebrachial fascia and inserted onto the base of the fifth proximal phalanx. When traction was applied to the proximal portion of the muscle, flexion was produced at the fifth metacarpophalangeal joint. Other intrinsic muscles of the hand and the muscles of the flexor forearm compartment had normal morphology. Although muscular anomalies in the hypothenar region have been described, the muscular variant described here was distinct in its origin and size from those previously reported. Knowledge of anomalous muscles in the hand has important clinical significance in routine surgery and in determining associated pathology. Clin. Anat. 16:531–533, 2003. © 2003 Wiley‐Liss, Inc.
Relationship of the common peroneal nerve and its branches to the head and neck of the fibula
Authors: Ryan William , Mahony Nick , Delaney Maire , O'Brien Moira , Murray Paraic 
Published: October 2003

AbstractThe common peroneal nerve (CPN) lies on the neck of the fibula, which forms the floor of the so‐called ‘fibular tunnel.’ The tunnel entrance is a musculo‐aponeurotic arch derived from the soleus and peroneus longus muscles and it is here that the CPN is commonly compressed in cases of peroneal nerve palsy. This study aims to define the relationship of the CPN and its branches to the apex of the head of the fibula and to the tunnel, with special regard to possible sites of entrapment. The distances from the apex of the fibula to the opening of the fibular tunnel, the CPN bifurcation, and the exit point of the deep peroneal nerve (DPN) from the tunnel, were measured in 30 legs to ascertain possible sites of entrapment. The angle that the CPN subtended with the long axis of the fibula was measured to gauge the range of positions of the CPN at the neck of the fibula. An unyielding musculo‐aponeurotic fibular arch at the entrance to the fibular tunnel was confirmed in all specimens. The DPN exited through a crescentic opening in the anterior intermuscular septum in all cases and no DPN branches were found in the lateral compartment in any specimen. The mean (±SD) distance from the apex of the head of the fibula to the opening of the fibular tunnel was 3.2 ± 1.0 cm, to the CPN bifurcation was 3.8 ± 0.9 cm, and to the DPN exit point was 7.0 ± 1.5 cm. The mean angle subtended anteriorly from the long axis of the fibula by the CPN was 18.9 ± 9.0°. We recommend further study of the mean distances and reference angle in relation to fibular landmarks, for use in possible minimally invasive surgical procedures to decompress the fibular tunnel. Clin. Anat. 16:501–505, 2003. © 2003 Wiley‐Liss, Inc.
Outcomes of the gross and developmental anatomy teaching assistant experience
Authors: Ocel Joseph J. , Palmer Brian A. , Wittich Christopher M. , Carmichael Stephen W. , Pawlina Wojciech 
Published: October 2003

AbstractDuring the first‐year Gross and Developmental Anatomy Course at Mayo Medical School, third‐year medical students volunteer as teaching assistants (TAs). Their responsibilities include preparing for dissection, instructing students during dissection, writing examination questions, and giving a lecture. To evaluate the academic and professional impact of this experience on former TAs, a survey instrument was developed, and was sent to former TAs from the past 17 years. Seventy‐two percent of the surveys were returned. Most respondents (84%) indicated that the TA experience was beneficial during their third‐year surgical rotation. Over 60% identified benefits during Neurology, Obstetrics and Gynecology, and Internal Medicine rotations. The majority (62%) indicated they regularly use the knowledge gained from the TA experience. Communication was the most highly ranked area of skill development, with 86% of respondents indicating gains in lecture effectiveness and 97% in one‐on‐one teaching. Among respondents, 32% entered surgical or radiological fields, roughly paralleling the non‐TA medical student population. All respondents indicated that they would repeat the experience and recommend it to other medical students. Although benefits for long‐term career development have not yet been established, the Gross and Developmental Anatomy TA experience had perceived short‐term benefits with respect to clinical rotations and teaching skill development. Clin. Anat. 16:526–530, 2003. © 2003 Wiley‐Liss, Inc.
Orthoesters versus 2‐O‐Acyl Glycosides as Glycosyl Donors: Theorectical and Experimental Studies
Authors: Fraser‐Reid Bert , Grimme Stefan , Piacenza Manuel , Mach Mateuz , Schlueter Urs 
Published: October 2003

Abstractn‐Pentenyl orthoesters (NPOEs) undergo routine acid catalyzed rearrangement into 2‐O‐acyl n‐pentenyl glycosides (NPGs). The reactant and product can both function as glycosyl donors affording 1,2‐trans linked glycosides predominantly. However, both donors differ in their rates of reactions, the yields they produce, and the nature of their byproducts, indicating that the NPOE/NPG pair may not be reacting through the same intermediates. We have therefore applied quantum chemical calculations using DFT methods and MP second order perturbation theory to learn more about orthoesters and their 2‐O‐acyl glycosidic counterparts. The calculations show that in the case of a manno NPG and NPOE pair, each donor goes initially to a different cationic intermediate. Thus, the former goes to a high‐energy oxocarbenium ion before descending to a trioxolenium ion in which the charge is distributed over the pyrano ring oxygen, as well as the carbonyl and ether oxygen atoms of the putative C2 ester. On the other hand, ionization of the NPOE produces a dioxolenium ion lying slightly above the more stable trioxolenium counterpart. For the gluco pair, the NPG also goes to a very high‐energy oxocarbenium ion, which also descends to a trioxolenium ion. However, unlike the manno analogue, the gluco NPOE does not give a dioxolenium ion; indeed, the dioxolenium is not energetically distinguishable from the trioxolenium counterpart. The theoretical observations have been tested experimentally. Thus, it was found that with manno derivatives, the orthoester is a more reactive donor than the corresponding NPG donor, whereas, for gluco derivatives, there is no advantage to using one over the other, unless one resorts to carefully selected promoters.