bluuebunny/crossref_metadata_2025_split huggingface dataset:
The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments
Authors: Mansfield Elizabeth , Chae Jae Jin , Komarow Hirsh D. , Brotz Tilmann M. , Frucht David M. , Aksentijevich Ivona , Kastner Daniel L. 
Published: July 2002

AbstractFamilial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and intense inflammation. FMF attacks are unique in their sensitivity to the microtubule inhibitor colchicine, contrasted with their refractoriness to the anti-inflammatory effects of glucocorticoids. The FMF gene,MEFV, was recently identified by positional cloning; it is expressed at high levels in granulocytes and monocytes. The present study investigated the subcellular localization of the normal gene product, pyrin. These experiments did not support previously proposed nuclear or Golgi localizations. Instead fluorescence microscopy demonstrated colocalization of full-length GFP- and epitope-tagged pyrin with microtubules; this was markedly accentuated in paclitaxel-treated cells. Moreover, immunoblot analysis of precipitates of stabilized microtubules with recombinant pyrin demonstrated a direct interaction in vitro. Pyrin expression did not affect the stability of microtubules. Deletion constructs showed that the unique N-terminal domain of pyrin is necessary and sufficient for colocalization, whereas disease-associated mutations in the C-terminal B30.2 (rfp) domain did not disrupt this interaction. By phalloidin staining, a colocalization of pyrin with actin was also observed in perinuclear filaments and in peripheral lamellar ruffles. The proposal is made that pyrin regulates inflammatory responses at the level of leukocyte cytoskeletal organization and that the unique therapeutic effect of colchicine in FMF may be dependent on this interaction.
Purification of human von Willebrand factor–cleaving protease and its identification as a new member of the metalloproteinase family
Authors: Fujikawa Kazuo , Suzuki Hiroshi , McMullen Brad , Chung Dominic 
Published: July 2002

Abstract
von Willebrand factor (vWF) is synthesized in megakaryocytes and endothelial cells as a very large multimer, but circulates in plasma as a group of multimers ranging from 500 to 10 000 kd. An important mechanism for depolymerization of the large multimers is the limited proteolysis by a vWF-cleaving protease present in plasma. The absence or inactivation of the vWF-cleaving protease results in the accumulation of large multimers, which may cause thrombotic thrombocytopenic purpura. The vWF-cleaving protease was first described as a Ca++-dependent proteinase with an apparent molecular weight of approximately 300 kd. Thus far, however, it has not been isolated and characterized. In this study, the purification of human vWF-cleaving protease from a commercial preparation of factor VIII/vWF concentrate by means of several column chromatographic steps, including 2 steps of heparin-Sepharose column, is reported. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis analysis of the anion exchange and gel filtration column fractions showed that the vWF-cleaving protease activity corresponded to a protein band of 150 kd. After reduction, it migrated with an apparent weight of 190 kd. The amino terminal sequence of the 150-kd band was AAGGIL(H)LE(L)L(D)AXG(P)X(V)XQ (single-letter amino acid codes), with the tentative residues shown in parentheses. A search of the human genome sequence identified the vWF-cleaving protease as a new member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin type I motif) family of metalloproteinase. An active site sequence of HEIGHSFGLEHE (single-letter amino acid codes) was located at 150 residues from the N terminus of the protein.
Molecular regulation of CC-chemokine receptor 3 expression in human T helper 2 cells
Authors: Scotet Emmanuel , Schroeder Susanne , Lanzavecchia Antonio 
Published: July 2002

AbstractIn developing T helper 1 (Th1) and Th2 cells the acquisition of effector function is intimately connected with the acquisition of new migratory capacities, as exemplified by differential expression of chemokine receptors. This study investigates the molecular mechanisms responsible for Th2-restricted expression of the CC-chemokine receptor 3 (CCR3). The minimal promoter in T cells was identified in the −149 base pair (bp) upstream sequence that contains a positive regulatory element. A strong negative element was also localized in the flanking intronic sequence. The study further investigates the role of chromatin remodeling in the regulation of this Th2-specific gene. Drugs that affect the chromatin structure facilitate CCR3 expression in T cells. Furthermore, in differentiating Th2 cells, selected regions are associated with acetylated-H3 histones and become more accessible to DNase I. These results suggest that in Th2 cells both cytokine production and migratory capacity are regulated through a similar mechanism involving chromatin remodeling.
Cytokine-inducible CD40 expression in human endothelial cells is mediated by interferon regulatory factor-1
Authors: Wagner Andreas H. , Gebauer Matthias , Pollok-Kopp Beatrix , Hecker Markus 
Published: July 2002

AbstractGiven the significance of CD40–CD40 ligand interactions in chronic inflammatory diseases including atherosclerosis, the transcriptional regulation of CD40 expression as a potential therapeutic target was investigated in human umbilical vein cultured endothelial cells. Exposure to interferon-γ (IFN-γ) plus tumor necrosis factor-α resulted in a marked synergistic de novo expression of CD40, which, according to electrophoretic mobility shift analysis, was attributable to activation of the transcription factors nuclear factor-κB (NF-κB), signal transducer and activator of transcription-1 (STAT-1), and interferon regulatory factor-1 (IRF-1). Subsequent time-course studies revealed that de novo synthesis of IRF-1 preceded that of CD40. Decoy oligodeoxynucleotide (ODN) neutralization of STAT-1 or IRF-1, but not of NF-κB, inhibited cytokine-stimulated CD40 expression by 60% at both the mRNA and protein levels, and this effect was mimicked by antisense ODN blockade of IRF-1 synthesis. In contrast, CD40 expression in response to IFN-γ stimulation was sensitive to neutralization of STAT-1 only. These findings suggest that depending on the cytokine composition, CD40 expression in human endothelial cells under proinflammatory conditions is governed by STAT-1 either directly or indirectly through de novo synthesis of IRF-1. Moreover, decoy ODN neutralization of these transcription factors may provide a novel therapeutic option for interfering with CD40–CD40 ligand-mediated inflammatory responses in vivo.
Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement
Authors: Inabe Kazunori , Kurosaki Tomohiro 
Published: July 2002

AbstractCD19 is a coreceptor that amplifies signaling initiated by antigen cross-linking of the B-cell antigen receptor (BCR). CD19 can also signal independently of BCR coligation. This study shows thatB-cell adaptor forphosphoinositide 3-kinase (BCAP), previously characterized as a substrate of the tyrosine kinases upon BCR engagement, is phosphorylated by cross-linking of CD19. Tyrosine phosphorylation of BCAP, mediated by Lyn, provides binding site(s) for phosphoinositide 3-kinase (PI3K), thereby participating in Akt activation. Thus, these results provide evidence that BCAP serves as an adaptor molecule for CD19 to activate the PI3K pathway in B cells.
Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival
Authors: Myers Laurie A. , Patel Dhavalkumar D. , Puck Jennifer M. , Buckley Rebecca H. 
Published: July 2002

AbstractAll genetic types of severe combined immunodeficiency (SCID) can be cured by stem cell transplantation from related donors. The survival rate approaches 80%, and most deaths result from opportunistic infections acquired before transplantation. It was hypothesized that the survival rate and kinetics of immune reconstitution would be improved for infants receiving transplants in the neonatal period (first 28 days of life), prior to the development of infections. A 19.2-year retrospective/prospective analysis compared immune function in 21 SCID infants receiving transplants in the neonatal period with that in 70 SCID infants receiving transplants later. Lymphocyte phenotypes, proliferative responses to mitogens, immunoglobulin levels, and T-cell antigen receptor excision circles (TRECs) were measured before transplantation and sequentially after transplantation. Of 21 SCID infants with transplantations in the neonatal period, 20 (95%) survive. Neonates were lymphopenic at birth (1118 ± 128 lymphocytes per cubic millimeter). Infants receiving transplants early developed higher lymphocyte responses to phytohemagglutinin and higher numbers of CD3+ and CD45RA+ T cells in the first 3 years of life than those receiving transplants late (P &lt; .05). TRECs peaked earlier and with higher values (P &lt; .01) in the neonatal transplantations (181 days to 1 year) than in the late transplantations (1 to 3 years). SCID recipients of allogeneic, related hematopoietic stem cells in the neonatal period had higher levels of T-cell reconstitution and thymic output and a higher survival rate than those receiving transplants after 28 days of life. An improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so that transplantation could be performed under favorable thymopoietic conditions.
Mechanism of factor VIIa–dependent coagulation in hemophilia blood
Authors: Butenas Saulius , Brummel Kathleen E. , Branda Richard F. , Paradis Sara G. , Mann Kenneth G. 
Published: July 2002

AbstractThe ability of factor VIIa to initiate thrombin generation and clot formation in blood from healthy donors, blood from patients with hemophilia A, and in anti–factor IX antibody–induced (“acquired”) hemophilia B blood was investigated. In normal blood, both factor VIIa–tissue factor (TF) complex and factor VIIa alone initiated thrombin generation. The efficiency of factor VIIa was about 0.0001 that of the factor VIIa–TF complex. In congenital hemophilia A blood and “acquired” hemophilia B blood in vitro, addition of 10 to 50 nM factor VIIa (pharmacologic concentrations) corrected the clotting time at all TF concentrations tested (0-100 pM) but had little effect on thrombin generation. Fibrinopeptide release and insoluble clot formation were only marginally influenced by addition of factor VIIa. TF alone had a more pronounced effect on thrombin generation; an increase in TF from 0 to 100 pM increased the maximum thrombin level in “acquired” hemophilia B blood from 120 to 480 nM. Platelet activation was considerably enhanced by addition of factor VIIa to both hemophilia A blood and “acquired” hemophilia B blood. Thus, pharmacologic concentrations of factor VIIa cannot restore normal thrombin generation in hemophilia A and hemophilia B blood in vitro. The efficacy of factor VIIa (10-50 nM) in hemophilia blood is dependent on TF.
Dielectric permittivity and resistivity mapping using high‐frequency, helicopter‐borne EM data
Authors: Huang Haoping , Fraser Douglas C. 
Published: July 2002

The interpretation of helicopter‐borne electromagnetic (EM) data is commonly based on the transformation of the data to the apparent resistivity under the assumption that the dielectric permittivity is that of free space and so displacement currents may be ignored. While this is an acceptable approach for many applications, it may not yield a reliable value for the apparent resistivity in resistive areas at the high frequencies now available commercially for some helicopter EM systems.We analyze the feasibility of mapping spatial variations in the dielectric permittivity and resistivity using a high‐frequency helicopter‐borne EM system. The effect of the dielectric permittivity on the EM data is to decrease the in‐phase component and increase the quadrature component. This results in an unwarranted increase in the apparent resistivity (when permittivity is neglected) for the pseudolayer half‐space model, or a decrease in the apparent resistivity for the homogeneous half‐space model. To avoid this problem, we use the in‐phase and quadrature responses at the highest frequency to estimate the apparent dielectric permittivity because this maximizes the response of displacement currents. Having an estimate of the apparent dielectric permittivity then allows the apparent resistivity to be computed for all frequencies. A field example shows that the permittivity can be well resolved in a resistive environment when using high‐frequency helicopter EM data.
A Randomized Clinical Trial of Oral versus Intramuscular Delivery of Steroids in Acute Exudative Pharyngitis
Authors: Marvez‐Valls Eduardo G. , Stuckey Ashley , Ernst Amy A. 
Published: July 2002

AbstractPrevious study has shown that the use of intramuscular (IM) steroid leads to improved symptoms in patients with group A beta‐hemolytic streptococcus (GABHS). Objective: To compare oral with IM steroids as an adjunct to antibiotic therapy in the treatment of acute exudative pharyngitis. The null hypothesis was that there would be no difference in effectiveness of oral versus IM steroids. Methods: The study was a randomized, double‐blind outpatient clinical trial. After consent was obtained, each patient was asked to rate his or her pain on a 10‐cm numbered visual analog scale (VAS; 0‐10). All of the patients received injectable benzathine penicillin or, if allergic to penicillin, a ten‐day course of polyenteric‐coated erythromycin. Each patient was randomized to receive either injectable steroid plus oral placebo or injectable placebo plus oral steroid. All medications were given in the emergency department. All patients were contacted by telephone at 24 hours (first follow‐up) and 48 hours (second follow‐up) by one of the study investigators and asked to rate their pain based on another VAS. If their pain was not resolved by 48 hours, they were called again daily for the third to seventh day after the initial visit. The time to total resolution of the sore throat was documented. The main outcome measures were time to complete relief of pain and VAS scores. Pain medication was not controlled; however, use of pain medications and amounts were recorded. Results: A total of 78 patients were initially enrolled in the study. Eight patients were excluded from the statistical analysis because of inability to follow up. A total of 70 were entered, with 35 randomized to IM steroid plus oral placebo and 35 to IM placebo plus oral steroid. There was no difference in pain scores for the oral versus IM group at first follow‐up (p = 0.13) and second follow‐up (p = 0.82), and in number of hours to relief of pain (p = 0.06). Using repeated‐measures analysis of variance, no difference in the effects of the two medications over time was detected (p = 0.83). Conclusions: The results of this clinical trial suggest that oral steroid and IM steroid provide similar levels of pain relief in acute exudative pharyngitis.
Activity of Oxaliplatin in Patients With Relapsed or Cisplatin-Refractory Germ Cell Cancer: A Study of the German Testicular Cancer Study Group
Authors: Kollmannsberger C. , Rick O. , Derigs H.-G. , Schleucher N. , Schöffski P. , Beyer J. , Schoch R. , Sayer H.G. , Gerl A. , Kuczyk M. , Spott C. , Kanz L. , Bokemeyer C. 
Published: July 2002

PURPOSE: To investigate the efficacy and toxicity of oxaliplatin, a diaminocyclohaxane platinum derivative with incomplete cross-resistance to cisplatin in patients with relapsed or cisplatin-refractory germ cell cancer. PATIENTS AND METHODS: Thirty-two patients with nonseminomatous cisplatin-refractory germ cell cancer or relapsed disease after high-dose chemotherapy (HDCT) plus autologous stem-cell support were treated with single-agent oxaliplatin 60 mg/m2 on days 1, 8, and 15 repeated every 4 weeks (group 1; n = 16) or oxaliplatin 130 mg/m2 given on days 1 and 15 of a 4-week cycle (group 2; n = 16). Patients were pretreated with a median of seven (range, three to 13) cisplatin-containing treatment cycles; 78% had received carboplatin/etoposide-based HDCT before oxaliplatin therapy. Twenty-seven patients (84%) were considered refractory (n = 20; 63%) or absolutely refractory (n = 7; 22%) to cisplatin therapy. RESULTS: Overall, four patients achieved a partial remission (13%; 95% confidence interval, 1% to 24%). Two additional patients achieved disease stabilization. All responses were observed in cisplatin-refractory patients, including three who had not responded to previous HDCT. Patients received a median two cycles of oxaliplatin with a median cumulative dose of 350 mg/m2. Hematologic toxicity was generally mild, with five patients developing grade 3/4 thrombocytopenia. Nonhematologic side effects consisted mainly of nausea/vomiting. One patient developed grade 3 neurotoxicity. CONCLUSION: Considering the particularly unfavorable prognostic characteristics of this patient population compared with patients from previous trials for new drugs in germ cell cancer, eg, paclitaxel and gemcitabine, a 13% overall response rate and a 19% response rate in the group treated with oxaliplatin 130 mg/m2 seems to be of interest. Oxaliplatin may be a palliative treatment option for this patient population, and evaluation in combination regimens is warranted.
Second Primary Cancer After Chimeric Antigen Receptor–T-Cell Therapy
Authors: Patel Shyam A. , Spiegel Jay Y. , Dahiya Saurabh 
Published: December 2024

ImportanceThe commercialization of chimeric antigen receptor–T-cell (CAR-T) therapy has changed the landscape of treatment of hematological cancers. Numerous studies from the early 2000s paved the way for cell-based targeted therapeutics, which have been established as practice-changing therapies in lymphoma, leukemia, and multiple myeloma. However, there has been some recent concern about the risk for second primary cancers (SPCs).ObservationsMultiple cases of SPCs arising after CAR-T therapy have been reported to the US Food and Drug Administration. Most SPCs have been negative for the chimeric antigen receptor transgene, with rare reports of transgene-positive cancers. This review summarizes the most salient literature on epidemiology and pathobiology of SPCs after CAR-T therapy. Additionally, a discussion is provided on potential mitigation strategies for SPCs after CAR-T therapies.Conclusions and RelevanceThe results of this review suggest that there are limited data to suggest that inadvertent transgene insertion is associated with SPCs in the post–CAR-T setting. Nonetheless, evidence-based practical solutions and scientific strategies for risk mitigation can be implemented. These include optimization of T-cell manufacturing, application of safer synthetic immunobiology, and implementation of high-fidelity genomic testing, including baseline screening for clonal hematopoiesis. These strategies may inform optimal design of the next generation of CAR-T products that confer minimal risk for SPCs such that the risk-benefit profile remains favorable to proceed with CAR-T administration for eligible patients.
Oncological Safety of MRI-Informed Biopsy Decision-Making in Men With Suspected Prostate Cancer
Authors: Hamm Charlie A. , Asbach Patrick , Pöhlmann Anna , Schoots Ivo G. , Kasivisvanathan Veeru , Henkel Thomas O. , Johannsen Manfred , Speck Thomas , Baur Alexander D. J. , Haas Matthias , Collettini Federico , Penzkofer Tobias , Savic Lynn J. , Konietschke Frank , Weißbach Lothar , Hamm Bernd , König Frank , Cash Hannes 
Published: December 2024

ImportanceThe magnetic resonance imaging (MRI) pathway for diagnosing clinically significant prostate cancer (csPCa; defined as International Society of Urological Pathology grade group ≥2) uses multiparametric MRI (mpMRI) for prostate biopsy (PB) decision-making. However, the intermediate impact on patient outcomes in men with negative MRI results avoiding PB and men with positive MRI results without PCa remains unknown.ObjectiveTo assess the feasibility and safety of a community-based MRI diagnostic strategy in men with suspected PCa using 3-year active monitoring.Design, Setting, and ParticipantsThis multisite, longitudinal cohort trial took place across 54 community-based urology practices and 2 radiology imaging centers at a referral academic institution in Berlin, Germany. Eligible participants aged 18 to 75 years with clinically suspected PCa were enrolled between September 2016 and December 2017 and monitored for 3 years. Final analysis was reported on December 23, 2023.ExposuresParticipants underwent 3-T mpMRI. Men with findings suspected to be PCa were recommended for targeted PB (diagnostic phase). Men with negative mpMRI results or positive mpMRI results with benign findings at PB were systematically monitored for 3 years (monitoring phase). Clinical visits were recommended every 6 months.Main Outcomes and MeasuresThe total proportion of men avoiding PB and those with csPCa.ResultsA total of 593 men (median [IQR] age, 64 [58-70] years) underwent mpMRI, with 286 (48%) having negative MRI results, 261 (44%) avoiding PB initially, and 242 (41%) avoiding PB over 3 years. csPCa was detected in 161 (27%) men after immediate PB, increasing to 172 (29%) men after 3 years. Seven men with negative MRI results were diagnosed with PCa by immediate PB (including 4 cases of csPCa), while 279 entered monitoring. Three-year monitoring was completed by 233 (84%) men, with 7 diagnoses of csPCa. Of 307 men with positive MRI results, 58 (19%) showed no PCa after immediate PB, of which 41 (71%) completed monitoring and 4 (7%) were diagnosed with csPCa.Conclusions and RelevanceIn this cohort study, men with negative mpMRI results avoiding biopsy were not at elevated risk of csPCa. The study confirms the oncological safety of the prebiopsy MRI strategy of avoiding an immediate PB after negative MRI results when a programmatic safety net is in place.
A Magnetically Self‐Aligning, Fast Full‐Device Self‐Healing, Skin‐Attachable Liquid Metal Strain Sensor Based on Photothermal Polyurethane
Authors: Kim Jung Wook , Kim Somin , Lee Jinyoung , Kim Yongju , Ha Jeong Sook 
Published: December 2024

AbstractThere is a growing need for research on self‐healing materials capable of spontaneously repairing physical damage, allowing the fabrication of highly durable wearable devices featuring flexibility and stretchability. Herein, the study reports on the fabrication of a novel, magnetically aligning, fully and rapidly self‐healing skin‐attachable biosensor based on newly synthesized photothermally self‐healing polyurethane. By introducing photothermal amine‐capped aniline trimers to selectively self‐healable polyurethane, the synthesized self‐healing polymer achieves a fast and high recovery rate of 81.1% from complete bisection upon laser irradiation for just 3 min. Additionally, a thin‐film type strain sensor fabricated via the spray patterning of liquid metal EGaIn as an electrode onto the surface of the self‐healing polymer exhibits a high sensitivity to strain from deformation, enabling the real‐time monitoring of bio‐signals. Furthermore, the integration of a magnetic aligning layer directly patterned and embedded onto the self‐healing polymer enhances the self‐healing performance of the sensor after damage by 4.3 times on average, compared to when using manual alignment. In short, this work demonstrates a high‐performance fully self‐healing electronic device via the synthesis of novel fast self‐healing photothermal polymers and the introduction of patterned liquid metal electrodes and magnetic alignment layers.