bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression, regulation, and signaling of the pattern‐recognition receptor nucleotide‐binding oligomerization domain 2 in rheumatoid arthritis synovial fibroblasts
Authors: Ospelt Caroline , Brentano Fabia , Jüngel Astrid , Rengel Yvonne , Kolling Christoph , Michel Beat A. , Gay Renate E. , Gay Steffen 
Published: January 2009

AbstractObjectiveSince pattern‐recognition receptors (PRRs), in particular Toll‐like receptors (TLRs), were found to be overexpressed in the synovium of rheumatoid arthritis (RA) patients and to play a role in the production of disease‐relevant molecules, we sought to determine the expression, regulation, and function of the PRR nucleotide‐binding oligomerization domain 2 (NOD‐2) in RA.MethodsExpression of NOD‐2 in synovial tissues was analyzed by immunohistochemistry. Expression and induction of NOD‐2 in RA synovial fibroblasts (RASFs) were measured by conventional and real‐time polymerase chain reaction (PCR) analyses. Levels of interleukin‐6 (IL‐6) and IL‐8 were measured by enzyme‐linked immunosorbent assay (ELISA) and expression of matrix metalloproteinases (MMPs) by ELISA and/or real‐time PCR. NOD‐2 expression was silenced with small interfering RNA. Western blotting with antibodies against phosphorylated and total p38, JNK, and ERK, as well as inhibitors of p38, JNK, and ERK was performed. Activation of NF‐κB was measured by electrophoretic mobility shift assay.ResultsNOD‐2 was expressed by fibroblasts and macrophages in the synovium of RA patients, predominantly at sites of invasion into articular cartilage. In cultured RASFs, no basal expression of messenger RNA for NOD‐2 was detectable, but was induced by poly(I‐C), lipopolysaccharide, and tumor necrosis factor α. After up‐regulation of NOD‐2 by TLR ligands, its ligand muramyl dipeptide (MDP) increased the expression of IL‐6 and IL‐8 via p38 and NF‐κB. Stimulation with MDP further induced the expression of MMP‐1, MMP‐3, and MMP‐13.ConclusionNot only TLRs, but also the PRR NOD‐2 is expressed in the synovium of RA patients, and activation of NOD‐2 acts synergistically with TLRs in the production of proinflammatory and destructive mediators. Therefore, NOD‐2 might contribute to the initiation and perpetuation of chronic, destructive inflammation in RA.
Genetic risk factors for rheumatoid arthritis differ in caucasian and Korean populations
Authors: Lee Hye‐Soon , Korman Benjamin D. , Le Julie M. , Kastner Daniel L. , Remmers Elaine F. , Gregersen Peter K. , Bae Sang‐Cheol 
Published: January 2009

AbstractObjectiveRecent studies have identified a number of novel rheumatoid arthritis (RA) susceptibility loci in Caucasian populations. The aim of this study was to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case–control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well‐established autoimmune disease–associated gene.MethodsWe designed an experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region, using tag single‐nucleotide polymorphisms (SNPs) and disease‐associated SNPs at 5 RA‐associated loci recently identified in Caucasians, in 1,128 Korean patients with RA and 1,022 ethnically matched control subjects. We also resequenced the PTPN22 gene to seek novel coding variants that might be contributing to disease in this population.ResultsNone of the susceptibility loci identified in Caucasian patients with RA contributed significantly to disease in Koreans. Although tag SNPs covering the PTPN22 linkage disequilibrium block were polymorphic, they did not reveal any disease association, and resequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were nonpolymorphic in this population, and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association with RA in this population of Korean patients.ConclusionThe genetic risk factors for RA are different in Caucasian and Korean patients. Although patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean patients with RA.
Altered integrin mechanotransduction in human nucleus pulposus cells derived from degenerated discs
Authors: Le Maitre Christine Lyn , Frain Jennie , Millward‐Sadler Jane , Fotheringham Andrew P. , Freemont Anthony John , Hoyland Judith Alison 
Published: January 2009

AbstractObjectiveSeveral studies have demonstrated biologic responses of intervertebral disc (IVD) cells to loading, although the mechanotransduction pathways have not been elucidated. In articular chondrocytes, which have a phenotype similar to that of IVD cells, a number of mechanoreceptors have been identified, with α5β1 integrin acting as a predominant mechanoreceptor. The purpose of this study was to investigate the role of integrin signaling in IVD cells during mechanical stimulation and to determine whether RGD integrins are involved.MethodsHuman nucleus pulposus (NP) cells derived from nondegenerated and degenerated discs were subjected to dynamic compressive loading in the presence of an RGD inhibitory peptide. Expression of the α5β1 heterodimer in IVD tissue was examined by immunohistochemistry and possible alternative mechanoreceptors by real‐time quantitative polymerase chain reaction.ResultsAggrecan gene expression was decreased following loading of NP cells from nondegenerated and degenerated discs. This response was inhibited by treatment with an RGD peptide in cells from nondegenerated, but not degenerated, IVDs. Immunohistochemistry demonstrated that expression of the α5β1 heterodimer was unaltered in degenerated IVD tissue as compared with normal IVD tissue.ConclusionOur results indicate that the mechanotransduction pathways are altered in cells from degenerated IVDs. Mechanosensing in NP cells from nondegenerated discs occurs via RGD integrins, possibly via the α5β1 integrin, while cells from degenerated discs show a different signaling pathway that does not appear to involve RGD integrins.
Tissue targeting of anti‐RNP autoimmunity: Effects of T cells and myeloid dendritic cells in a murine model
Authors: Greidinger Eric L. , Zang YunJuan , Fernandez Irina , Berho Mariana , Nassiri Mehdi , Martinez Laisel , Hoffman Robert W. 
Published: January 2009

AbstractObjectiveTo explore the role of immune cells in anti‐RNP autoimmunity in a murine model of pneumonitis or glomerulonephritis, using adoptive transfer techniques.MethodsDonor mice were immunized with 50 μg of U1–70‐kd small nuclear RNP fusion protein and 50 μg of U1 RNA adjuvant. Whole splenocytes as well as CD4+ cell and dendritic cell (DC) subsets from the immunized mice were infused into naive syngeneic recipients. Anti‐RNP and T cell responses were assessed by immunoblotting, enzyme‐linked immunosorbent assay, and flow cytometry. Development of renal or lung disease was assessed by histology and urinalysis.ResultsUnfractionated splenocytes from donor mice without proteinuria induced predominantly lung disease in recipients (8 [57%] of 14 versus 2 [14%] of 14 developing renal disease; P = 0.046). However, infusion of CD4+ cells from donors without proteinuria induced renal disease more frequently than lung disease (7 [70%] of 10 versus 2 [20%] of 10; P = 0.01); adoptive transfer of RNP+CD4+ T cells from short‐term culture yielded similar results (renal disease in 8 [73%] of 11 recipients versus lung disease in 3 [27%] of 11). Cotransfer of splenic myeloid DCs and CD4+ T cells from immunized donors prevented induction of renal disease in all 5 recipients (P = 0.026 versus recipients of fresh CD4+ cells alone), although lung disease was still observed in 1 of 5 mice. Transfer of myeloid DCs alone from immunized donors induced lung disease in 3 (60%) of 5 recipients, without evidence of nephritis. Cotransfer of splenocytes from mice with and those without nephritis led to renal disease in 4 of 5 recipients, without evidence of lung disease.ConclusionThese findings indicate that RNP+CD4+ T cells are sufficient to induce anti‐RNP autoimmunity, tissue targeting in anti‐RNP autoimmunity can be deviated to either a renal or pulmonary phenotype depending on the presence of accessory cells such as myeloid DCs, and DC subsets can play a role in both propagation of autoimmunity and end‐organ targeting.
Increased expression of CD40 on bone marrow CD34+ hematopoietic progenitor cells in patients with systemic lupus erythematosus: Contribution to Fas‐mediated apoptosis
Authors: Pyrovolaki Katerina , Mavroudi Irene , Sidiropoulos Prodromos , Eliopoulos Aristides G. , Boumpas Dimitrios T. , Papadaki Helen A. 
Published: January 2009

AbstractObjectivePatients with systemic lupus erythematosus (SLE) display increased apoptosis of bone marrow (BM) CD34+ hematopoietic progenitor cells. This study was undertaken to evaluate the expression of CD40 and CD40L in the BM of SLE patients, and to explore the possible involvement of these molecules in apoptosis of CD34+ cells.MethodsThe proportion and survival characteristics of CD40+ cells within the BM CD34+ fraction from SLE patients and healthy controls were evaluated by flow cytometry. The production of CD40L by BM stromal cells was assessed using long‐term BM cultures, and the effect of CD40L on the survival characteristics and clonogenic potential of CD34+ cells was evaluated ex vivo by flow cytometry and clonogenic assays.ResultsSLE patients displayed an increased proportion of CD40+ cells within the CD34+ fraction as compared with controls. The CD34+CD40+ subpopulation contained an increased proportion of apoptotic cells compared with the CD34+CD40− fraction in patients and controls, suggesting that CD40 is involved in the apoptosis of CD34+ cells. Stimulation of patients' CD34+ cells with CD40L increased the proportion of apoptotic cells and decreased the proportion of colony‐forming cells as compared with untreated cultures. The CD40L‐mediated effects were amplified following treatment with recombinant Fas ligand, suggesting that the effects of these ligands are synergistic. CD40L levels were significantly increased in long‐term BM culture supernatants and adherent layers of BM cells from SLE patients as compared with controls.ConclusionThese data reveal a novel role for the CD40/CD40L dyad in SLE by demonstrating that up‐regulation and induction of CD40 on BM CD34+ cells from patients with SLE contribute to the amplification of Fas‐mediated apoptosis of progenitor cells.
Unmasking of a protective tumor necrosis factor receptor I–mediated signal in the collagen‐induced arthritis model
Authors: Williams‐Skipp Cheryll , Raman Thiagarajan , Valuck Robert J. , Watkins Herschel , Palmer Brent E. , Scheinman Robert I. 
Published: January 2009

AbstractObjectiveTo examine the relative importance of tumor necrosis factor receptor I (TNFRI) signaling in the hematopoietic tissue compartment in the progression of collagen‐induced arthritis (CIA), a model of rheumatoid arthritis (RA).MethodsDBA/1 mice were administered a lethal radiation dose and were then rescued with bone marrow derived from either DBA/1 or TNFRI−/− mice. CIA was then induced, and disease progression was characterized.ResultsSurprisingly, mice with CIA that received TNFRI−/− donor marrow developed increased disease severity as compared with control mice with CIA. This could not be attributed to an increased primary response to collagen or to the contribution of a non‐DBA genetic background. In mice that received TNFRI−/− bone marrow, histologic markers of advanced disease were evident shortly after initiation of the immune response to collagen and long before clinical evidence of disease. Serum TNFα was undetectable, whereas serum interleukin‐12 p40 levels were increased, at the end point of the study in mice that received TNFRI−/− bone marrow.ConclusionThese data raise the intriguing possibility of the existence of an antiinflammatory, TNFRI‐mediated circuit in the hematopoietic compartment. This circuit bears a resemblance to the switch in TNFα function that has been observed during the resolution of bacterial infections. These data suggest that TNFRI‐mediated signals in the radioresistant tissues contribute to disease progression, whereas TNFRI‐mediated signals in the radiosensitive tissues can contribute to protection from disease. We thus put forward the hypothesis that the degree of response to TNFα blockade in RA is dependent in part on the relative genetic strengths of these 2 pathways.
Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double‐blind, methotrexate‐controlled study of patients with active rheumatoid arthritis
Authors: Cohen Stanley B. , Cheng Tien‐Tsai , Chindalore Vishala , Damjanov Nemanja , Burgos‐Vargas Ruben , DeLora Patricia , Zimany Kathleen , Travers Helen , Caulfield John P. 
Published: January 2009

AbstractObjectiveTo determine the efficacy and safety of pamapimod (a selective inhibitor of the α‐isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA).MethodsPatients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double‐blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs.ResultsPatients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50‐, 150‐, and 300‐mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300‐mg dose appeared to be more toxic than either the 2 lower doses or MTX.ConclusionThe present results showed that pamapimod was not as effective as MTX in the treatment of active RA.
Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration
Authors: Pockert Aneta J. , Richardson Stephen M. , Le Maitre Christine L. , Lyon Malcolm , Deakin Jonathan A. , Buttle David J. , Freemont Anthony J. , Hoyland Judith A. 
Published: January 2009

AbstractObjectiveIntervertebral disc degeneration is linked to loss of extracellular matrix (ECM), particularly the early loss of aggrecan. A group of metalloproteinases called aggrecanases are important mediators of aggrecan turnover. The present study was undertaken to investigate the expression of the recognized aggrecanases and their inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP‐3), in human intervertebral disc tissue.MethodsTwenty‐four nondegenerated and 30 degenerated disc samples were analyzed for absolute messenger RNA (mRNA) copy number of ADAMTS 1, 4, 5, 8, 9, and 15 and TIMP‐3 by real‐time reverse transcription–polymerase chain reaction. Thirty‐six formalin‐fixed embedded intervertebral disc samples of varying grades of degeneration were used for immunohistochemical analyses. In addition, samples from 8 subjects were analyzed for the presence of matrix metalloproteinase (MMP)– and aggrecanase‐generated aggrecan products.ResultsMessenger RNA for all the aggrecanases other than ADAMTS‐8 was identified in intervertebral disc tissue, as was mRNA for TIMP‐3. Levels of mRNA expression of ADAMTS 1, 4, 5, and 15 were significantly increased in degenerated tissue compared with nondegenerated tissue. All these aggrecanases and TIMP‐3 were also detected immunohistochemically in disc tissue, and numbers of nucleus pulposus cells staining positive for ADAMTS 4, 5, 9, and 15 were significantly increased in degenerated tissue compared with nondegenerated tissue. Aggrecan breakdown products generated by MMP and aggrecanase activities were also detected in intervertebral disc tissue.ConclusionThe aggrecanases ADAMTS 1, 4, 5, 9, and 15 may contribute to the changes occurring in the ECM during intervertebral disc degeneration. Targeting these enzymes may be a possible future therapeutic strategy for the prevention of intervertebral disc degeneration and its associated morbidity.
Detection of arthritis‐susceptibility loci, including Ncf1, and variable effects of the major histocompatibility complex region depending on genetic background in rats
Authors: Rintisch Carola , Förster Michael , Holmdahl Rikard 
Published: January 2009

AbstractObjectiveTo characterize the arthritis‐modulating effects of 3 non–major histocompatibility complex (MHC) quantitative trait loci (QTLs) in rat experimental arthritis in the disease‐resistant E3 strain, and to investigate the disease‐modulating effects of the MHC region (RT1) in various genetic backgrounds.MethodsA congenic fragment containing Ncf1 along with congenic fragments containing the strongest remaining loci, Pia5/Cia3 and Pia7/Cia13 on chromosome 4, were transferred from the arthritis‐susceptible DA strain into the background of the completely resistant E3 strain. The arthritis‐regulatory potential of the transferred alleles was evaluated by comparing the susceptibility to experimental arthritis in congenic rats with that in E3 rats. The RT1u haplotype from the E3 strain was transferred into the susceptible DA strain (RT1av1), and various F1 and F2 hybrids were generated to assess the effects of RT1 on arthritis susceptibility.ResultsThe DA allele of Ncf1 did not break the arthritis resistance of the E3 rats, although it led to enhanced autoimmune B cell responses, as indicated by significantly elevated levels of anticollagen antibodies in congenic rats. Introgressing Pia5 and Pia7 loci on chromosome 4 broke the resistance to arthritis, and the MHC locus on chromosome 20 in DA rats enhanced arthritis when RT1 interacted with E3 genes.ConclusionThe findings in these congenic lines confirm the existence of 3 major QTLs that regulate the severity of arthritis and are sufficient to induce the transformation of a completely arthritis‐resistant rat strain into an arthritis‐susceptible strain. This study also reveals a dramatic difference in the arthritis‐regulatory potential of the rat MHC depending on genetic background, suggesting that strong epistatic interactions occur between MHC and non‐MHC genes.
Personal exposure to mobile communication networks and well‐being in children—A statistical analysis based on a functional approach
Authors: Kühnlein Anja , Heumann Christian , Thomas Silke , Heinrich Sabine , Radon Katja 
Published: January 2009

AbstractThe MobilEe‐study was the first cross‐sectional population‐based study to investigate possible health effects of mobile communication networks on children using personal dosimetry. Exposure was assessed every second resulting in 86,400 measurements over 24 h for each participant. Therefore, a functional approach to analyze the exposure data was considered appropriate. The aim was to categorize exposure taking into account the course of the measurements over 24 h. The analyses were based on the 480 maxima of each 3 min time interval. Exposure was classified using a nonparametric functional method. Heterogeneity of a sample of functional data was assessed by comparing the functional mode and mean of the distribution of a functional variable. The partition was built within a descending hierarchical method. The resulting exposure groups were compared with categories derived from a standard method, which used the average exposure over 24 h and set the cut‐off at the 90th percentile. The functional classification resulted in a splitting of the exposure data into two groups. Plots of the mean curves showed that the groups could be interpreted as children with “low exposure” (88%) and “higher exposure” (12%). These groups were comparable with categories of the standard method. No association between the categorized exposure and well‐being was observed in logistic regression models. The functional classification approach yielded a plausible partition of the exposure data. The comparability with the standard approach might be due to the data structure and should not be generalized to other exposures. Bioelectromagnetics 30:261–269, 2009. © 2009 Wiley‐Liss, Inc.
Two New Solanapyrone Analogues from the Endophytic Fungus Nigrospora sp. YB‐141 of Azadirachta indica
Authors: Wu Shao‐Hua , Chen You‐Wei , Shao Shi‐Cheng , Wang Li‐Dong , Yu Ying , Li Zhi‐Ying , Yang Li‐Yuan , Li Shao‐Lan , Huang Rong 
Published: January 2009

Abstractmagnified imageTwo new solanapyrone analogues, solanapyrones N and O (1 and 2, resp.), and three known compounds, solanapyrone C (3), nigrosporalactone (4), and phomalactone (5), were isolated from the fermentation culture of Nigrospora sp. YB‐141, an endophytic fungus isolated from Azadirachta indica A. Juss. The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The antifungal activities of 1–5 towards seven phytopathogenic fungi were tested. Most of the compounds exhibited no or only weak antifungal activities.
Two New Daphniphyllum Alkaloids from the Stems and Leaves of Daphniphyllum calycinum
Authors: Li Zhen‐Yu , Peng Shu‐Ying , Fang Li , Yang Yi‐Ming , Guo Yue‐Wei 
Published: January 2009

Abstractmagnified imageTwo new Daphniphyllum alkaloids, 9,10‐epoxycalycinine A (1) and homodaphniphyllate (2), together with eight known related alkaloids, were isolated from the stems and leaves of Daphniphyllum calycinum. The structures of the new compounds 1 and 2 were elucidated on the basis of in‐depth spectroscopic‐data analysis, by chemical derivatization, and by comparison of their spectroscopic data with those of known compounds.