Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 16367949 | Cytokine profile during latent and slowly progressive primary tuberculosis: a possible rol | 2006 Jan | Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection. | |
| 18672895 | The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal con | 2008 Aug 26 | Inhibitors of dihydroorotate dehydrogenase (DHODH) have been suggested for the treatment of rheumatoid arthritis, psoriasis, autoimmune diseases, Plasmodium, and bacterial and fungal infections. Here we present the structures of N-terminally truncated (residues Met30-Arg396) DHODH in complex with two inhibitors: a brequinar analogue (6) and a novel inhibitor (a fenamic acid derivative) (7), as well as the first structure of the enzyme to be characterized without any bound inhibitor. It is shown that 7 uses the "standard" brequinar binding mode and, in addition, interacts with Tyr356, a residue conserved in most class 2 DHODH proteins. Compared to the inhibitor-free structure, some of the amino acid side chains in the tunnel in which brequinar binds and which was suggested to be the binding site of ubiquinone undergo changes in conformation upon inhibitor binding. Using our data, the loop regions of residues Leu68-Arg72 and Asn212-Leu224, which were disordered in previously studied human DHODH structures, could be built into the electron density. The first of these loops, which is located at the entrance to the inhibitor-binding pocket, shows different conformations in the three structures, suggesting that it may interfere with inhibitor/cofactor binding. The second loop has been suggested to control the access of dihydroorotate to the active site of the enzyme and may be an important player in the enzymatic reaction. These observations provide new insights into the dynamic features of the DHODH reaction and suggest new approaches to the design of inhibitors against DHODH. | |
| 18653583 | Predictors of adverse events in surgical admissions in Australia. | 2008 Dec | OBJECTIVE: The purpose of this study was to determine risk factors of adverse events in five surgical procedures. DESIGN: Retrospective record review was used to determine adverse events and risk factors of 1,177 surgical admissions. Procedures included in this study were transurethral resection of prostate, hysterectomy, hip and knee arthroplasty, cholecystectomy and herniorrhaphy. Risk factors included comorbidity, lifestyle factors and medications. Stepwise multiple logistic regression was used to determine predictors of adverse events. SETTING: Two teaching hospitals in regional New South Wales, Australia. PARTICIPANTS: 1,177 surgical admissions for five high volume procedures. MAIN OUTCOME MEASURES: Identified predictors of adverse events in surgical admissions. RESULTS: The adverse event rate was 23.1% for all procedures (range 17.5-33.7% for the five procedures). Two factors were strongly predictive of an adverse event in all surgical admissions: age >70 years [odds ratio (OR) 1.9, 95% confidence intervals (CI) 1.3-2.6] and duration of operation (P = 0.005). Other predictive factors were: contaminated surgical site (OR 2.1, 95% CI 1.2-3.7) and anaemia (OR 1.8, 95% CI 1.1-2.8). Predictive factors of individual procedures included: urine retention (transurethral resection of the prostate); extended duration of operation and asthma (hysterectomy); acute admissions and extended duration of operation (cholecystectomy); and warfarin type drugs, ethanol abuse, failed prostheses, GI ulcer/inflammation, rheumatoid arthritis, and ischaemic heart disease (hip and knee joint arthroplasty). CONCLUSIONS: The results of this study suggest that five factors should be routinely monitored for patients undergoing these procedures: age >70 years, type of procedure, duration of operation >2 h, contaminated surgical site and anaemia. | |
| 18555860 | [Metal-on-metal hip replacement using Metasul cups cemented into Muller reinforcement ring | 2008 Jun | PURPOSE OF THE STUDY: Early loosening, before a three-year follow-up, has been observed with cemented cups having a metal-on-metal insert in a polyethylene cup. The metal-on-metal bearing has been incriminated as the source of the problem because of its rigidity (particularly for small cups measuring less than 50 mm) and the creation of stress conditions unfavorable for a cemented fixation. The purpose of this retrospective study was to determine whether this phenomenon is observed when the cement is fixed not directly into the bone, but via a Muller reinforcement ring. MATERIAL AND METHODS: From 1998 to 2004, 23 arthroplasties using a cemented Metasul cup in a reinforcement ring were implanted in 22 patients (16 women and six men) aged on average 44 years (range 24-56 years). The series included six primary total hip arthroplasties (three for dysplasia, two for protrusions, one for rheumatoid arthritis and one for arthritic degradation) and seventeen revisions (two septic). The Metasul cup (Zimmer-Centerpulse) combined a 28 mm modular head anchored in a femoral implant (two cemented, 21 pressfit) and a polyethylene cup with a Metasul insert (13 of 23 measuring<50mm). In all cases, the cup was fixed with low-viscosity cement in a Myller metal reinforcement ring fixed with screws (Zimmer-Centerpulse). All patients were reviewed clinically and radiographically at a mean 5-year follow-up (range 3-8 years). Acetabular and femoral fixation were analysed (search for lucency and implant migration). RESULTS: Revision was not necessary in any patient for failure of the acetabular fixation. The mean Postel-Merle-d'Aubigné score improved from 12.9 points (range 7-17) to 17.5 points (range 16-18). The radiographic analysis did not reveal any sign of lucency between the cup and ring, nor any migration of the ring. There was no evidence of femoral osteolysis but one femoral revision was needed due to fracture of the lateral cortical identified six weeks after implantation. DISCUSSION AND CONCLUSION: Cementing the metal-on-metal cup into a reinforcement ring can avoid the risk of loosening observed after direct cementing into bone. In our study, the large number of small cups (13/23) would have been expected to produce a high rate of acetabular lucent lines and/or a high rate of early revision, as reported by others, as early as 24 months. Our series was also different from others by the use of pressfit femoral implants in most patients, which should reduce the risk of cement debris in the bearing. Longer follow-up will be necessary to confirm the good results observed to date which suggest that direct cementing of the cup into the bone should be incriminated rather than the metal-on-metal bearing to explain the reported failure of cemented Metasul cups. | |
| 18490742 | Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocyt | 2008 Jun 1 | Chronic inflammatory diseases are characterized by local tissue injury caused by immunocompetent cells, in particular CD4(+) T lymphocytes, that are involved in the pathogenesis of these disorders via the production of distinctive sets of cytokines. Here, we have characterized single CD4(+) T cells that infiltrate inflamed tissue taken from patients with psoriasis, Crohn's disease, rheumatoid arthritis, or allergic asthma. Results from a cytokine production and gene profile analysis identified a population of in vivo differentiatedretinoid-related orphan receptor gamma-expressing T cells, producing high levels of IL-17, that can represent up to 30% of infiltrating T lymphocytes. Activated Th17 cells produced IL-26, TNF-alpha, lymphotoxin-beta, and IL-22. IL-17 and IL-22 concentrations secreted by tissue infiltrating Th17 cells could reach up to 100 nM and were inversely correlated with the production of Th1- and Th2-associated cytokines. In addition, tissue-infiltrating Th17 cells are also characterized by high cell surface expression of CCR6, a chemokine receptor that was not expressed by Th1 and Th2 cells, isolated from the same lesions, and by the production of CCL20/MIP3alpha, a CCR6 ligand, associated with tissue infiltration. Culture supernatants of activated Th17 cells, isolated from psoriatic lesions, induced the expression of gene products associated with inflammation and abnormal keratinocyte differentiation in an IL-17 and IL-22-dependent manner. These results show that tissue-infiltrating Th17 cells contribute to human chronic inflammatory disease via the production of several inflammatory cytokines and the creation of an environment contributing to their migration and sequestration at sites of inflammation. | |
| 18292978 | FRAX and the assessment of fracture probability in men and women from the UK. | 2008 Apr | A fracture risk assessment tool (FRAX) is developed based on the use of clinical risk factors with or without bone mineral density tests applied to the UK. INTRODUCTION: The aim of this study was to apply an assessment tool for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The clinical risk factors, identified from previous meta-analyses, comprised body mass index (BMI, as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily. METHODS: Four models were constructed to compute fracture probabilities based on the epidemiology of fracture in the UK. The models comprised the ten-year probability of hip fracture, with and without femoral neck BMD, and the ten-year probability of a major osteoporotic fracture, with and without BMD. For each model fracture and death hazards were computed as continuous functions. RESULTS: Each clinical risk factor contributed to fracture probability. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m(2)) ranged from 0.2% at the age of 50 years for women without CRF's to 22% at the age of 80 years with a parental history of hip fracture (approximately 100-fold range). In men, the probabilities were lower, as was the range (0.1 to 11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5% to 31% in women, and from 2.8% to 15% in men in the example above. The presence of one or more risk factors increased probabilities in an incremental manner. The differences in probabilities between men and women were comparable at any given T-score and age, except in the elderly where probabilities were higher in women than in men due to the higher mortality of the latter. CONCLUSION: The models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD. | |
| 17602710 | Type IV collagen-derived angiogenesis inhibitors. | 2007 Sep | The concept of anti-angiogenesis therapy was introduced by Judah Folkman in 1971 and since then, a plethora of pro- and anti-angiogenic factors have been identified. In the recent years, it has become clear that angiogenesis, the formation of new capillaries from a pre-existing capillary network, is highly regulated by the action of pro- and anti-angiogenic factors. In the healthy adult organism the "angiogenic-switch" is likely turned "Off", i. e. anti-angiogenic factors are likely counteracting the pro-angiogenic factors resulting in a non-angiogenic state. Angiogenesis is encountered during wound healing processes, the female menstrual cycle and endometrial remodeling, as well as during embryonic development and organ growth. In the pathological setting, angiogenesis plays an important role in different diseases like rheumatoid arthritis, psoriasis, macular degeneration, diabetic retinopathy, and tumor growth. In this regard, recent studies have described several endogenous inhibitors of angiogenesis, with a subset derived from extracellular matrix (ECM) proteins. This review will particularly focus on the type IV collagen-derived angiogenesis inhibitors Arresten, Canstatin and Tumstatin. | |
| 17456793 | Estrogen-enhanced peptidylarginine deiminase type IV gene (PADI4) expression in MCF-7 cell | 2007 Jul | Human peptidylarginine deiminase type IV (PAD4), a Ca(2+)-dependent enzyme known to convert arginine residues to citrulline residues in histones, has been shown to be associated with the development of rheumatoid arthritis. Recently, it was noted that the human peptidylarginine deiminase type IV gene (PADI4) regulates the expression of estrogen-responsive genes by modifying the methylated arginine sites in histones H3 and H4. In this study, we demonstrated that PADI4 was expressed in MCF-7 cells and was responsive to estrogen at the transcriptional level. Using the luciferase reporter gene fused to wild-type or mutated 5'-flanking region of PADI4, we characterized that as few as 348 bp upstream from the transcription initiation site were sufficient to direct transcription of the reporter gene. Chromatin immunoprecipitation and small interfering RNA assays revealed that activator protein-1, Sp1/Sp3, and nuclear factor-Y were cis-acting factors bound to the minimal promoter of PADI4 and that they regulated gene expression in a cooperative manner. Moreover, it was indicated that estrogen stimulated PADI4 expression through binding of estrogen receptor (ER)-alpha to the upstream of the PADI4 gene and ERalpha-mediated enhancement of activator protein-1, Sp1, and nuclear factor-Y levels. These findings indicated that estrogen stimulated PADI4 expression through both of the classical and nonclassical ER-mediated pathways. | |
| 17437686 | Tumor necrosis factor inhibitors for the treatment of asthma. | 2007 May | Asthma is a unique form of chronic airway inflammation characterized by reversible airway obstruction, airway hyperresponsiveness and the production of specific inflammatory mediators. Local activation of both immune and nonimmune cells in the lung triggers the release of these immunomodulator molecules. Among them, tumor necrosis factor (TNF)-alpha, a multipotent pro-inflammatory mediator, plays a critical role in immunoregulation of asthma by contributing to bronchopulmonary inflammation and airway hyperresponsiveness. Blocking TNF-alpha activity has already shown outstanding efficacy in other chronic inflammatory diseases including rheumatoid arthritis, Crohn's disease, and psoriasis. The successful treatment of these other chronic inflammatory diseases provides hope that TNF inhibitors may have application for the treatment of asthma. Recent developments in animal models and clinical trials in patients with severe asthma provide strong support for the concept that blocking TNF-alpha activity represents a new approach in asthma therapy. In this review, we address the multipotential role of TNF-alpha in asthma and the efficacy and safety of TNF-alpha blocking agents in asthma. | |
| 17292918 | The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain. | 2007 Mar 30 | c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases (RTKs), is the receptor for macrophage colony stimulating factor (CSF-1) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal expression of c-fms proto-oncogene is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target. To further understand the regulation of c-Fms, we determined the 2.7 A resolution crystal structure of the cytosolic domain of c-Fms that comprised the kinase domain and the juxtamembrane domain. The structure reveals the crucial inhibitory role of the juxtamembrane domain (JM) that binds to a hydrophobic site immediately adjacent to the ATP binding pocket. This interaction prevents the activation loop from adopting an active conformation thereby locking the c-Fms kinase into an autoinhibited state. As observed for other members of the PDGF receptor family, namely c-Kit and Flt3, three JM-derived tyrosine residues primarily drive the mechanism for autoinhibition in c-Fms, therefore defining a common autoinhibitory mechanism within this family. Moreover the structure provides an understanding of c-Fms inhibition by Gleevec as well as providing a platform for the development of more selective inhibitors that target the inactive conformation of c-Fms kinase. | |
| 17200162 | Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders s | 2007 Mar | CONTEXT: A four-marker haplotype in the 5' region of the Fc receptor-like 3 gene (markers FCRL3_3 to FCRL3_6) has been identified recently as contributing to rheumatoid arthritis (RA) susceptibility in the Japanese population. The promoter FCRL3_3*C allele also showed significant association with autoimmune thyroid disease and systemic lupus erythematosus. These findings raise the possibility that this locus may influence autoimmune disease susceptibility across many populations. PATIENTS AND DESIGN: We analyzed the same four 5' FCRL3 single nucleotide polymorphism markers, together with three additional exonic single nucleotide polymorphisms in the FCRL3 gene, in cohorts of white Caucasians with Graves' disease (n = 625), type 1 diabetes (n = 279), autoimmune Addison's disease (AAD; n = 200), and RA (n = 769). Healthy controls from the United Kingdom (n = 490) and New Zealand (n = 593) were used. RESULTS: Six of the seven FCRL3 markers showed association with AAD (P = 0.005-0.0001), with maximum evidence at the FCRL3_3*T allele [P([corrected]) = 0.0008; odds ratio (OR), 1.61; 5-95% confidence intervals (CIs), 1.26-2.05]. The most common seven-marker FCRL3 haplotype (TGGGAAA) was also found to be significantly associated with AAD (P([corrected]) = 1.1 x 10(-4); OR, 1.71; 5-95% CIs, 1.33-2.18). There was nominal evidence for allelic association at the marker FCRL3_8 in Graves' disease (OR, 1.50; 5-95% CIs, 1.06-2.13) and at FCRL3_9 with RA (OR, 1.25; 5-95% CIs, 1.01-1.54). CONCLUSIONS: The FCRL3 haplotype that is associated with AAD in Caucasians appears to be protective for autoimmune diseases in the Japanese population, demonstrating that this haplotype is unlikely to contain a single primary etiological allele for autoimmunity. Our observations suggest that the susceptibility to autoimmunity at the FCRL3 locus is more complex than initially thought and may extend either side of the currently associated region to include the adjacent FCRL2 gene. | |
| 16766656 | IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of | 2006 Jun 20 | IL-15 is closely associated with inflammatory diseases. IL-15 targeting is effective in treating experimental and clinical rheumatoid arthritis (RA). Because hyperalgesia accompanies RA, we investigated the ability of IL-15 to induced nociceptor sensitization (hypernociception). We report here that IL-15 induced time- and dose-dependent mechanical hypernociception in mice. IL-15-induced hypernociception was inhibited by treatment with a dual endothelin receptor type A (ET(A))/endothelin receptor type B (ET(B)) antagonist (bosentan), ET(A) receptor antagonist (BQ123), or cyclooxygenase inhibitor (indomethacin). Moreover, IL-15 failed to induce hypernociception in IFN-gamma(-/-) mice, suggesting that IL-15 mediated hypernociception via an IFN-gamma-, endothelin (ET)-, and prostaglandin-dependent pathway. Consistent with this finding, IFN-gamma and ET-1 induced dose- and time-dependent mechanical hypernociception that was inhibited by BQ123 or indomethacin but not BQ788 (an ET(B) receptor antagonist). IFN-gamma induced the production of ET-1 and the expression of its mRNA precursor (preproET-1, PPET-1). Moreover, IL-15 also induced ET-1 production and PPET-1 mRNA expression in an IFN-gamma-dependent manner. Prostaglandin E(2) (PGE(2)) production was induced by IL-15, IFN-gamma, or ET-1. We also found that hypernociception induced by ovalbumin (OVA) in OVA-immunized mice was significantly diminished by treatment with sIL-15Ralpha (soluble IL-15 receptor alpha-chain), bosentan, BQ123, or indomethacin. Furthermore, OVA challenge induced the expression of PPET-1 mRNA in WT mice but not in IFN-gamma(-/-) mice. The PPET-1 mRNA expression was also inhibited by sIL-15Ralpha pretreatment. Therefore, our results demonstrate the sequential mechanical hypernociceptive effect of IL-15 --> IFN-gamma --> ET-1 --> PGE(2) and suggest that these molecules may be targets of therapeutic intervention in antigen-induced hypernociception. | |
| 16269426 | Differential influence of p38 mitogen activated protein kinase (MAPK) inhibition on acute | 2006 Jul | BACKGROUND: Inhibition of intracellular signal transduction is considered to be an interesting target for treatment in inflammation. p38 MAPK inhibitors, especially, have been developed and are now in phase II clinical trials for rheumatoid arthritis (RA). OBJECTIVE: To investigate the influence of p38 MAPK inhibition on acute phase protein (APP) production, which is dependent on both JAK/STAT and p38 MAPK pathways. METHODS: The effects of p38 MAPK inhibition on APP production and mRNA expression in four human hepatoma cell lines was investigated, after stimulation with interleukin (IL)6 and/or IL1beta or tumour necrosis factor alpha. RESULTS: Two out of four cell lines produced C reactive protein (CRP), especially after combined IL6 and IL1beta stimulation. CRP production was significantly inhibited by the p38 MAPK specific inhibitor RWJ 67657 at 1 micromol/l, which is pharmacologically relevant. Fibrinogen production was also inhibited at 1 micromol/l in all cell lines. Serum amyloid A (SAA) was produced in all four lines. In contrast with CRP, SAA production was not inhibited by RWJ 67657 at 1 micromol/l. CONCLUSION: Production and mRNA expression of CRP and fibrinogen, but not SAA production and mRNA expression, were significantly inhibited by p38 MAPK specific inhibitor in hepatoma cell lines. For p38 MAPK inhibitor treatment in RA SAA might be a better marker of disease activity than CRP and fibrinogen, because SAA is not directly affected by p38 MAPK inhibition. | |
| 18951733 | EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate. | 2009 | Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein-Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation. | |
| 18675462 | Granzyme B: evidence for a role in the origin of myasthenia gravis. | 2008 Sep 15 | PURPOSE OF RESEARCH: Although the pathogenesis of myasthenia gravis (MG) as an antibody mediated disorder of acetylcholine receptors (AChRs) at neuromuscular junctions is well understood, the origin of the autoimmune response is unclear. The thymus is intimately involved in initiation of the autoimmune response; the antigen, AChR, is present in the thymus, but how the autoimmune response is triggered is not known. Granzyme B (GrB), a proteolytic enzyme present in cytolytic T cells and natural killer (NK) cells, selectively cleaves many potential autoantigens (but few non-autoantigens), generating novel fragments that trigger autoreactive responses. This protease has been strongly implicated in the pathogenesis of several autoimmune diseases including lupus, rheumatoid arthritis, dermatomyositis, and others. In the studies described in this manuscript, we examined the ability of GrB to cleave the AChR subunits, and performed biochemical, immunohistochemical and molecular studies on thymus glands from myasthenic patients and controls to assess GrB expression. MAIN RESULTS: GrB efficiently and specifically cleaves subunits of AChR, especially the epsilon subunit. GrB is present in thymus glands from myasthenia patients, but is absent in control thymuses. CONCLUSIONS: Our results provide evidence supporting a potential role for GrB in the process of initiation of MG, and are consistent with the concept of an immunodominant epsilon epitope. | |
| 20641575 | 4-[(18)F]Fluorobenzoyl-NAVPNLRGDLQVLAQKVART. | 2004 | Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3) and α(v)β(6). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). The α(v)β(6) integrin plays an important role in the development of epithelial cells and is nearly undetectable in adult normal tissues. However, levels of the α(v)β(6) integrin can be upregulated during tissue remodeling and wound healing (11). On the other hand, α(v)β(6) integrin is strongly expressed on tumor cells of the oral cavity, pancreas, breast, ovary, colon, and stomach (12-14). The α(v)β(6) integrin affects tumor growth, tumor invasiveness, and metastasis (13). α(v)β(6) binds to the RGD motif in fibronectin, tenascin, and the viral protein 1 (VP1) of the foot-and-mouth disease virus (FMDV) (15). FMDV binds to cells through the RGD motif of the GH loop of the VP1. A consensus α(v)β(6)-binding motif DLXXL was identified with phage display screening with minimal binding to α(v)β(3), α(IIb)β(3), and α(v)β(5) (16). A peptide of 20 amino acids, NAVPNLRGDLQVLAQKVART (A20FMDV2), was identified as a ligand binding to α(v)β(6) integrin (15). A20FMDV2 was radiolabeled with N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) to study in vivo biodistribution of the tracer in tumor-bearing mice (17). [(18)F]FB-A20FMDV2 was found to have specific accumulation in α(v)β(6)-positive tumor. | |
| 18434566 | Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus C | 2008 Jun | We determined cyclo-oxygenase-1 and cyclo-oxygenase-2 inhibition in healthy middle-aged subjects (41-65 years) randomly assigned to four 7-day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double-blind, randomized, 4-period crossover study. Maximum inhibition of thromboxane B(2) (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E(2) in whole blood (cyclo-oxygenase-2 activity) was assessed on day 7 (0-24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B(2) versus each comparator (P < .001); placebo 2.4% (95% confidence interval: -8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E(2) synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo-oxygenase-1 and cyclo-oxygenase-2, whereas etoricoxib and celecoxib significantly inhibit cyclo-oxygenase-2 and do not substantially inhibit cyclo-oxygenase-1. | |
| 18164590 | Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation | 2008 Mar | Strong evidence suggests that neutrophils may play an active role in acute and chronic inflammatory disorders, such as rheumatoid arthritis and atherosclerosis. Given the role of pro-inflammatory cytokine TNF-alpha in these inflammatory processes, we planned the present study to investigate the effect of short term incubation with TNF-alpha on neutrophil migration to CCL3, a chemokine produced in inflammatory sites and normally devoid of neutrophil chemotactic properties. We found that TNF-alpha primed neutrophils for migration to CCL3 via CCR5. TNF-alpha-induced migration was a consequence of the TNF-alpha-induced up-regulation of integrin CD11b/CD18 (Mac-1) on neutrophil surface. Furthermore, TNF-alpha activity was found to be strictly dependent on the activation of ERK 1/2 p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical chemoattractants (CXCL8) or priming agents (GM-CSF). On the contrary, the effect of TNF-alpha on neutrophil migration to CCL3 was not dependent on JNK 1/2. In conclusion, the present report shows that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1. TNF-alpha regulates Mac-1 up-regulation through signalling pathways, involving various kinases, but not JNK 1/2. Although highly speculative, ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutrophil-mediated adverse activities in TNF-alpha-mediated inflammatory states. | |
| 17997386 | Targeting phosphoinositide 3-kinase: moving towards therapy. | 2008 Jan | Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PIK3CA locus coding for PI3Kalpha, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3Kgamma (p110gamma) and PI3Kdelta (p110delta) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3Kgamma have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PK(cs)) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of >400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase I) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II). | |
| 17898653 | Red blood cell methotrexate polyglutamate concentrations in inflammatory bowel disease. | 2007 Oct | Methotrexate (MTX) use in inflammatory bowel disease (IBD) is complicated by unpredictable efficacy and toxicity. In rheumatoid arthritis, total and individual red blood cell MTX polyglutamates (RBC MTXGlu1-5) correlate with disease activity and possibly toxicity, and therefore may be useful in guiding treatment. It is unclear if this applies in IBD. The aim of this pilot study was to measure total and individual RBC MTXGlu1-5 concentrations in patients with IBD to see if these relate to efficacy and adverse effects. RBC MTXGlu1--5 concentrations were measured on three occasions in 18 patients with IBD receiving MTX at a constant dose for 3 or more months. The intrapatient variability, expressed as the coefficient of variation, of RBC MTXGlu1-5 concentrations at steady state was determined, and disease activity and adverse effects were assessed against concentrations. The intrapatient coefficients of variation of individual MTXGlu1-5 varied from 12% to 27%. In Crohn's disease, higher RBC MTXGlu4&5 concentrations correlated with worse disease activity (r = 0.42 and 0.53, respectively, P |