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ID PMID Title PublicationDate abstract
22647870 Identification of new autoantigens for primary biliary cirrhosis using human proteome micr 2012 Sep Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology and is considered to be an autoimmune disease. Autoantibodies are important tools for accurate diagnosis of PBC. Here, we employed serum profiling analysis using a human proteome microarray composed of about 17,000 full-length unique proteins and identified 23 proteins that correlated with PBC. To validate these results, we fabricated a PBC-focused microarray with 21 of these newly identified candidates and nine additional known PBC antigens. By screening the PBC microarrays with additional cohorts of 191 PBC patients and 321 controls (43 autoimmune hepatitis, 55 hepatitis B virus, 31 hepatitis C virus, 48 rheumatoid arthritis, 45 systematic lupus erythematosus, 49 systemic sclerosis, and 50 healthy), six proteins were confirmed as novel PBC autoantigens with high sensitivities and specificities, including hexokinase-1 (isoforms I and II), Kelch-like protein 7, Kelch-like protein 12, zinc finger and BTB domain-containing protein 2, and eukaryotic translation initiation factor 2C, subunit 1. To facilitate clinical diagnosis, we developed ELISA for Kelch-like protein 12 and zinc finger and BTB domain-containing protein 2 and tested large cohorts (297 PBC and 637 control sera) to confirm the sensitivities and specificities observed in the microarray-based assays. In conclusion, our research showed that a strategy using high content protein microarray combined with a smaller but more focused protein microarray can effectively identify and validate novel PBC-specific autoantigens and has the capacity to be translated to clinical diagnosis by means of an ELISA-based method.
22589256 Evaluation of a shared autoimmune disease-associated polymorphism of TRAF6 in systemic scl 2012 Jun OBJECTIVE: We evaluated whether a single-nucleotide polymorphism (SNP) of the TRAF6 gene previously associated with systemic lupus erythematosus and rheumatoid arthritis may be a common risk factor for systemic sclerosis (SSc) and giant cell arteritis (GCA). METHODS: A total of 1185 patients with SSc, 479 patients with biopsy-proven GCA, and 1442 unrelated healthy controls of white Spanish origin were genotyped for the rs540386 variant using a specifically designed TaqMan(©) allele discrimination assay. RESULTS: No significant associations of this SNP with global SSc or GCA were found. This was also the case when the potential associations of the TRAF6 polymorphism with the main clinical phenotypes of the 2 diseases (e.g., limited cutaneous and diffuse cutaneous SSc, or presence of polymyalgia rheumatica and visual ischemic manifestations in GCA) were assessed. CONCLUSION: Our data do not support a role of the rs540386 TRAF6 variant as a key component of the genetic network underlying SSc and GCA.
22177922 Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation 2011 Dec 23 Ectopic lymphoid follicles are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögren's syndrome, and myasthenia gravis. However, the effector cells and mechanisms that induce their development are unknown. Here we showed that in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, Th17 cells specifically induced ectopic lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin (Pdp), which was expressed on Th17 cells, but not on other effector T cell subsets. Pdp was also crucial for the development of secondary lymphoid structures: Pdp-deficient mice lacked peripheral lymph nodes and had a defect in forming normal lymphoid follicles and germinal centers in spleen and lymph node remnants. Thus, Th17 cells are uniquely endowed to induce tissue inflammation, characterized by ectopic lymphoid follicles within the target organ.
22171395 (64)Cu-1,4,8,11-Tetraazacyclotetradecane-regioselectively addressable functionalized templ 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 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. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A peptide 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). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (IC(50), 7–40 nM) but not to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Hydrazinonicotinic acid (HYNIC) is a coupling agent for (99m)Tc labeling of peptides that can achieve high specific activities without affecting receptor-binding ability of the amino acid sequence. (99m)Tc is bound to the hydrazine group, and other coordination sites could be occupied by one or more coligands. Liu et al. (13) reported the success of radiolabeling cylco(Arg-Gly-Asp-d-Phe-Lys) (c(RGDfK)) tetramer linked by glutamic acid that was conjugated with HYNIC, which showed high tumor accumulation in nude mice bearing human tumor xenografts. Boturyn et al. (14) generated a versatile molecular “Regioselectively Addressable Functionalized Template” (RAFT) platform with a cyclic decapeptide [c(-Lys(Boc)-Lys(Alloc)-Lys(Boc)-Pro-Gly-Lys(Boc)-Lys(Alloc)-Lys(Boc)-Pro-Gly-)] with two attachment sides. The upper side is linked to four copies of the c(RGDfK) peptide for targeting of integrin α(v)β(3), and the bottom side is linked to (99m)Tc (15) or (111)In (16) for single-photon emission computed tomography imaging or to other labels for other imaging modalities. (99m)Tc-RAFT-c(-RGDfK-)(4) and (111)In-RAFT-c(-RGDfK-)(4) efficiently accumulated in tumors in mice. Jin et al. (17) conjugated RAFT-c(-RGDfK-)(4) with a bifunctional chelator, 1,4,8,11-tetraazacyclotetradecane (cyclam), for radiolabeling with (64)Cu. (64)Cu-Cyclam-RAFT-c(-RGDfK-)(4) is an integrin-targeted molecular imaging agent developed for positron emission tomography (PET) imaging of tumor vasculature and tumor angiogenesis.
22102701 Value of infliximab (Remicade®) in patients with low-risk myelodysplastic syndrome: final 2012 Apr Tumor-necrosis factor alpha activity has been correlated to ineffective erythropoiesis in lower risk myelodysplastic syndromes. Infliximab (Remicade(®)) is an anti-tumor necrosis factor alpha chimeric antibody that is used in the treatment of patients with rheumatoid arthritis or Crohn's disease. Forty-six patients with myelodysplastic syndromes and a relatively low risk of developing acute leukemia were included in a randomized phase II study assessing the therapeutic activity of two dosages of infliximab administration (3 mg/kg vs. 5 mg/kg). The primary end point was the response rate. Responses were observed in 3 of 22 patients (13.1%) randomized to the 3 mg/kg arm, versus 0 of 21 patients randomized in the 5 mg/kg arm. According to the statistical design of the current study, neither of the two infliximab dose schedules tested showed sufficient activity as a single agent in this cohort of unselected patients with early myelodysplastic syndrome.
21810522 FRAX(®) Clinical Task Force of the 2010 Joint International Society for Clinical Densitom 2011 Jul The World Health Organization fracture risk assessment tool, FRAX(®), is an advance in clinical care that can assist in clinical decision-making. However, with increasing clinical utilization, numerous questions have arisen regarding how to best estimate fracture risk in an individual patient. Recognizing the need to assist clinicians in optimal use of FRAX(®), the International Osteoporosis Foundation (IOF) in conjunction with the International Society for Clinical Densitometry (ISCD) assembled an international panel of experts that ultimately developed joint Official Positions of the ISCD and IOF advising clinicians regarding FRAX(®) usage. As part of the process, the charge of the FRAX(®) Clinical Task Force was to review and synthesize data surrounding a number of recognized clinical risk factors including rheumatoid arthritis, smoking, alcohol, prior fracture, falls, bone turnover markers and glucocorticoid use. This synthesis was presented to the expert panel and constitutes the data on which the subsequent Official Positions are predicated. A summary of the Clinical Task Force composition and charge is presented here.
21190368 Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids. 2011 Jan 27 The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC(50) values between 0.27 and 6.2 μM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyp's direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds.
21047980 Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone mar 2011 Jan 1 PURPOSE: The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematologic malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well understood. This study used a series of complementary knockout and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT. EXPERIMENTAL DESIGN: We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on GVHD and GVT by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1. RESULTS: Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1. CONCLUSION: MR16-1 treatment reduced GVHD and preserved sufficient GVT. Tocilizumab, a humanized anti-IL-6R monoclonal antibody (mAb), is approved in several countries including the United States and European Union for the treatment of rheumatoid arthritis and other inflammatory diseases. Blockade of IL-6 with anti-IL-6R mAb therapy may be testable in clinical trials as an adjunct to prevent GVHD in BMT patients without a significant loss of GVT.
23180593 Vasoactive exposures during pregnancy and risk of microtia. 2013 Jan BACKGROUND: Little is known about the etiology of nonsyndromic microtia. This study investigated the hypothesis that microtia is caused by vascular disruption. METHODS: The study analyzed data from the population-based National Birth Defects Prevention Study (NBDPS) for deliveries between 1997 and 2005. Four hundred eleven nonsyndromic cases of microtia, with or without additional defects, were compared to 6560 nonmalformed infants with respect to maternal exposures to vasoactive medications and smoking during the periconceptional period and conditions that have previously been associated with vascular events (multiple gestation, maternal history of type 1, type 2, or gestational diabetes, and hypertension). Odds ratios (ORs) were estimated with multivariable models, controlling for the effects of race/ethnicity, education, periconceptional folic acid use, and study center. RESULTS: Risk estimates for vasoactive medications and smoking were not meaningfully increased. Maternal type 1/2 diabetes was diagnosed before or during the index pregnancy in 4% and 1% of cases, respectively, compared to 1% and 0.05% of controls; the adjusted OR for these two groups combined was 7.2 (95% confidence interval [CI], 3.9-13.1). Gestational diabetes was observed for 9% of cases and 6% of controls; the OR was moderately elevated (OR, 1.4; 95% CI, 0.9-2.0). ORs were also increased for multiple gestations (OR, 2.5; 95% CI, 1.5-4.2) and pre-existing hypertension (OR, 1.6; 95% CI, 1.0-2.5). CONCLUSIONS: Because ORs were only elevated for diabetes and not for vasoactive exposures or other potential vascular events, findings suggest that some microtia occurrences may be part of the diabetic embryopathy rather than manifestations of vascular disruption. Birth Defects Research (Part A), 2013. © 2012 Wiley Periodicals, Inc.
23088223 FRAX® tool, the WHO algorithm to predict osteoporotic fractures: the first analysis of it 2012 Oct 22 BACKGROUND: The WHO has recently published the FRAX® tool to determine the absolute risk of osteoporotic fracture at 10 years. This tool has not yet been validated in Spain. METHODS/DESIGN: A prospective observational study was undertaken in women in the FRIDEX cohort (Barcelona) not receiving bone active drugs at baseline. Baseline measurements: known risk factors including those of FRAX® and a DXA. Follow up data on self-reported incident major fractures (hip, spine, humerus and wrist) and verified against patient records. The calculation of absolute risk of major fracture and hip fracture was by FRAX® website. This work follows the guidelines of the STROBE initiative for cohort studies. The discriminative capacity of FRAX® was analyzed by the Area Under Curve (AUC), Receiver Operating Characteristics (ROC) and the Hosmer-Lemeshow goodness-of-fit test. The predictive capacity was determined using the ratio of observed fractures/expected fractures by FRAX® (ObsFx/ExpFx). RESULTS: The study subjects were 770 women from 40 to 90 years of age in the FRIDEX cohort. The mean age was 56.8 ± 8 years. The fractures were determined by structured telephone questionnaire and subsequent testing in medical records at 10 years. Sixty-five (8.4%) women presented major fractures (17 hip fractures). Women with fractures were older, had more previous fractures, more cases of rheumatoid arthritis and also more osteoporosis on the baseline DXA. The AUC ROC of FRAX® for major fracture without bone mineral density (BMD) was 0.693 (CI 95%; 0.622-0.763), with T-score of femoral neck (FN) 0.716 (CI 95%; 0.646-0.786), being 0.888 (CI 95%; 0.824-0.952) and 0.849 (CI 95%; 0.737-0.962), respectively for hip fracture. In the model with BMD alone was 0.661 (CI 95%; 0.583-0.739) and 0.779 (CI 95%; 0.631-0.929). In the model with age alone was 0.668 (CI 95%; 0.603-0.733) and 0.882 (CI 95%; 0.832-0.936). In both cases there are not significant differences against FRAX® model. The overall predictive value for major fracture by ObsFx/ExpFx ratio was 2.4 and 2.8 for hip fracture without BMD. With BMD was 2.2 and 2.3 respectively. Sensitivity of the four was always less than 50%. The Hosmer-Lemeshow test showed a good correlation only after calibration with ObsFx/ExpFx ratio. CONCLUSIONS: The current version of FRAX® for Spanish women without BMD analysed by the AUC ROC demonstrate a poor discriminative capacity to predict major fractures but a good discriminative capacity for hip fractures. Its predictive capacity does not adjust well because leading to underdiagnosis for both predictions major and hip fractures. Simple models based only on age or BMD alone similarly predicted that more complex FRAX® models.
23012917 [Mid-term effectiveness of total hip arthroplasty with collum femoris preserving prosthesi 2012 Aug OBJECTIVE: To discuss the clinical application of total hip arthroplasty (THA) with collum femoris preserving (CFP) prosthesis and to analyze the mid-term effectiveness. METHODS: Between January 2004 and February 2007, 45 patients (48 hips) underwent THA with CFP prosthesis. There were 29 males (31 hips) and 16 females (17 hips) with an average age of 48.8 years (range, 38-60 years), including 20 left hips, 22 right hips, and 3 bilateral hips. The causes of hip replacement were osteoarthritis (20 cases), avascular necrosis of femoral head (13 cases), dysplasia (4 cases), rheumatoid arthritis (3 cases), posttraumatic osteoarthritis (2 cases), ankylosing spondylitis (2 cases), and Perths disease (1 case). The average disease duration was 6.1 years (range, 2-13 years). Harris scores, visual analogue scale (VAS) score, and the hip range of motion (ROM) were recorded at pre- and post-operation. The X-ray films were taken at pre- and post-operation to observe the position, loosening of the prosthesis, and ectopic ossification. The gait of patients were also evaluated during follow-up. Short-form 36 health survey scale (SF-36) was used to evaluate the life quality of patients. RESULTS: All 45 patients were followed up 5-8 years with an average of 6.4 years. All the incisions healed by first intention. No infection, hip dislocation, nerve injury, or deep vein thrombosis occurred. Six cleavage fractures (13.3%) of the lateral femoral diaphysis at the distal prosthesis occurred during operation, which healed at 8 months postoperatively without any treatment. Mild ectopic ossification occurred in 4 patients (8.9%) who had no discomfort. Five patients (11.1%) had bone mineral density loss in the region of the proximal femur. The survival rates of the cups and stems were all 100% at last follow-up. The results of Harris score, VAS score, and ROM of the hip joint at 1 year postoperatively and last follow-up were significantly better than preoperative ones (P < 0.05). No significant difference was found in VAS score and ROM of the hip joint between at 1 year postoperatively and at last follow-up (P > 0.05) except the Harris score (P < 0.05). According to Harris functional assessment at last follow-up, the results were excellent in 31 hips, good in 11 hips, and fair in 6 hips with an excellent and good rate of 87.5%. The physiological role, body pain, and total health scores were significantly lower than the reference value of urban men from Sichuan province (P < 0.05), but no significant difference was found in the other scores of the SF-36 when compared with the reference value (P > 0.05). CONCLUSION: THA with CFP prosthesis is a good option for the young patient with complete collum femoris and without osteoporosis, and can achieve good mid-term effectiveness.
22759851 E-health: Web-guided therapy and disease self-management in ulcerative colitis. Impact on 2012 Jul Ulcerative Colitis (UC) together with Crohn's disease (CD) belongs to inflammatory bowel diseases (IBD). IBD is to date as frequent as Insulin Dependent Diabetes (IDDM) and is second to Rheumatoid Arthritis (RA) in its chronicity. The majority (91%) of patients with UC have a mild to moderate disease course eligible for 5-ASA treatment. Poor adherence in UC is a well known phenomenon, which is associated with a 5-fold increased risk of relapse and increased health care costs. Web-based treatment solution with self-initiated 5-ASA treatment in UC based on the patient's pattern recognition of the disease course had not been published previously. The aims of the thesis were: 1) In a European evidence based consensus to assess the IBD patients' need for Quality of Health Care (QoHC); 2) To validate the influence of a Patient Educational Center (PEC) and a web-based treatment solution program, www.constant-care.dk, on patients' disease self-management, adherence, Quality of Life, and disease course after 1 year of self-initiated 5-ASA treatment. UC patients in a conventional out-patient setting were used as controls; 3) To validate two new quantitative rapid tests (RT scanning and HT photo) for Faecal Calprotectin (FC) measurement, and to assess whether HT photo can be useful as a home test to help the patients deciding on self-initiated treatment. The ECCO Consensus found evidence for optimising QoHC by "information"; "education", "benchmarking", and "psychological analysis", which could help to improve patient compliance, QoL, and to decrease depression and anxiety. UC patients, educated in the PEC, significantly improved the level of disease specific knowledge. Patient education and training on www.constant-care.dk, being validated on first 21 Danish patients and subsequently on 233 Danish and 100 Irish patients, showed that the new web guided approach was feasible, safe, and cost effective for the selected group of the patients included in the trial. Use of the web concept increased patients adherence to acute 5-ASA treatment, (p = 0.005) and community effectiveness up to 33%, improved Quality of Life, (p = 0.004), increased patients' ability to sufficient self-initiated treatment and reduce out-patient visits, (p < 0.0001). Patients' morbidity and depression remained unchanged. Median duration of relapse in the web-group was 59 days shorter than in the control-group possibly due to high dose of systemic 5-ASA treatment, (p < 0.0001). We found that the new rapid home test (HT photo) was accurate and comparable with the Enzyme-Linked Immunosorbent Assay (ELISA) with a 90% specificity and a 96% sensitivity. The rapid test can be useful in clinical settings concerning disease self-monitoring at home, which would decrease the use of endoscopy in some cases. The findings corresponded well with action plan for a European e-Health Area and could be a helpful tool to provide more efficient health care for UC patients. Widespread implementation of the "Constant-Care" is possible, but it may require a reshaping of the current health care for IBD patients both legally and economically. It may also empower patients in disease self-management and reduce dependency on doctors. Future long-term studies are needed to investigate, if this concept could possibly change the natural disease course.
22649804 (68)Ga-1,4,7-Triazacyclononane-1,4,7-triacetic acid-c(RGDfK)-human serum albumin-tissue in 2004 Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3). Several families of MMPs are involved in atherogenesis, myocardial infarction, angiogenesis, and tumor invasion and metastases (4-7). MMP expression is highly regulated in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages. Elevated levels of MMPs have been found in tumors associated with a poor prognosis for cancer patients (8). There are four members of endogenous tissue inhibitors of metalloproteinases (TIMPs), which regulate the activity of MMPs leading to inhibition of tumor growth and metastasis (9, 10). TIMP-2 (TIMP2) is a bifunctional inhibitor of angiogenesis by inhibition of proteinase activity of MMPs and endothelial cell proliferation via binding to α(3)β(1) (the N-terminal domain) and by MMP-independent anti-angiogenic activity (the C-terminal domain) (11, 12). Kang et al. (13) fused the N-terminal domain of TIMP2 to the C-terminus of human serum albumin (HSA) to form HSA/TIMP2 fusion protein (HSA-TIMP2), which is readily secreted by the transfected yeast Saccharomyces cerevisiae. HSA-TIMP2 retains its anti-angiogenic activity at the C-terminal domain with little MMP inhibitory activity at the N-terminal domain. Lee et al. (14) have evaluated Cy5.5-HSA/TIMP2 (Cy5.5-HSA-TIMP2) for in vivo near-infrared (NIR) fluorescence imaging of rat prostate MLL tumors in nude mice showing maximum tumor accumulation at 2 d after injection. Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (15). 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 (16-21). 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 peptide sequence 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). The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents (18, 22, 23). Various radiolabeled RGD peptides (antagonists) have been introduced for imaging of tumors and tumor angiogenesis (24). Choi et al. (25) conjugated multiple c(RGDfK) peptides to HSA-TIMP2 to enhance the binding capacity of the protein (RGD-HSA-TIMP2) to tumors and their vasculatures. (68)Ga-NOTA-RGD-HSA-TIMP2 and (68)Ga-NOTA-HSA-TIMP2 have been studied as potential positron emission tomography (PET) probes for imaging α(v)β(3) integrin receptors in nude mice bearing human glioblastoma U87MG tumors.
22649803 (123)I-c(RGDfK)-human serum albumin-tissue inhibitor of matrix metalloproteinase 2 fusion 2004 Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3). Several families of MMPs are involved in atherogenesis, myocardial infarction, angiogenesis, and tumor invasion and metastases (4-7). MMP expression is highly regulated in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages. Elevated levels of MMPs have been found in tumors associated with a poor prognosis for cancer patients (8). There are four members of endogenous tissue inhibitors of metalloproteinases (TIMPs), which regulate the activity of MMPs leading to inhibition of tumor growth and metastasis (9, 10). TIMP-2 (TIMP2) is a bifunctional inhibitor of angiogenesis by inhibition of proteinase activity of MMPs and endothelial cell proliferation via binding to α(3)β(1) (the N-terminal domain) and by MMP-independent anti-angiogenic activity (the C-terminal domain) (11, 12). Kang et al. (13) fused the N-terminal domain of TIMP2 to the C-terminus of human serum albumin (HSA) to form HSA/TIMP2 fusion protein (HSA-TIMP2), which is readily secreted by the transfected yeast Saccharomyces cerevisiae. HSA-TIMP2 retains its anti-angiogenic activity at the C-terminal domain with little MMP inhibitory activity at the N-terminal domain. Lee et al. (14) have evaluated Cy5.5-HSA/TIMP2 (Cy5.5-HSA-TIMP2) for in vivo near-infrared (NIR) fluorescence imaging of rat prostate MLL tumors in nude mice showing maximum tumor accumulation at 2 d after injection. Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (15). 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 (16-21). 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 peptide sequence 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). The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents (18, 22, 23). Various radiolabeled RGD peptides (antagonists) have been introduced for imaging of tumors and tumor angiogenesis (24). Choi et al. (25) conjugated multiple c(RGDfK) peptides to HSA-TIMP2 to enhance the binding capacity of the protein (RGD-HSA-TIMP2) to tumors and their vasculatures. (123)I-RGD-HSA-TIMP2 and (123)I-HSA-TIMP2 have been studied as potential single-photon emission computed tomography (SPECT) probes for imaging α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
22419293 Single dose oral celecoxib for acute postoperative pain in adults. 2012 Mar 14 BACKGROUND: This is an update of a review published in The Cochrane Library 2008, Issue 4. Celecoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor usually prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis. Celecoxib is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). Its effectiveness in acute pain was demonstrated in the earlier reviews. OBJECTIVES: To assess analgesic efficacy and adverse effects of a single oral dose of celecoxib for moderate to severe postoperative pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, and ClinicalTrials.gov. The most recent search was to 3 January 2012. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) of adults prescribed any dose of oral celecoxib or placebo for acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies for quality and extracted data. We converted summed pain relief (TOTPAR) or pain intensity difference (SPID) into dichotomous information, yielding the number of participants with at least 50% pain relief over four to six hours, and used this to calculate the relative benefit (RB) and number needed to treat to benefit (NNT) for one patient to achieve at least 50% of maximum pain relief with celecoxib who would not have done so with placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. MAIN RESULTS: Eight studies (1380 participants) met the inclusion criteria. We identified five potentially relevant unpublished studies in the most recent searches, but data were not available at this time. The number of included studies therefore remains unchanged.The NNT for celecoxib 200 mg and 400 mg compared with placebo for at least 50% of maximum pain relief over four to six hours was 4.2 (95% confidence interval (CI) 3.4 to 5.6) and 2.5 (2.2 to 2.9) respectively. The median time to use of rescue medication was 6.6 hours with celecoxib 200 mg, 8.4 with celecoxib 400 mg, and 2.3 hours with placebo. The proportion of participants requiring rescue medication over 24 hours was 74% with celecoxib 200 mg, 63% for celecoxib 400 mg, and 91% for placebo. The NNT to prevent one patient using rescue medication was 4.8 (3.5 to 7.7) and 3.5 (2.9 to 4.6) for celecoxib 200 mg and 400 mg respectively. Adverse events were generally mild to moderate in severity, and were experienced by a similar proportion of participants in celecoxib and placebo groups. One serious adverse event probably related to celecoxib was reported. AUTHORS' CONCLUSIONS: Single-dose oral celecoxib is an effective analgesic for postoperative pain relief. Indirect comparison suggests that the 400 mg dose has similar efficacy to ibuprofen 400 mg.
22067224 Identification, characterization, and comparative genomic distribution of the HERV-K (HML- 2011 Nov 8 BACKGROUND: Integration of retroviral DNA into a germ cell may lead to a provirus that is transmitted vertically to that host's offspring as an endogenous retrovirus (ERV). In humans, ERVs (HERVs) comprise about 8% of the genome, the vast majority of which are truncated and/or highly mutated and no longer encode functional genes. The most recently active retroviruses that integrated into the human germ line are members of the Betaretrovirus-like HERV-K (HML-2) group, many of which contain intact open reading frames (ORFs) in some or all genes, sometimes encoding functional proteins that are expressed in various tissues. Interestingly, this expression is upregulated in many tumors ranging from breast and ovarian tissues to lymphomas and melanomas, as well as schizophrenia, rheumatoid arthritis, and other disorders. RESULTS: No study to date has characterized all HML-2 elements in the genome, an essential step towards determining a possible functional role of HML-2 expression in disease. We present here the most comprehensive and accurate catalog of all full-length and partial HML-2 proviruses, as well as solo LTR elements, within the published human genome to date. Furthermore, we provide evidence for preferential maintenance of proviruses and solo LTR elements on gene-rich chromosomes of the human genome and in proximity to gene regions. CONCLUSIONS: Our analysis has found and corrected several errors in the annotation of HML-2 elements in the human genome, including mislabeling of a newly identified group called HML-11. HML-elements have been implicated in a wide array of diseases, and characterization of these elements will play a fundamental role to understand the relationship between endogenous retrovirus expression and disease.
21763644 T-cell specific defect in expression of the NTPDase CD39 as a biomarker for lupus. 2011 Regulatory T cells (T(regs)) are critical for maintenance of peripheral tolerance via suppression of T-cell responses, and absence of T(regs) results in autoimmunity. The role of aberrations in the T(reg) pool for the development of systemic lupus erythematosus (SLE, lupus) remains uncertain. T(reg)-mediated generation of adenosine, dependent on the ectonucleotidase CD39, is an important mechanism for suppression of T-cell responses. We tested whether decreases in numbers of T(regs), and specifically CD39-expressing T(regs), are associated with human lupus. We studied 15 SLE patients, six patients with rheumatoid arthritis (RA) and 24 healthy controls. T(reg) phenotypic markers, including CD39 expression, were studied by flow cytometry. Varying numbers of sorted T(regs) cells were co-cultured with responder T (T(resp)) cells, with proliferation assessed by (3)H-thymidine incorporation. The proportion of T(regs) as defined by Foxp3(+) CD25(+high) CD127(-/low) was similar in lupus and control populations. CD39-expressing T(regs) comprised 37±13% of the T(reg) population in healthy controls and 36±21% in lupus subjects using nonsteroidal immunosuppressants to control active disease, but was nearly absent in five of six lupus subjects with minimally active disease. In contrast to healthy controls and lupus subjects without the CD39 defect, in SLE subjects with the CD39 defect, adenosine-dependent T(reg)-mediated suppression was nearly absent. These results suggest that functional defects in T(regs), rather than reduced T(reg) numbers, are important for the loss of peripheral tolerance in lupus. Presentation of this defect may serve as a biomarker for untreated disease.
21672030 Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 2011 Sep TNF is critically involved in the pathogenesis of psoriasis. TL1A is a TNF-like cytokine, which, after binding to death domain receptor DR3, provides costimulatory signals to lymphocytes, amplifies Th1- and Th17-mediated immune responses and induces apoptotic cell death. These functions are inhibited when TL1A associates to decoy receptor DcR3. In the present study, we investigated the expression profiles for TL1A, DR3 and DcR3 in the normal skin and in psoriatic skin lesions. By use of immunohistochemistry, we were able to demonstrate constitutive cutaneous expression of DR3 and DcR3 but not of TL1A in healthy skin. On the other hand, in patients with active psoriasis, we observed abundant immunostaining for TL1A and significant upregulation of its receptors (P < 0.05 in comparison to healthy skin). TL1A, DR3 and DcR3 proteins, as well as mRNA transcripts reflecting in situ production of TL1A and DcR3, were also specifically increased in lesional as compared to non-lesional skin from patients with psoriasis (P < 0.05). These proteins were upregulated in cell populations that are critically involved in the pathogenesis of chronic skin inflammation, such as keratinocytes, macrophages in deep dermis and cells at the perivascular/endothelial area. Finally, we provide evidence for the existence of nuclear localization of TL1A in inflammatory cells from psoriatic lesions. This was also observed in inflamed synovia from patients with rheumatoid arthritis, but not in neoplastic TL1A-expressing cell lines. We conclude that interactions between TL1A and its two receptors may be involved in the pathogenesis of chronic skin inflammation that takes place in psoriasis.
21656984 Quantum dot800-poly(ethylene glycol)-c(Arg-Gly-Asp-d-Tyr-Lys). 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Fluorescent semiconductor quantum dots (QDs) are nanocrystals made of CdSe/CdTe-ZnS with radii of 1–10 nm (6-8). They can be tuned to emit signals in a range of wavelengths by changing their sizes and composition, thus providing broad excitation profiles and high absorption coefficients. They have narrow, symmetric emission spectra with long, excited-state lifetimes (20–50 ns) compared with those of fluorescent dyes (1–10 ns). They process good quantum yields of 40%–90% and possess high extinction coefficients. They are more photo-stable than conventional organic dyes. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds, which have been tested in vitro and in vivo (8-12). Although many cells have been labeled with QDs in vitro with little cytotoxicity, there are limited studies of long-term toxicity of QDs in small animals (13-21); little is known about the toxicity and the mechanisms of clearance and metabolism of QDs in humans. The performance of various nanoparticles for biomedical imaging has been reviewed (22, 23). Integrins are a family of heterodimeric, cell-surface glycoproteins that mediate diverse biological events involving cell–cell and cell–matrix interactions (24). Integrins comprise an α and a β subunit, and they are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor class, affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (25-30). The α(v)β(3) integrin is strongly expressed on tumor cells and activated endothelial cells. In contrast, expression of α(v)β(3) integrin is weak on resting endothelial cells and on most normal tissues. The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (29, 31, 32). A tripeptide sequence comprising 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). Various radiolabeled cyclic RGD peptides have been introduced for tumor imaging and tumor angiogenesis (33). QDs that do not contain Cd (non-Cd QDs) have been prepared as an alternative to the more toxic Cd-based QDs. These newly developed non-Cd QDs exhibit improved blood half-life and minimal reticuloendothelial system accumulation with rapid renal clearance (34). These QDs easily extravasate leaky tumor blood vessels because of their enhanced permeability and retention effects. Gao et al. (35) coated non-Cd QD800 (InAs/InP/ZnSe, emission maximum at 800 nm) with di-stearoyl-poly(ethylene glycol)-phosphatidylethanolamine 2000 (DSPE-PEG2000) and c(RGDyK) to form QD800-PEG-RGD for NIR fluorescence imaging of α(v)β(3) integrin expression in the tumor vasculature in mice. QD800-PEG-RGD has been shown to have a high accumulation in tumors with little extravasation and a predominant liver accumulation.
21543188 Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. 2011 Jul BACKGROUND: Recent findings in psoriasis research have shown that psoriasis is frequently associated with systemic comorbidities. OBJECTIVES: This study aims to describe the epidemiology of psoriasis and the prevalence of comorbidities in patients with psoriasis in Taiwan. METHODS: Patients who had at least one outpatient visit or admission with ICD-9-CM diagnosis code 696.0-1 in the Taiwan National Health Insurance (NHI) claims database during 2006 were identified as psoriasis cases. The cases were further classified into moderate to severe psoriasis (sPsO) for those who had previously received systemic therapy during the study period and mild psoriasis (mPsO) for those who had not. The cases were matched in a 1:4 ratio with controls from a sample cohort of 997,771 enrolees representative of the Taiwan population. Matching variables included age, gender and residential area. Prevalence of comorbidities was assessed using prevalence relative risk (RR) based upon a Cox proportional regression model. RESULTS: 51,800 psoriasis cases were identified (prevalence=0.235%; mean age=46.4±18.6; male:female=1.6:1) and 17.5% of cases were sPsO type. Psoriasis was associated with a significantly increased prevalence ratio (RR; [95% confidence interval]) for hypertension (1.51; [1.47, 1.56]), diabetes (1.64; [1.58, 1.70]), hyperglyceridaemia (1.61; [1.54, 1.68]), heart disease (1.32; [1.26, 1.37]), hepatitis B viral infection (1.73; [1.47, 2.04]), hepatitis C viral infection (2.02; [1.67, 2.44]), rheumatoid arthritis (3.02; [2.68, 3.41]), systemic lupus erythematosus (6.16; [4.70, 8.09]), vitiligo (5.94; [3.79, 9.31]), pemphigoid (14.75; [5.00, 43.50]), pemphigus (41.81; [12.41, 140.90]), alopecia areata (4.71; [2.98, 7.45]), lip, oral cavity and pharynx cancer (1.49; [1.22, 1.80]), digestive organs and peritoneum cancer (1.57; [1.41, 1.74]), depression (1.50; [1.39, 1.61]), fatty liver (2.27; [1.90, 2.71]), chronic airways obstruction (1.47; [1.34, 1.61]), sleep disorder (3.89; [2.26, 6.71]), asthma (1.29; [1.18, 1.40]), and allergic rhinitis (1.25; [1.18, 1.33]). Conversely, psoriasis was not associated with an increased risk of Crohn's disease. CONCLUSIONS: Psoriasis was associated with a significantly increased risk of comorbidities, especially for those patients with moderate to severe disease. These health associations should be taken into consideration when evaluating the burdens of psoriasis and designing effective treatment plans.