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ID PMID Title PublicationDate abstract
22250082 Tetracyclines convert the osteoclastic-differentiation pathway of progenitor cells to prod 2012 Feb 15 Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti-GM-CSF-neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c(+) cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.
22147109 Comparison of qualitative and quantitative analysis of capillaroscopic findings in patient 2012 Dec No guidelines for the application of qualitative and quantitative analysis of the capillaroscopic examination in the rheumatologic practice exist. The aims of the study were to compare qualitative and quantitative analysis of key capillaroscopic parameters in patients with common rheumatic diseases and to assess the reproducibility of the qualitative evaluation of the capillaroscopic parameters, performed by two different investigators. Two hundred capillaroscopic images from 93 patients with different rheumatic diseases were analysed quantitatively and qualitatively by two different investigators. The distribution of the images according to the diagnosis and the microvascular abnormalities was as follows-group 1: 73 images from systemic sclerosis patients ("scleroderma" type pattern), group 2: 10 images from dermatomyositis ("scleroderma-like" pattern), group 3: 25 images from undifferentiated connective tissue disease and different forms of overlap (24 "scleroderma-like"), group 4: 26 images from systemic lupus erythematosus patients, group 5: 46 images from rheumatoid arthritis and group 6: 20 images from primary Raynaud's phenomenon patients. All the images were mixed and blindly presented to both investigators. For comparison of the quantitative and qualitative method, investigator 1 assessed presence of dilated, giant capillaries and avascular areas quantitatively by the available software programme and his estimates were compared with the results of investigator 2, who assessed the parameters qualitatively. In addition, the capillaroscopic images were evaluated qualitatively by the investigator 1 and 2 for presence of dilated, giant capillaries, avascular areas and haemorrhages. The comparison of the quantitative and qualitative assessment of the two investigators demonstrated statistically significant difference between the two methods for the detection of dilated and giant capillaries (P < 0.05) but no significant difference regarding the detection of avascular areas (P > 0.05). As we further analysed the results for the capillaroscopic images, demonstrating a "scleroderma" and a "scleroderma-like" pattern (170/200), analogous results were found for the evaluated parameters. Among the 20 capillaroscopic images from patients with primary RP, the estimates for the absence of giant capillaries and avascular areas were equal in 100% (P > 0.05). Comparing the qualitative assessment of the two investigators, a statistically significant difference between estimates of the two investigators was found for the presence of dilated capillaries (P < 0.05), while for giant capillaries, avascular areas and haemorrhages the difference was not statistically significant (P > 0.05). The results of the study have shown that qualitative assessment of capillaroscopic parameters in patients with rheumatic diseases is an adequate method for the everyday rheumatologic practice, especially in cases with primary RP for exclusion presence of microangiopathy. No significant difference between qualitative and quantitative methods of assessment was found for the detection of avascular areas. However, the quantitative analysis is more precise especially for the detection of capillary dilation. A good reproducibility of the qualitative evaluation, performed by two different investigators was also found.
21971827 Comparison of polymeric siRNA nanocarriers in a murine LPS-activated macrophage cell line: 2012 Mar PURPOSE: Tumor necrosis factor α (TNF-α) plays a key role in the progression of rheumatoid arthritis and is an important target for anti-rheumatic therapies. TNF-α expression can be silenced with small interfering RNA (siRNA), but efficacy is dependent on efficient and safe siRNA delivery vehicles. We aimed to identify polymeric nanocarriers for anti-TNF-α siRNA with optimal efficacy and minimal off-target effects in vitro. METHODS: TNF-α silencing with polymeric siRNA nanocarriers was compared in lipopolysaccharide-activated RAW 264.7 macrophages by real-time reverse transcription (RT)-PCR. Expression of non-target genes involved in inflammation, apoptosis, and cell cycle progression was determined by RT-PCR, toxicity evaluated by propidium iodide and annexin V staining. RESULTS: PAMAM dendrimers (G4 and G7) and dextran nanogels mediated remarkably high concentration-dependent gene silencing and low toxicity; dioleoyltrimethylammoniumpropane-modified poly(DL-lactide-co-glycolide acid) nanoparticles, thiolated, trimethylated chitosan and poly[(2-hydroxypropyl)methacrylamide 1-methyl-2-piperidine methanol] polyplexes were less efficient transfectants. There were minor changes in the regulation of off-target genes, mainly dependent on nanocarrier and siRNA concentration. CONCLUSIONS: Dextran nanogels and PAMAM dendrimers mediated high gene silencing with minor toxicity and off-target transcriptional changes and are therefore expected to be suitable siRNA delivery systems in vivo.
21896924 Ofatumumab: a novel anti-CD20 monoclonal antibody for treatment of refractory chronic lymp 2011 Oct OBJECTIVE: To present the current clinical evidence on ofatumumab for use in refractory chronic lymphocytic leukemia (CLL). DATA SOURCES: A literature search was performed using MEDLINE and PubMed (both 1966-May 2011), as well as the American Society of Hematology abstracts (2000-May 2011), using the primary search terms ofatumumab and HuMax-CD20. STUDY SELECTION AND DATA EXTRACTION: Clinical studies and abstracts available in the English language, describing the pharmacology, pharmacokinetics, clinical activity, and safety of ofatumumab in CLL were included in this review. DATA SYNTHESIS: Ofatumumab is a human immunoglobulin monoclonal antibody that binds to B-lymphocytes expressing CD-20 cell surface antigens. Ofatumumab was granted accelerated approval by the Food and Drug Administration in October 2009 for the treatment of CLL refractory to fludarabine and alemtuzumab. A Phase 1/2 trial has established the safety and tolerability of single-agent ofatumumab at an initial dose of 300 mg intravenously on week 1, followed by 2000 mg once weekly for 7 doses (weeks 2-8), followed by 2000 mg once every 4 weeks for 4 doses (weeks 9-12), for a total of 12 doses. The final analysis of a pivotal international multicenter trial has shown promising activity in patients with CLL refractory to fludarabine and alemtuzumab, demonstrating overall response rates of 44-51%, with prolonged progression-free and overall survival. Ofatumumab activity has also been shown in a variety of other malignant and nonmalignant conditions, including non-Hodgkin lymphoma, rheumatoid arthritis, and multiple sclerosis. The most common adverse effect is grade 1 and 2 infusion reactions. Other adverse effects include infection, neutropenia, anemia, rash, fever, and diarrhea. CONCLUSIONS: Clinical evidence suggests that ofatumumab is an effective agent in patients with CLL refractory to fludarabine and alemtuzumab. Data are awaited comparing ofatumumab to other salvage regimens. Until results of head-to-head trials are conducted comparing ofatumumab to existing regimens, it cannot be said whether ofatumumab is more efficacious or tolerable than currently available therapies.
21841214 Talbot phase-contrast x-ray imaging for the small joints of the hand. 2011 Sep 7 A high-resolution radiographic method for soft tissues in the small joints of the hand would aid in the study and treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), which often attacks these joints. Of particular interest would be imaging with <100 µm resolution the joint cartilage, whose integrity is a main indicator of disease. Differential phase-contrast (DPC) or refraction-based x-ray imaging with Talbot grating interferometers could provide such a method, since it enhances soft tissue contrast and can be implemented with conventional x-ray tubes. A numerical joint phantom was first developed to assess the angular sensitivity and spectrum needed for a hand DPC system. The model predicts that, due to quite similar refraction indexes for joint soft tissues, the refraction effects are very small, requiring high angular resolution. To compare our model to experiment we built a high-resolution bench-top interferometer using 10 µm period gratings, a W anode tube and a CCD-based detector. Imaging experiments on animal cartilage and on a human finger support the model predictions. For instance, the estimated difference between the index of refraction of cartilage and water is of only several percent at ∼25 keV mean energy, comparable to that between the linear attenuation coefficients. The potential advantage of DPC imaging thus comes mainly from the edge enhancement at the soft tissue interfaces. Experiments using a cadaveric human finger are also qualitatively consistent with the joint model, showing that refraction contrast is dominated by tendon embedded in muscle, with the cartilage layer difficult to observe in our conditions. Nevertheless, the model predicts that a DPC radiographic system for the small hand joints of the hand could be feasible using a low energy quasi-monochromatic source, such as a K-edge filtered Rh or Mo tube, in conjunction with a ∼2 m long 'symmetric' interferometer operated in a high Talbot order.
21800108 Risk of Herpes zoster in patients with underlying diseases: a retrospective hospital-based 2011 Dec PURPOSE: To determine the incidence of Herpes zoster in patients with one of 17 specific underlying diseases compared with that in patients with other underlying diseases. METHODS: We conducted a retrospective hospital-based cohort study using data from patients' electronic medical records for the period 2001-2007 of the Kitano Hospital Research Database. These analyses included 55,492 patients with one of 17 underlying diseases, which were those reported as related to the contraction of Herpes zoster. Of these, 769 patients contracted Herpes zoster. The main outcome measure was the clinical diagnosis of Herpes zoster. RESULTS: The adjusted hazard ratios (95% confidence interval) for Herpes zoster in patients with the 17 diseases were compared with other patients, with the following results: brain tumor [3.84 (2.51-5.88)], lung cancer [2.28 (1.61-3.22)], breast cancer [2.41 (1.52-3.82)], esophageal cancer [4.19 (2.16-8.11)], gastric cancer [1.95 (1.39-2.72)], colorectal cancer [1.85 (1.33-2.56)], gynecologic cancer [3.45 (2.08-5.70)], malignant lymphoma [8.23 (6.53-10.38)], systemic lupus erythematosus [3.90 (2.66-5.70)], rheumatoid arthritis [2.00 (1.60-2.50)], diabetes mellitus [2.44 (2.10-2.85)], hypertension [2.04 (1.75-2.38)], renal failure [2.14 (1.65-2.79)], and disk hernia [2.18 (1.52-3.13)]. CONCLUSIONS: Patients with diabetes mellitus, renal failure, and malignancies have a 1.8-8.4-fold higher risk of a Herpes zoster event than patients with other diseases. Future studies should investigate alteration of the immune system in the underlying diseases and approaches for Herpes zoster prevention.
21793633 Adalimumab treatment in Crohn's disease does not induce early changes in regulatory T cell 2011 Oct OBJECTIVE: Anti-TNF-α antibodies has been suggested to modulate regulatory T cell (Treg) percentages in rheumatoid arthritis, but results from studies of Crohn's disease (CD) are conflicting. We investigated dynamic changes of circulating Tregs in CD during treatment with the anti-TNF-α-antibody adalimumab (Humira®, Abbott Laboratories A/S, Emdrupvej 28C, DK-2100 Copenhagen). MATERIAL AND METHODS: Blood samples from 26 CD patients were analysed using flow cytometry before and 1 and 26 weeks after initiation of adalimumab treatment to determine the percentage of Tregs among CD4+ T cells. RESULTS: In spite of a significant decline in disease activity scores and biochemical markers of inflammation, during the first week of treatment, we did not observe early modulating effects of adalimumab on Treg percentages. However, we found a long-term increase in Treg percentages in responders who had low Treg percentages (<5%) at baseline (p = 0.04). Treg percentage was inversely associated with disease activity (CD activity index or CDAI) (Spearman's rank correlation, ρ = -0.47, p = 0.02). High Treg percentages among CD4+ T cells at baseline predicted clinical response to adalimumab. CONCLUSIONS: Adalimumab treatment did not induce early modulatory effects on Treg percentage, even in responders. This finding suggests that adalimumab does not have a direct or selective effect on Tregs. However, Treg percentage was associated with disease activity and high Treg percentage predicted response to adalimumab.
21745165 Thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a cl 2011 Dec We investigated six new cases of primary thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) to further characterize the clinicopathological and genetic features. The male to female ratio was 1:1. One female patient had suffered from systemic lupus erythematosus. Another female patient was diagnosed with rheumatoid arthritis after thymectomy. One patient had a concurrent tumor in the eyelid. Radiologically, all tumors were located in the prevascular space and presented as asymmetric heterogeneously enhanced cystic and solid masses. MALT1, BCL10 or IGH translocations and trisomy 18 were not observed in any cases by fluorescence in situ hybridization (FISH) analysis. Trisomy 3 was detected in one patient and another showed a TNFAIP3/A20 deletion. Meta-analysis (n = 51) including the present and previously reported cases revealed that the prevalence of autoimmunity was much lower in males with thymic MALT lymphoma compared to females (33% vs. 87%, p = 0.001). Additionally, the average age of females or patients with autoimmunity was about 10 years younger than that of males or patients without autoimmunity (p = 0.003 and p = 0.008, respectively). In summary, thymic MALT lymphoma arising without underlying autoimmunity frequently involves males or older patients. Trisomy 3 and an A20 deletion might play a role in the pathogenesis of thymic MALT lymphoma.
21422731 Hyaluronan inhibits Akt, leading to nuclear factor-κB down-regulation in lipopolysacchari 2011 Hyaluronan (HA) of high molecular weight is used in the treatment of osteoarthritis and rheumatoid arthritis by intra-articular injection. While HA has been shown to suppress nuclear factor (NF)-κB activation by proinflammatory cytokines and lipopolysaccharide (LPS), intracellular upstream events that cause NF-κB down-regulation in response to HA remain unclear. Thus, this study was performed to investigate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of the LPS-activated NF-κB pathway by HA in U937 macrophages. In adherent U937 macrophage cultures, pretreatment with HA of 2700 kDa (1 mg/ml, 1 h) significantly inhibited interleukin-6 (IL-6) production by LPS (200 ng/ml, 24 h)-stimulated U937 cells. LPS (200 ng/ml) activated Akt and NF-κB, whereas HA (1 mg/ml) down-regulated LPS-stimulated phosphorylation of Akt and NF-κB. Inhibition studies using LY294002 (20 µM) revealed the requirement of the PI3K/Akt pathway for LPS-stimulated IL-6 production and NF-κB activation. Pretreatment with anti-intercellular adhesion molecule-1 (ICAM-1) antibody (20 µg/ml) reversed the inhibitory effects of HA on LPS-induced production of IL-6 and activation of Akt and NF-κB. Herein, we provided the first evidence that HA suppresses the LPS-activated PI3K/Akt pathway, leading to down-regulation of NF-κB with diminished IL-6 production through interaction with ICAM-1.
21281743 Comparative assessment of vascular function in autoimmune rheumatic diseases: consideratio 2011 May Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to increased cardio- and cerebrovascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated atherosclerosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or spondyloarthropathies (SpA), obliterative vasculopathy may rather be characteristic for systemic sclerosis (SSc) or mixed connective tissue disease (MCTD). Antiphospholipid antibodies have been implicated in vasculopathies underlying SLE, antiphospholipid syndrome (APS), RA and MCTD. There is also heterogeneity with respect to inflammatory risk factors. Cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) and immune complexes are primarily involved in arthritides, such as RA, SpA, as well as in SLE. On the other hand, autoantibodies including anti-oxLDL anti-cardiolipin and anti-β2GPI are rather involved in SLE- and APS-associated vasculopathies. Regarding the non-invasive assessment of vascular function, endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have just been published, and similar recommendations in connective tissue diseases are to be developed soon.
21270693 Impact of the O-C2 angle on the oropharyngeal space in normal patients. 2011 May 15 STUDY DESIGN: Radiographic analysis using normal patients. OBJECTIVE: To analyze the relationship between the cervical alignment and the oropharyngeal space. SUMMARY OF BACKGROUND DATA: Few clinical studies stress the effect of the occipito-C2 (O-C2) alignment on the oropharyngeal space. A previous study showed dysphagia and/or dyspnea after occipitocervical fusion was caused by oropharyngeal stenosis resulting from O-C2 fixation in a flexed position. Other independent researchers showed that development or improvement of obstructive sleep apnea in rheumatoid arthritis patients was related to the O-C2 alignment. However, there are limited basic data demonstrating the relationship between the O-C2 alignment and the oropharyngeal space. METHODS: Plain lateral cervical radiographs in five tested positions--neutral, flexion, extension, protrusion, and retraction--of 40 asymptomatic volunteers were collected. The O-C2 angle, the C2-C6 angle, and the anterior-posterior distance of the narrowest oropharyngeal airway space (nPAS) were measured, and the changes in value from the neutral to the other four positions were calculated for each patient. RESULTS: According to the multiple regression analysis, there was an extremely strong linear correlation of the change in the O-C2 angle with the percentage change in the nPAS. Referring to the multiple regression analysis, a decrease of 10° in the O-C2 angle caused a 37% reduction in the nPAS in the neutral position. In contrast, no significant correlation was found between the change in the C2-C6 angle and the percentage change in the nPAS. CONCLUSION: Our results show the impact of the O-C2 angle on the oropharyngeal space. This knowledge will be useful for the diagnosis and treatment of the upper cervical lesion combined with the upper airway stenosis, and for the determination of the optimal fixation angle in occipitocervical fusion.
21161531 Inhibitors of p38 and ERK1/2 MAPkinase and hydrogen sulphide block constitutive and IL-1β 2012 Mar Mitogen-activated protein kinases (MAPKs) play a central role in inflammatory processes, and their blockage represents pharmacological approaches in the treatment of autoimmune diseases like rheumatoid arthritis (RA). Alternatively, H(2)S has long been used in sulphur bath therapy for patients suffering from different types of rheumatic disorders, but reports about the beneficial effects of this form of therapy are controversial, rare and of poor scientific quality. The human chondrocyte cell line C-28/I2 was treated with two different MAPK inhibitors (SB203580 and U0126) or with various concentrations of the H(2)S donor Natrium hydrogen sulphide (NaHS). Thereafter, the secretion of IL-6 and IL-8 was quantified by enzyme-linked immunosorbent assays (ELISAs). The impact of NaHS on the regulation of p38 and ERK1/2 MAPK was confirmed by Western blot experiments. Furthermore, IL-6 and IL-8 expression was quantified by real-time polymerase chain reaction (RT-PCR) and ELISAs from cells which were exposed to SB203580, U0126 and NaHS and stimulated by IL-1β. The C-28/I2 cells constitutively expressed large quantities of IL-6 and IL-8. The data provided prove that in these cells, constitutive as well as IL-1β-induced IL-6 and IL-8 expression was partially and transiently blocked by the treatment of cells with both MAPK inhibitors and NaHS. Presented data seem to be important in evaluating the beneficial functions of MAPK inhibitors and H(2)S in immune-pathophysiological processes.
22377454 Luteolin downregulates TLR4, TLR5, NF-κB and p-p38MAPK expression, upregulates the p-ERK 2012 Apr 11 BACKGROUND: Inflammatory damage is known to be involved in ischemic stroke. Luteolin has been proved to elicit a series of biologic effects through its anti-inflammatory property in multiple sclerosis and rheumatoid arthritis. Whether this protective effect applies to ischemic injury in brain is still unknown, we therefore investigate the potential neuroprotective role of luteolin in ischemic stroke and the underlying mechanisms. METHODS: Male Sprague-Dawley rats were subjected to pMCAO and luteolin was administered intraperitoneally immediately after surgery, then once daily thereafter. Neurological deficit, infarct volume, and brain water content were measured at 24 h and 72 h after stroke. The expression of TLR4, TLR5, and NF-κB were measured by real-time PCR, immunohistochemical staining (IHC), and Western blot. P38MAPK and extracellular signal-regulated kinase (ERK) were detected by IHC, and Western blot. RESULTS: Compared with pMCAO group, luteolin significantly alleviated neurological deficit, decreased infarct volume and suppressed edema after ischemic stroke, which were accompanied with decreased expression of TLR4, TLR5, NF-κB and p-p38MAPK. Meanwhile, luteolin activated the expression of p-ERK1/2 (P<0.05). CONCLUSIONS: Luteolin protected the brain from the damage caused by pMCAO, and this effect may be through downregulation of TLR4, TLR5, NF-κB, p38MAPK and upregulation of ERK expression.
20641531 Cyclo(Arg-Gly-Asp-d-Tyr-Lys)-Cy5.5. 2004 Integrins are a family of cell surface heterodimeric glycoproteins that mediate diverse biological events involving cell-cell and cell-matrix interactions (1). They consist of an α and a β subunit. 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 (2-7). 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 most normal tissues. The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents (4, 8, 9) and the agonists as angiogenic agents for coronary angiogenesis (10, 11). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) is 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 were introduced for imaging of tumors and tumor angiogenesis (12). Optical fluorescence imaging is increasingly used to obtain biological functions of specific targets (13, 14). However, the intrinsic fluorescence of biomolecules poses a problem when visible light (350-700 nm) absorbing fluorophores are used. Near-infrared (NIR) fluorescence (700-1000 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 non-invasive alternative to radionuclide imaging. Cyclo(RGDyK) was conjugated with Cy5.5 to study in vivo biodistribution of the tracer in tumor-bearing mice. Cy5.5 is a NIR fluorescent dye with absorbance maximum at 675 nm and emission maximum at 694 nm with a high extinction coefficient of 250,000 (mol/L)(-1)cm(-1). RGD-Cy5.5 or c(RGDyK)-Cy5.5 was found to have a high and long-lasting accumulation in α(v)β(3)-positve U87MG human glioblastoma tumor cells in nude mice (15). The binding of RGD-Cy5.5 to the integrin receptor was found to be specific both in vitro and in vivo.
23253631 1,25-dihydroxyvitamin D3 downregulates aromatase expression and inflammatory cytokines in 2012 Nov OBJECTIVES: Vitamin D deficiency seems to be involved in the development and severity of autoimmune/inflammatory diseases such as rheumatoid arthritis (RA). To evaluate the influence of calcitriol (1,25-dihydroxyvitamin D3, 1,25(OH)2D3) on aromatase expression in cultures of human macrophages, as a new target for vitamin D cell modulation and pro-inflammatory cytokine production. METHODS: Cultures of human monocytic THP-1 cells were activated to macrophages and treated for 24 hours with 1,25(OH)2D3 (10-8M), 17β-estradiol (E2, 10-8M) both alone and in combination, in order to evaluate the effects on the intracrine estrogen metabolism. Untreated human macrophages were used as controls (basal). P450-aromatase synthesis was evaluated by immunocytochemistry (ICC) and western blot analysis (WB). The expression of P450-aromatase gene (CYP19A1) was investigated by real-time PCR (RT-PCR). Macrophage pro-inflammatory cytokines IL1-β, IL-6 and TNF-α were evaluated by ELISA and WB. RESULTS: In E2 untreated condition, 1,25(OH)2D3 reduced P450-aromatase synthesis and CYP19A1 gene expression in cultured cells. Moreover, pro-inflammatory cytokine production (IL1-β, IL-6 and TNF-α) was significantly reduced by 1,25(OH)2D3 treatment (p<0.001 vs. basal for all cytokines). However, 1,25(OH)2D3 was found to significantly downregulate the E2-mediated increase in P450-aromatase synthesis and gene expression (p<0.001 for both vs. E2-treated macrophages), as well as the production of all pro-inflammatory cytokines (p<0.001 vs. E2-treated cells). CONCLUSIONS: Our data suggest that 1,25(OH)2D3 may downregulate the pro-inflammatory cytokine production in human activated macrophages by significantly decreasing the aromatase activity, especially in presence of an estrogenic milieu such as in the RA synovial tissue.
22764877 Month of birth, vitamin D and risk of immune-mediated disease: a case control study. 2012 Jul 6 BACKGROUND: A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation. METHODS: The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient. RESULTS: The distributions of ID births significantly differed from that of the general population (P = 5e-12) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P < 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P < 0.0001). Stratification by disease subtype showed seasonality in all ID but Crohn's disease. The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003). CONCLUSIONS: The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.
22739348 Epidemiology of environmental exposures and human autoimmune diseases: findings from a Nat 2012 Dec Autoimmune diseases (AID) are a collection of many complex disorders of unknown etiology resulting in immune responses to self-antigens and are thought to result from interactions between genetic and environmental factors. Here we review the epidemiologic evidence for the role of environmental factors in the development of human AID, the conclusions that can be drawn from the existing data, critical knowledge gaps, and research needed to fill these gaps and to resolve uncertainties. We specifically summarize the state of knowledge and our levels of confidence in the role of specific agents in the development of autoimmune diseases, and we define the areas of greatest impact for future investigations. Among our consensus findings we are confident that: 1) crystalline silica exposure can contribute to the development of several AID; 2) solvent exposure can contribute to the development of systemic sclerosis; 3) smoking can contribute to the development of seropositive rheumatoid arthritis; and 4) an inverse association exists between ultraviolet radiation exposure and the risk of development of multiple sclerosis. We suggest that more studies of phenotypes, genotypes, and multiple exposures are needed. Additional knowledge gaps needing investigation include: defining important windows in the timing of exposures and latencies relating to age, developmental state, and hormonal changes; understanding dose-response relationships; and elucidating mechanisms for disease development. Addressing these essential issues will require more resources to support research, particularly of rare AID, but knowledge of the risks conferred by environmental factors in specific genetic contexts could pave the way for prevention of AID in the future.
22703852 Immunotherapies in rheumatologic disorders. 2012 May Over the past several decades, rheumatology has directed its focus to understanding and countering the immune dysregulation underlying autoimmune diseases with rheumatologic manifestations. Older therapies, effective though poorly understood, are being scrutinized anew and are yielding the immune-modulating mechanisms behind their efficacy. New therapies, the "biologics," are drugs tailored to address specific immune defects and imbalances. This article discusses the current standard and biologic immunotherapies of the rheumatic diseases, correlating our current understanding of their mechanisms with dysfunctions believed to be present in the major autoimmune syndromes, especially rheumatoid arthritis and systemic lupus erythematosus.
22647435 Expression and biological characterization of an anti-CD20 biosimilar candidate antibody: 2012 Jul The CD20 molecule is a non-glycosylated protein expressed mainly on the surface of B lymphocytes. In some pathogenic B cells, it shows an increased expression, thus becoming an attractive target for diagnosis and therapy. Rituximab is a chimeric antibody that specifically recognizes the human CD20 molecule. This antibody is indicated for the treatment of non-Hodgkin lymphomas and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. In this work, we describe the stable expression and biological evaluation of an anti-CD20 biosimilar antibody. While rituximab is produced in fed-batch culture of recombinant Chinese hamster ovary (CHO) cells, our biosimilar antibody expression process consists of continuous culture of recombinant murine NS0 myeloma cells. The ability of the purified biosimilar antibody to recognize the CD20 molecule on human tumor cell lines, as well as on peripheral blood mononuclear cells from humans and primates, was demonstrated by flow cytometry. The biosimilar antibody induced complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and apoptosis on human cell lines with high expression of CD20. In addition, this antibody depleted CD20-positive B lymphocytes from peripheral blood in monkeys. These results indicate that the biological properties of the biosimilar antibody compare favorably with those of the innovator product, and that it should be evaluated in future clinical trials.
22612424 Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimm 2012 Jul INTRODUCTION: In the last few years, several tyrosine kinase inhibitors (TKIs) have been synthesized and become available for preclinical studies and clinical trials. This article summarizes recent achievements in the mechanism of action, pharmacological properties, and clinical activity and toxicity, as well as the emerging role of TKIs in lymphoid malignancies, allergic diseases, and autoimmune disorders. AREAS COVERED: A literature review was conducted of the MEDLINE database PubMed for articles in English. Publications from 2000 through January 2012 were scrutinized. The search terms used were Bruton's tyrosine kinase (Btk) inhibitors, PCI-32765, GDC-0834, LFM-A13, AVL-101, AVL-292, spleen tyrosine kinase (Syk) inhibitors, R343, R406, R112, R788, fostamatinib, BAY-61-3606, C-61, piceatannol, Lyn, imatinib, nilotinib, bafetinib, dasatinib, GDC-0834, PP2, SU6656 in conjunction with lymphoid malignancy, NHL, CLL, autoimmune disease, allergic disease, asthma, and rheumatoid arthritis. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION: The use of TKIs, especially inhibitors of Btk, Syk, and Lyn, is a promising new strategy for targeted treatment of B-cell lymphoid malignancies, autoimmune disorders and allergic diseases. However, definitive data from ongoing and future clinical trials will aid in better defining the status of TKIs in the treatment of these disorders.