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ID PMID Title PublicationDate abstract
16972617 [A case of systemic amyloidosis treated by chemotherapy with autologous peripheral blood s 2006 Aug A 67-year-old woman was admitted to our hospital because of breathlessness. Systemic amyloidosis had been diagnosed 5 years previously. Her chest X-ray film showed multiple nodules in both lung fields. Chest computed tomography (CT) revealed some of the nodules had calcifications. Bronchoscopy demonstrated amyloid deposits in the bronchial walls. The serum titer of anti-SS-A antibody was high. Results of both the Schirmer Test and the Rose-Bengal Test were positive. The final diagnosis was systemic amyloidosis with Sjögren's syndrome. She was treated by chemotherapy using high dose melphalan with autologous peripheral blood stem cell transplantation (PBSCT). It was obvious that her chest X-ray film findings and bronchoscopic findings had improved 9 months after high dose chemotherapy with PBSCT. The disappearance of M protein and improvement of thirst, a symptom of Sjögren's syndrome, were also observed.
19122828 MUC16 expression in Sjogren's syndrome, KCS, and control subjects. 2008 PURPOSE: To investigate the expression of MUC16 protein in tears and conjunctival cell membranes and MUC16 mRNA in conjunctival cells of Sjogren's syndrome (SS), keratoconjunctivitus sicca (KCS) and non-dry eyed (NDE) subjects. The relationship of tear flow and soluble MUC16 concentration was also measured. METHODS: Seventy-six subjects were recruited for this study: 25 SS (confirmed via American-European Consensus Criteria 2002), 25 KCS (confirmed by symptoms and Schirmer scores < or =10 mm) and 26 NDE. Tear flow was measured by the Schirmer test without anesthesia for 5 min. Tears were collected using an eye-wash technique. Protein and mRNA were isolated from conjunctival epithelial cells collected via impression cytology. Soluble and membrane bound MUC16 were quantified via western blotting and MUC16 mRNA was quantified by real time qPCR. RESULTS: The SS group demonstrated significantly higher concentrations of soluble MUC16 (7.28 [SS] +/- 3.97 versus 3.35 [KCS] +/- 4.54 [p=0.004] and versus 1.61 [NDE] +/- 1.22 [p<0.001]) and MUC16 mRNA (4.66 [SS] +/- 5.06 versus 1.84 [KCS] +/- 2.26 [p=0.01] and 1.52 [NDE] +/- 1.04 [p=0.003]) compared to both KCS and NDE groups, respectively. No differences in soluble MUC16 or MUC16 mRNA were found between the KCS and NDE groups. Membrane bound MUC16 was similar in all three groups. No significant correlation was found between mean Schirmer values and any measure of MUC16 expression. CONCLUSIONS: These results demonstrate that SS subjects display a significant increase in both soluble MUC16 and MUC16 mRNA concentrations compared to other forms of aqueous deficient dry eye and non dry-eyed individuals. There was no correlation between tear flow and soluble MUC16 concentration.
18809413 Effects of oral consumption of the green tea polyphenol EGCG in a murine model for human S 2008 Oct 24 SIGNIFICANCE: Protection of glandular cells from autoimmune-induced damage would be of significant clinical benefit to Sjogren's syndrome (SS) patients. Epigallocatechin-3-gallate (EGCG) possesses anti-apoptotic, anti-inflammatory, and autoantigen-inhibitory properties. AIMS: To investigate if EGCG protects against certain autoimmune-induced pathological changes in the salivary glands of the non-obese diabetic (NOD) mouse model for SS. MAIN METHODS: Animals were provided with either water or water containing 0.2% EGCG. At the age of 8, 16 and 22 weeks, submandibular salivary gland tissue and serum samples were collected for pathological and serological analysis. KEY FINDINGS: Significant lymphocyte infiltration was observed in the salivary glands of the water-fed group at the age of 16 weeks, while the EGCG group showed reduced lymphocyte infiltration. By 22 weeks of age, water-fed animals demonstrated elevated levels of apoptotic activity within the lymphocytic infiltrates, and high levels of serum total anti-nuclear antibody, compared to EGCG-fed animals. Remarkably, proliferating cell nuclear antigen (PCNA) and Ki-67 levels in the salivary glands of water-fed NOD mice were significantly elevated in comparison to BALB/c control mice; in contrast, PCNA and Ki-67 levels in EGCG-fed NOD animals were similar to BALB/c mice. These results indicate that EGCG protects the NOD mouse submandibular glands from autoimmune-induced inflammation, and reduces serum autoantibody levels. Abnormal proliferation, rather than apoptosis, appears to be a characteristic of the NOD mouse gland that is normalized by EGCG. The evidence suggests that EGCG could be useful in delaying or managing SS-like autoimmune disorders.
18798702 Systemic pilocarpine for treatment of xerostomia. 2008 Oct BACKGROUND: Xerostomia is the feeling of dryness in the mouth, usually owing to hypofunctioning of the salivary glands. Causes of xerostomia include medications, the effects of radiation therapy on the salivary glands during the treatment of head and neck cancer or thyroid cancer, and autoimmune diseases such as Sjögren's syndrome. The primary treatment to reduce xerostomia is oral pilocarpine. OBJECTIVE: This review discusses the randomized trials available on the efficacy and tolerability of oral pilocarpine for the treatment of xerostomia. METHODS: The randomized trials of pilocarpine for xerostomia available in the medical literature are reviewed. RESULTS/CONCLUSION: Pilocarpine has some efficacy in the treatment of xerostomia from radiation therapy, graft-versus-host disease and Sjögren's syndrome. It has limited activity for the prevention of xerostomia during radiation therapy. It may have increased efficacy in combination with newer forms of radiation therapy.
17286801 Different temporal expression of immunodominant Ro60/60 kDa-SSA and La/SSB apotopes. 2007 Apr Opsonization of apoptotic cardiocytes by maternal anti-Ro/SSA and anti-La/SSB antibodies contributes to tissue injury in the neonatal lupus syndrome. The objective of the current study was to quantify the surface membrane expression of Ro/La components during different phases of apoptosis and map the Ro/La apotopes (epitopes expressed on apoptotic cells) bound by cognate antibodies. Multi-parameter flow cytometry was used to define early and late apoptotic populations and their respective binding by monospecific anti-Ro and anti-La IgGs. Anti-Ro60 bound specifically to early apoptotic Jurkat cells and remained accessible on the cell surface throughout early and late apoptosis. In contrast, anti-La bound exclusively to late apoptotic cells in experiments controlled for non-specific membrane leakage of IgG. Ro52 was not accessible for antibody binding on either apoptotic population. The immunodominant NH2-terminal and RNA recognition motif (RRM) epitopes of La were expressed as apotopes on late apoptotic cells, confirming recent in vivo findings. An immunodominant internal epitope of Ro60 that contains the RRM, and is recognized by a majority of sera from mothers of children with congenital heart block (CHB) and patients with primary Sjögren's syndrome, was also accessible as an apotope on early apoptotic cells. The distinct temporal expression of the immunodominant Ro60 and La apotopes indicates that these intracellular autoantigens translocate independently to the cell surface, and supports a model in which maternal antibody populations against both Ro60 and La apotopes act in an additive fashion to increase the risk of tissue damage in CHB.
17280777 Myasthenia gravis and scleroderma: two cases and a review of the literature. 2007 May Myasthenia gravis is uncommon in patients with scleroderma, and when diagnosed is usually associated with previous use of d-penicillamine. Clinically, both myasthenia and scleroderma may present with fatigue, weakness and bulbar symptoms, so one of diagnoses may be delayed. We report two new cases and review clinical features of 12 other reported cases of co-existing scleroderma and myasthenia gravis, unrelated to previous d-penicillamine therapy. Co-occurrence of myasthenia and scleroderma was reported almost exclusively (13/14) in women with a mean latency of 7.03 years. Most patients (10/11) had seropositive generalized myasthenia, and there were no cases with exclusively ocular symptoms. Three patients with pre-existing myasthenia were safely treated with d-penicillamine. Myasthenia and scleroderma occur in the context of an underlying autoimmune diathesis, but their co-occurrence could be underreported as the recognition of either disorder may be delayed by overlapping clinical symptoms. Our findings also suggest that d-penicillamine may be cautiously used in selected patients with pre-existing scleroderma and myasthenia, when potential benefits outweigh the risk of possible myasthenia exacerbation.
16751222 IL-12 overexpression in mice as a model for Sjögren lung disease. 2006 Oct Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjögren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that overexpresses IL-12 in the lungs. IL-12 transgenic mice developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjögren patients. Pathologically, lung abnormalities began at approximately 4 mo of age and were characterized by lymphocytic infiltrates around the bronchi, intraluminal periodic acid Schiff-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (P<0.05 vs. wild-type littermates) and increased oxidative stress (P<0.01). The pathological and functional abnormalities were accompanied by significant changes in lung natural killer (NK) cells. The number of NK cells was fourfold higher in IL-12 transgenic than wild-type lungs (20% of all lymphoid cells vs. 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of approximately 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjögren syndrome.
18755866 Hypocomplementemic urticarial vasculitis with Jaccoud's arthropathy and valvular heart dis 2008 Sep We describe a female Japanese patient with concomitant hypocomplementemic urticarial vasculitis, Jaccoud's arthropathy and valvular heart disease. In 1996, she developed arthritis with swelling of both proximal interphalangeal joints and urticarial vasculitis on both arms that was resolved by administration of glucocorticoid (prednisolone 30 mg/day). Tests for antineutrophil cytoplasmic antibodies, antinuclear antibody and rheumatoid factor gave negative results. The findings of a skin biopsy examination were consistent with 'leukocytoclastic vasculitis'. During 10 years of observation, the patient manifested polyarthritis leading to progressive deformity of the joints of the hands and feet (without loss of cartilage or erosion of bone), persistent urticaria exacerbated by cold and accompanied by hypocomplementemia and progressive cardiac valvular disease with mitral valve regurgitation. There are only three reports described previously documenting five patients with this rare combination of manifestations.
16868974 Evaluation of the genetic association of the PTPN22 R620W polymorphism in familial and spo 2006 Aug OBJECTIVE: The R620W (1858C-->T) polymorphism in PTPN22 has been implicated in type 1 diabetes mellitus, rheumatoid arthritis, Graves' disease, Hashimoto thyroiditis, autoimmune thyroid disease, and systemic lupus erythematosus (SLE). The aim of this study was to evaluate this polymorphism in patients with familial SLE and in those with sporadic SLE. METHODS: A total of 4,981 DNA samples were genotyped (from 1,680 SLE patients, 1,834 family members, and 1,467 controls). Both population-based case-control and family-based association designs were used for the analyses. RESULTS: In the European American familial SLE cohort, the minor 1858T allele was more common in randomly selected patients compared with controls (chi2= 5.61, P = 0.018, odds ratio [OR] 1.46, 95% confidence interval [95% CI] 1.07-1.99). The heterozygous C/T genotype was also more common in these European American patients compared with controls (OR 1.63, 95% CI 1.15-2.30). Family-based association tests showed preferential transmission of the 1858T allele to affected offspring (chi2 = 5.87, P = 0.015). In contrast, the frequency of the 1858T minor allele was not significantly increased in the European American patients with sporadic SLE compared with controls, nor did these patients have preferential transmission of the 1858T allele. Indeed, the difference in the 1858T allele frequency between patients with familial SLE and those with sporadic SLE was measurable (allelic chi2= 4.22, P = 0.04, OR 1.51, 95% CI 1.02-2.24). Our data also showed that among patients with SLE, the 1858T allele was separately associated with type 1 diabetes mellitus and with autoimmune thyroid disease, confirming the findings of other investigators. CONCLUSION: The 1858T allele of PTPN22 is associated with familial SLE but not with sporadic SLE in European Americans, thereby potentially explaining previous contradictory reports.
17265494 Autoantibodies to RNA helicase A: a new serologic marker of early lupus. 2007 Feb OBJECTIVE: To investigate the clinical and immunologic significance of autoantibodies to RNA helicase A (RHA) in patients with systemic rheumatic diseases. METHODS: The study group comprised 1,119 individuals enrolled in the University of Florida Center for Autoimmune Diseases registry from 2000 to 2005. Diagnoses were based on standard criteria. Autoantibodies were analyzed by immunoprecipitation and Western blot assays. RESULTS: Anti-RHA was observed in 17 (6.2%) of 276 patients with systemic lupus erythematosus (SLE), 2 patients with antiphospholipid antibodies, and 3 other patients, but anti-RHA was not observed in any patient with polymyositis/dermatomyositis, systemic sclerosis, rheumatoid arthritis, or Sjögren's syndrome. Anti-RHA was present in only 2.9% of African American patients, compared with 6.0% of white patients and 12-25% of patients of other races; this was in striking contrast to the frequency of anti-Sm in African American patients (27.2%). Among patients with SLE, anti-RHA was common in young patients (26% of those whose initial visit was at an age younger than 20 years versus 3-4% of those who were initially seen at ages 20-49 years) and at an early stage of disease (23% of those whose first clinic visit was within 1 year of disease onset versus 2-8% of those whose first visit was at least 1 year after disease onset). In 9 of 11 patients, levels of anti-RHA decreased to <10% of the initial value within 9-37 months, while levels of coexisting anti-Ro or anti-Su remained the same. New specificities developed in 2 patients (anti-nuclear RNP and anti-Sm, and anti-ribosomal P, respectively). These data suggest that the level of anti-RHA diminishes over time, and that anti-RHA is regulated via a mechanism different from that for other lupus-related autoantibodies. CONCLUSION: Anti-RHA is a new serologic marker for SLE. It is produced mainly in young non-African Americans at an early stage of their disease. Anti-RHA has a unique tendency to diminish over time. The production of anti-RHA may depend on a process restricted to early SLE, or it may be highly sensitive to treatment.
18981156 Induction of scavenger receptor class B type I is critical for simvastatin enhancement of 2008 Nov 15 Changes in plasma lipoprotein profiles, especially low levels of high-density lipoprotein (HDL), are a common biomarker for several inflammatory and immune diseases, including atherosclerosis and rheumatoid arthritis. We examined the effect of simvastatin on HDL-induced anti-inflammatory actions. HDL and sphingosine 1-phosphate (S1P), a bioactive lipid component of the lipoprotein, inhibited TNF alpha-induced expression of VCAM-1, which was associated with NO synthase (NOS) activation, in human umbilical venous endothelial cells. The HDL- but not S1P-induced anti-inflammatory actions were enhanced by a prior treatment of the cells with simvastatin in a manner sensitive to mevalonic acid. Simvastatin stimulated the expression of scavenger receptor class B type I (SR-BI) and endothelial NOS. As for S1P receptors, however, the statin inhibited the expression of S1P(3) receptor mRNA but caused no detectable change in S1P(1) receptor expression. The reconstituted HDL, a stimulator of SR-BI, mimicked HDL actions in a simvastatin-sensitive manner. The HDL- and reconstituted HDL-induced actions were blocked by small interfering RNA specific to SR-BI regardless of simvastatin treatment. The statin-induced expression of SR-BI was attenuated by constitutively active RhoA and small interfering RNA specific to peroxisome proliferator-activated receptor-alpha. Administration of simvastatin in vivo stimulated endothelial SR-BI expression, which was accompanied by the inhibition of the ex vivo monocyte adhesion in aortas from TNF alpha-injected mice. In conclusion, simvastatin induces endothelial SR-BI expression through a RhoA- and peroxisome proliferator-activated receptor-alpha-dependent mechanism, thereby enhancing the HDL-induced activation of NOS and the inhibition of adhesion molecule expression.
18971939 CD226 Gly307Ser association with multiple autoimmune diseases. 2009 Jan Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser(307) association with T1D (P=3.46 x 10(-9)) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 x 10(-4)) and rheumatoid arthritis (RA) (P=0.017). The Ser(307) allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.
18959108 Comparative study on early period of recovery between minimally invasive surgery total kne 2008 Aug 5 BACKGROUND: Different kinds of minimally invasive surgery (MIS) procedures have now been used in total knee arthroplasty (TKA). Compared with traditional TKA procedure with a long skin incision, clinical studies showed MIS procedures had some advantages. Quadriceps sparing (QS) procedures are the most minimally invasive MIS procedure until now. This study was aimed to find the insertion types for Chinese patients' vastus medialis and if the QS procedure had some advantages in patients' early recovery. METHODS: Between February 2006 and May 2007, 120 consecutive patients underwent unilateral primary TKA under general anesthesia, among whom 14 patients were lost to follow-up, the remaining 106 cases were enrolled in this study. Among the 106 cases there were 85 right knees, 21 left knees (15 men and 91 women, with a mean age of 65.1+/-7.4 years); osteoarthritis in 97 patients (91.5%) and rheumatoid arthritis in 9 patients (8.5%). MIS TKA was performed in 49 cases (MIS TKA group), while MIS-QS TKA in 57 cases (MIS-QS TKA group). During the operation, the type I, II and III insertions of the vastus medialis for all patients were recorded. Each knee was rated post-operatively according to the Hospital of Special Surgery (HSS) scoring system. Clinical follow-up was undertaken at 1 week, 2, 6, 12 and 24 weeks. Operating time and complications were recorded. RESULTS: There was no statistically significant difference between the two groups for gender distribution, age, left or right knee incidence, pre-operative diagnosis, incidence of varus or valgus deformity. Of the 106 cases there was 1 (0.9%) case with a type I insertion of the vastus medialis, 4 (3.8%) cases with type II insertions, 101 (95.3%) cases with type III insertions. The HSS scoring was significantly different between the MIS-QS TKA group and MIS TKA group within the first two weeks post operation. From 2 weeks later to 24 weeks, no significant difference was found. The average operating time was (53.3+/-12.4) minutes in the MIS TKA group and (64.1+/-15.1) minutes in the MIS-QS TKA group (P<0.001). In the MIS-QS TKA group, 1 patient had delayed healing of the partial skin incision (1.8%). No other complications were found in either group. CONCLUSIONS: Although most of the Chinese patients had type III insertions of the vastus medialis, the MIS-QS TKA procedure showed less injury to the quadriceps than the standard MIS TKA and this could contribute to the earlier recovery of the patients. But a shorter skin incision and more tension on the skin may also lead to more skin complications.
18953941 [A clinical analysis of 32 patients with diffuse alveolar hemorrhage in diffuse connective 2008 May OBJECTIVE: To provide clues to diagnosis and treatment for diffuse alveolar hemorrhage (DAH) in patients with diffuse connective tissue diseases (CTD). METHOD: To analyze retrospectively the data of clinical features, pulmonary images and bronchoalveolar lavage (BAL) in 32 patients hospitalized in Peking Union Medical College Hospital from April 2004 to June 2007. RESULTS: The data from 10 of the 17 (58.8%) patients with microscopic polyangiitis (MPA), 19 of the 1267 (1.5%) patients with systemic lupus erythematosus (SLE), 2 of the 56 (3.6%) patients with Wegener's granulomatosis (WG) and 1 of the 570 (0.2%) patients with rheumatoid arthritis (RA) were consistent with the diagnosis of DAH. DAH in SLE occurred in younger patients (mean age at the time of diagnosis 27.3 +/- 13.1 years) and early in the course of disease (median duration of SLE from onset was 16.7 +/- 18.3 months), while these figures in MPA patients with DAH were 50.1 +/- 20.7 years and 10.6 +/- 18.7 months. At the time of DAH in SLE, the median systemic lupus erythematosus disease activity index (SLEDAI) score was 17.1 +/- 6.7 and anti-ds-DNA antibody titer elevated markedly, while the median C3 level was low. The levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) of patients with DAH in MPA, WG and RA showed marked elevation. The titer of antineutrophil cytoplasmic antibody (ANCA, MPO/PR3) in patients with MPA and WG was highly positive. The main clinical manifestations of DAH were hemoptysis, dyspnea and rapid decrease of hemoglobulin and hematocrit (HCT) in peripheral blood. Most patients presented with diffuse alveolar infiltration on chest X-ray and high resolution CT. DAH could be confirmed by bloody bronchoscopic lavage. 20 patients (62.5%) had secondary pulmonary infections at the time of DAH; fungus and combined bacterial infection were most frequently seen. The mortality of CTD with DAH was 59.4% (19 out of 32). 12 patients (63.2%) with SLE, 5 patients (50%) with MPA and both of the 2 patients with WG died. 12 of the lethal cases (63.2%) died of respiratory failure. CONCLUSIONS: CTD patients presenting with hemoptysis and dyspnea with rapid decrease of hemoglobulin, and diffuse alveolar infiltration on chest X-ray or high resolution CT should be seriously considered to be suffering from DAH. A bloody BAL may confirm the diagnosis of DAH. DAH in CTD is an acute, serious and frequently life-threatening situation resulting in respiratory failure and pulmonary infection. It is important for CTD patients with DAH to be diagnosed early and treated vigorously.
18775681 15-Deoxy-Delta(12,14)-prostaglandin J(2) rescues PC12 cells from H2O2-induced apoptosis th 2008 Dec 1 Oxidative stress induced by reactive oxygen intermediates has been implicated in a variety of human diseases including rheumatoid arthritis and neurodegenerative disorders. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a terminal dehydration product of prostaglandin D(2), is an endogenous ligand of peroxisome proliferator-activated receptor-gamma and exhibits a number of biological activities including the proapoptotic activity. Recent studies have revealed that this cyclopentenone prostaglandin, at non-toxic concentrations, can also exert antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of 15d-PGJ(2) on the H2O2-induced cytotoxicty were explored using cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with H2O2 underwent apoptosis, which was attenuated by pretreatment with non-toxic concentrations of 15d-PGJ(2). Treatment of the PC12 cells with 15d-PGJ(2) resulted in increased nuclear translocation, DNA-binding and transcriptional activity of NF-E2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase-1 (HO-1) expression, which provided an adaptive survival response against the H2O2-derived oxidative cytotoxicity. Transfection of PC12 cells with dominant-negative Nrf2 gene abolished the 15d-PGJ(2)-derived induction of HO-1 expression. Moreover, the 15d-PGJ(2)-mediated increases in Nrf2-ARE binding and ARE luciferase activity were suppressed by the dominant-negative mutation as well as the pharmacological inhibition of Akt/protein kinase B or extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these findings suggest that 15d-PGJ(2) augments cellular antioxidant defense capacity through activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction, thereby protecting the PC12 cells from H2O2-induced oxidative cell death.
18771438 Identification of the most active interleukin-32 isoform. 2009 Apr Cytokines are crucial in host defence against pathogens such as bacteria, viruses, fungi and parasites. A newly described cytokine, interleukin-32 (IL-32), induces various proinflammatory cytokines (tumour necrosis factor-alpha, IL-1beta, IL-6) and chemokines in both human and mouse cells through the nuclear factor-kappaB and p38 mitogen-activated protein kinase inflammatory signal pathway. The IL-32 primarily acts on monocytic cells rather than T cells. In an attempt to isolate the IL-32 soluble receptor, we used an IL-32 ligand-affinity column to purify neutrophil proteinase 3, which is a serine proteinase involved in many inflammatory diseases. IL-32 has biological activity associated with Mycobacterium tuberculosis and chronic proinflammatory diseases such as rheumatoid arthritis. IL-32 is transcribed as six alternative splice variants and the biological activity of each individual isoform remains unknown. Here, we cloned the complementary DNA of the four IL-32 isoforms (alpha, beta, gamma and delta) that are the most representative IL-32 transcripts. To produce recombinant protein with a high yield, the amino acids of two cysteine residues were mutated to serine residues, because serine residues are not conserved among different species. The multi-step purified recombinant IL-32 isoform proteins were assessed for their biological activities with different cytokine assays. The gamma isoform of IL-32 was the most active, although all isoforms were biologically active. The present study will provide a specific target to neutralize endogenous IL-32, which may contribute to basic and clinical immunology.
20641486 Gadolinium diethylenetriamine pentaacetic acid-Arg-Gly-Asp peptidomimetic. 2004 Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used in imaging because of their abundance in water molecules. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends primarily on the density of the nucleus (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal, and T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the development of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (2). 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 (3-8). 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 (7, 9, 10). 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). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (11). Gadolinium (Gd), a lanthanide metal ion with seven unpaired electrons, has been shown to be very effective in enhancing proton relaxation because of its high magnetic moment and water coordination (12, 13). Gd-Labeled diethylenetriamine pentaacetic acid (Gd-DTPA) was the first intravenous MRI contrast agent used clinically, and a number of similar Gd chelates have been developed in an effort to further improve clinical use. However, these low molecular weight Gd chelates have short blood and tissue retention times, which limit their use as imaging agents in the vasculature and cancer. Various macromolecular Gd complexes have demonstrated superior contrast enhancement for MRI of the vasculature and carcinomas (14-16); however, these Gd complexes did not proceed into further clinical development because of high tissue accumulation and slow excretion of toxic Gd ions. Furthermore, they are largely nonspecific. A low molecular weight, non-peptide, RGD mimetic (g-mimRGD, 5-{N'-[5-(4-Methylpyridin-2-ylamino)pentanoyl]hydrazino}-3-(4-biphenyl)-5-oxopentanoic acid trifluoroacetate) was identified to have good affinity and selectivity for the α(v)β(3) integrin (50% inhibition concentration, 3 nM) (17). Burtea et al. (18) conjugated mimRGD to Gd-DTPA to form Gd-DTPA-g-minRGD for non-invasive in vivo MRI of α(v)β(3) integrin expression in transgenic apolipoprotein E–deficient (ApoE(-/-)) mice.
20641766 (64)Cu-Anti-human integrin α(v)β(3) monoclonal antibody. 2004 (64)Cu-Anti-human integrin α(v)β(3) monoclonal antibody ((64)Cu-DOTA-hLM609-II) is a radiolabeled antibody developed for positron emission tomography (PET) imaging of integrin α(v)β(3)−positive tumors (1). (64)Cu-DOTA-hLM609-II is labeled with (64)Cu which is a positron emitter with a half-life (t(½)) of 12.7 h. Cellular survival, invasion, and migration control embryonic development, angiogenesis, tumor metastasis, and other physiological processes. Among the molecules that regulate angiogenesis are integrins, a superfamily of cell adhesion proteins that form heterodimeric receptors for extracellular matrix (ECM) molecules (2, 3).These transmembrane glycoproteins consist of two noncovalently associated subunits, α and β (18 α- and 8 β-subunits in mammals), which are assembled into at least 24 α/β pairs. Several integrins, such as integrin α(v)β(3), have affinity for the arginine-glycine-aspartic acid (RGD) tripeptide motif, which is found in many ECM proteins. The integrin α(v)β(3) receptor is generally not found in normal tissue but is strongly expressed in vessels with increased angiogenesis, such as tumor vasculature. It is significantly upregulated in certain types of tumor cells and in almost all tumor vasculature. Increased levels of integrin α(v)β(3) expression are closely associated with increased cell invasion and metastasis. Molecular imaging of a probe that binds to the integrin α(v)β(3) can be used to image tumor vasculature and evaluate angiogenic response to tumor therapy (4, 5). Radiolabeled monoclonal antibodies (MAbs) have been developed for both the diagnosis and treatment of tumors (6-8). Radiometals with appropriate photon or positron emissions can be used to radiolabel antibodies and in imaging studies (9, 10). Cheresh and Harper (11, 12) first reported the synthesis of LM609 MAb, a murine IgG1 antibody (mLM609), which appeared to react with and recognize α(v)β(3) as one entity. The mLM609 was humanized by grafting the murine complementary-determining regions (CDRs) onto a human framework (13, 14). The humanized LM609 (hLM609) was shown to retain the affinity properties of the murine antibody. This first version of hLM609 (hLM609-I) was used in clinical studies for cancer therapy (15). These studies reported no significant toxicity or immune response from hLM609-I. However, (99m)Tc labeling of hLM609-I was unsuccessful due to the in vivo instability of the (99m)Tc label (16). Another clone (hLM609-II) with >50-fold enhanced affinity was also produced using a phage-expressed libraries and focused mutagenesis strategy in a stepwise fashion (13, 15). hLM609-II is currently in clinical trials for treatment of prostate cancer, psoriasis, melanoma, and rheumatoid arthritis. Cai et al. (1) successfully radiolabeled hLM609-II with (64)Cu using 1,4,7,10-tetra-azacyclododecane N,N',N'',N'''-tetraacetic acid (DOTA) as the bifunctional chelator.
18452647 Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis. 2008 Apr 30 Angiogenesis, the formation of blood vessels, is essential for preparing a closed circulatory system in the body, and for supplying oxygen and nutrition to tissues. Major diseases such as cancer, rheumatoid arthritis, and atherosclerosis include pathological angiogenesis in their malignant processes, suggesting anti-angiogenic therapy to be a new strategy for suppression of diseases. However, until the 1970s, the molecular basis of angiogenesis was largely unknown. In recent decades, extensive studies have revealed a variety of angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)-VEGFRs, Angiopoietin-Tie, Ephrin-EphRs and Delta-Notch to be the major regulators of angiogenesis in vertebrates. VEGF and its receptors play a central role in physiological as well as pathological angiogenesis, and functional inhibitors of VEGF and VEGFRs such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs have recently been approved for use to treat patients with colorectal, lung, renal and liver cancers. These drugs have opened a novel field of cancer therapy, i.e. anti-angiogenesis therapy. However, as yet they cannot completely cure patients, and cancer cells could become resistant to these drugs. Thus, it is important to understand further the molecular mechanisms underlying not only VEGF-VEGFR signaling but also the VEGF-independent regulation of angiogenesis, and to learn how to improve anti-angiogenesis therapy.
18266961 gamma-Secretase: a multifaceted regulator of angiogenesis. 2008 Jun Physiological angiogenesis is essential for development, homeostasis and tissue repair but pathological neovascularization is a major feature of tumours, rheumatoid arthritis and ocular complications. Studies over the last decade have identified gamma-secretase, a presenilin-dependent protease, as a key regulator of angiogenesis through: (i) regulated intramembrane proteolysis and transmembrane cleavage of receptors (e.g. VEGFR-1, Notch, ErbB-4, IGFI-R) followed by translocation of the intracellular domain to the nucleus, (ii) translocation of full length membrane-bound receptors to the nucleus (VEGFR-1), (iii) phosphorylation of membrane bound proteins (VEGFR-1 and ErbB-4), (iv) modulation of adherens junctions (cadherin) and regulation of permeability and (v) cleavage of amyloid precursor protein to amyloid-? which is able to regulate the angiogenic process. The gamma-secretase-induced translocation of receptors to the nucleus provides an alternative intracellular signalling pathway, which acts as a potent regulator of transcription. gamma-secretase is a complex composed of four different integral proteins (presenilin, nicastrin, Aph-1 and Pen-2), which determine the stability, substrate binding, substrate specificity and proteolytic activity of gamma-secretase. This seeming complexity allows numerous possibilities for the development of targeted gamma-secretase agonists/antagonists, which can specifically regulate the angiogenic process. This review will consider the structure and function of gamma-secretase, the growing evidence for its role in angiogenesis and the substrates involved, gamma-secretase as a therapeutic target and future challenges in this area.