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ID PMID Title PublicationDate abstract
12886135 Clinical and imaging findings of lymphoma in patients with Sjögren syndrome. 2003 Jul OBJECTIVE: To describe and correlate the clinical and imaging findings of lymphomas in patients with Sjögren syndrome. METHODS: The authors reviewed the medical and imaging records of 27 cases of lymphoma from among a total of 463 patients with Sjögren syndrome. The estimated prevalence of lymphoma in patients with Sjögren syndrome was 5.8%. There were 22 women and 5 men. Histopathologically, 26 of the 27 neoplasms were non-Hodgkin lymphoma, including 6 mucosa-associated lymphoid tissue lymphomas, and the other neoplasm was Hodgkin lymphoma. The clinical and imaging findings of lymphomas were analyzed. RESULTS: No obvious correlations were present between the duration or severity of Sjögren syndrome and the lymphoma development. At the initial diagnosis, extranodal involvement was observed in 14 (52%) of the 27 patients, including the salivary gland (n = 9), lacrimal gland (n = 2), lung (n = 2), and thyroid gland (n = 1), mostly in the neck organs. On the other hand, nodal involvement was observed in 21 (78%) of the 27 patients. Of these 21 patients, 19 had at least cervical lymph node involvement. CONCLUSION: Patients with Sjögren syndrome are at increased risk of lymphoma development. Because most lymphomas initially involve the neck organs, including the lymph nodes, meticulous imaging studies mainly focused on the cervical regions are recommended in the follow-up of patients with Sjögren syndrome.
12023392 HLA class II influences the immune response and antibody diversification to Ro60/Sjögren' 2002 Jun 1 Abs to Ro/SSA Ags in the sera of patients with systemic lupus erythematosus and Sjögren's syndrome are influenced by the HLA class II genes. To investigate the role of individual HLA class II genes in immune responses to human Ro60 (hRo60), mice lacking murine class II molecules and carrying either HLA genes DR2(DRB1*1502), DR3(DRB1*0301), DQ6(DQA1*0103/DQB1*0601), or DQ8(DQA1*0301/DQB1*0302), were immunized with rhRo60. The results show that hRo60 induces strong T and B cell responses in DR2, DR3, and DQ8 mice in comparison to weaker responses in DQ6 mice. In all mice, the majority of the dominant T cell epitopes were located in the amino portion (aa 61-185) and the carboxy portion (aa 381-525) of the hRo60 molecules. In contrast, the early dominant B cell epitopes were located in the middle and carboxy portion of the hRo60 molecule (aa 281-315 and 401-538). In DR2, DR3, and DQ8 mice, the B cell epitopes subsequently spread to the amino and carboxy portion of the hRo60 molecule but were limited to the middle and carboxy portion in DQ6 mice. The DR2 and DR3 mice produced the highest titers of immunoprecipitating Abs against hRo60 and native mouse Ro60. In addition, only DR2 mice exclusively produced immunoprecipitating Abs to native mouse Ro52 and Abs to mouse La by slot blot analysis, whereas in other strains of mice Abs to mouse La were cross-reactive with the immunogen. The results of the present study demonstrate the importance of HLA class II in controlling the immune responses to the Ro-ribonucleoprotein.
11846192 Treatment of gingival overgrowth induced by manidipine administration. A case report. 2002 Jan BACKGROUND: It is well known that severe gingival overgrowth (GO) is induced in patients taking certain calcium channel blockers (CCB) for the treatment of hypertension, angina pectoris, and other diseases. No case has been reported to date of severe GO induced by manidipine hydrochloride (manidipine), a second generation CCB. This case report describes severe GO induced by manidipine in a female patient (43 years old) with hypertension and Sjögren syndrome (SS). The patient was administered manidipine and carteolol hydrochloride (carteolol) as antihypertensive drugs, together with bromhexine hydrochloride for the treatment of SS. METHODS: At the initial periodontal examination, probing depth (PD, average 4.83 mm), plaque control record (PCR, 84.3%), bleeding on probing (BOP, 100%), and gingival overgrowth index (GOI, 2.42) were assessed. The patient received periodontal treatment without cessation or replacement of the causative drug. Initial treatment included oral hygiene and scaling and root planing (SRP) under local anesthesia. As corrective therapy, remaining pockets were surgically removed and fixed bridges placed to establish proper occlusion. RESULTS: Obvious reductions in PCR (10.0%), PD (1.93 mm), GOI (0.02), and BOP (4.7%), together with a disappearance of GO, were obtained. Salivary secretion was increased after the periodontal and prosthetic treatments. Histological features were similar to those of nifedipine-induced GO. CONCLUSIONS: This case indicated that manidipine may act as a potent inducer of severe GO, and that conventional periodontal treatments without a major change of the causative drugs can yield satisfactory clinical responses.
15604260 Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cell 2004 Dec 15 Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production. It has also been reported that TWEAK can stimulate blood vessel formation in the rat cornea angiogenesis assay, but it is presently unknown whether this cytokine could play a role in the pathological angiogenesis associated with human diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy. In the present study we investigated whether TWEAK was expressed in human tumors and whether it could promote tumor growth and angiogenesis in vivo. TWEAK mRNA expression was detected in many tumor types by cDNA array hybridization analysis, and TWEAK protein expression was confirmed in human colon cancer tissue by immunohistochemistry. As an initial approach to address whether TWEAK might act as a tumor angiogenesis factor, we established several human embryonic kidney cell lines that constitutively secrete a soluble TWEAK protein and examined their growth properties in vitro and in vivo. We found that although TWEAK-overexpressing cells do not have a growth advantage in vitro, they form larger and more highly vascularized tumors in athymic mice when compared with control, vector-transfected cells. This result suggests that the TWEAK-Fn14 signaling system may be a potential regulator of human tumorigenesis.
14990099 [Analysis of primary symptoms and disease spectrum in Epstein-Barr virus infected children 2004 Jan OBJECTIVE: To improve the clinical diagnostic standard and explore the mechanism of multiple clinical manifestation of Epstein-Barr virus (EBV) infection by studying the primary symptom and related disease spectrum in EBV infected children. METHODS: The primary symptom, disease spectrum and prognosis of 190 EBV infected children whose serum EBV-VCA-IgM was positive detected by enzyme-linked immunosorbent assay (ELISA) were retrospectively reviewed. RESULTS: The primary symptoms of EBV infection were diverse, the most common primary symptom was fever (66.8%), and followed by cough (14.2%), skin eruption (7.9%), lymphadenopathy (5.3%), eyelid edema (3.2%), pharyngalgia (1.6%), cardiac arrhythmia (1.6%), convulsion (1.6%), arthralgia (1.0%), gross hematuria (0.5%), etc. Most systems and organs were involved in the disease, including liver, spleen, lymph nodes, kidney, heart, lung, bone marrow, brain etc., which made the disease spectrum diverse. The most common disease caused by EBV infection was respiratory tract infection (40.5%), followed by infectious mononucleosis (17.9%), Kawasaki disease (6.3%), idiopathic thrombocytopenic purpura (5.8%), viral myocarditis (2.6%), viral encephalitis (2.6%), hemophagocytic syndrome (1.6%), rheumatoid arthritis (1.0%), acute lymphadenitis (1.0%), facial neuritis (1.0%), Evans syndrome (0.5%), systemic lupus erythematosus (0.5%), subacute necrotizing lymphadenitis (0.5%), non-Hodgkin's lymphoma (0.5%), acute aplastic anemia (0.5%), infantile hepatitis syndrome (0.5%), etc.; 9.5% of patients were ultimately diagnosed as EBV infection after long-term fever, and 10% of patients suffered from mixed infection. The prognosis of EBV infection was different due to involvement of different systems and organs. One patient died of hemophagocytic syndrome. CONCLUSION: The systems and organs impaired by EBV infection in children were diverse, and almost all the systems and organs were involved. Pediatricians should comprehensively analyze the clinical data and order corresponding laboratory examinations early to make the correct diagnosis and reduce the misdiagnosis rate and to treat appropriately.
14648712 Lymphoproliferative disorders in autoimmune diseases in Japan: analysis of clinicopatholog 2004 Jan 20 Lymphoproliferative disorders (LPD) occasionally develop in individuals with immune deficiencies such as immunosuppressive conditions and autoimmune diseases (AID). In our study, the clinicopathologic features and virus status were analyzed in 53 cases with LPD developing in rheumatoid arthritis (RA) and other AID. AID in only 4 of 53 patients had been treated with some sort of immunosuppressive therapy, including methotrexate. Median age at the diagnosis of LPD in AID was 60 years old with marked female predominance (M/F = 0.4). The median interval between the onset of AID and LPD development was 45 months, and longer in RA patients than in other AID (p < 0.01). The primary site of lymphoma was nodal in 21 cases and extra-nodal in 24, with clinical Stage I in 17, II in 5, III in 13, and IV in 13. Immunohistochemistry showed that 39 cases were B cell type, 10 were T cell type and 4 were Hodgkin lymphoma (HL). Then majority of B cell cases were diffuse large B cell lymphomas, and 2 were diffuse polymorphic type. EBER-1 in situ hybridization for Epstein-Barr virus (EBV) showed positive signals in tumor cells in 16 of 53 (30.2%) cases. The EBV-positive rate in T cell LPD (70%) was much higher than that in B cell LPD (12.8%) (p < 0.01). All 4 cases of HL were EBV-positive. Immunohistochemistry showed a latency II pattern of EBV infection (LMP-1(+) and EBNA-2(-)). Five-year overall survival rate was 33%. Multivariate analysis showed that only type of AID was an independent factor for survival of patients, i.e., LPD in RA showed the most favorable prognosis. In conclusion, LPD in AID generally shared common features with sporadic LPD except for a much higher EBV-positive rate in T cell LPD.
14575587 [A preliminary study on the treatment of severe autoimmune disease by autologous periphera 2003 Sep OBJECTIVE: To evaluate the feasibility of autologous peripheral CD(34)(+) cell transplantation for the treatment of severe autoimmune disease. METHODS: Ten patients received mobilized and purified CD(34)(+) cells transplantation. The mobilization regimen was CTX plus rhG-CSF and the CD(34)(+) cells were selected by CliniMACS. (1.98 +/- 0.95) x 10(8) CD(34)(+) cells were obtained. The purity of CD(34)(+) cells was (91.4 +/- 10.6)% and the recovering rate was (60.5 +/- 19.8)%. The conditioning regimens were CTX (200 mg/kg) plus ATG (90 mg/kg) or CTX (150 mg/kg) plus TBI (4 - 6 Gy). (2.14 +/- 1.05) x 10(6)/kg CD(34)(+) cells were infused. The time of ANC >or= 0.5 x 10(9)/L was 8.6 +/- 2.5 days, and platelet >or= 20 x 10(9)/L was 9.0 +/- 5.2 days. After the hematopoietic recovery, the levels of CD(3)(+) T cell, CD(19)(+) B cells and CD(16)(+)CD(56)(+) NK cells were all below that of pre-transplantation. The main transplant-related complication was CMV infection. The transplant-related mortality was 2/10. All patients who survived showed improvement of the disease with DAI score decreasing from 17 to 4 in systemic lupus erythematosus patients, DAS 28 score from 6.4 to 1.8 in rheumatoid arthritis patients. CONCLUSION: The result suggests that autologous peripheral CD(34)(+) cell transplantation is an alternative choice for the treatment of severe autoimmune disease. The short-term outcome is satisfying.
12884292 Oxidative-stress-induced T lymphocyte hyporesponsiveness is caused by structural modificat 2003 Aug In several human pathologies (e.g. cancer, rheumatoid arthritis, AIDS and leprosy) oxidative stress induces T cell hyporesponsiveness. Hyporesponsive T cells often appear to display impaired expression of some (e.g. TCR-zeta, p56(lck) and LAT) but not all (e.g. TCR-alphabeta and CD3-epsilon) crucial TCR-proximal signaling molecules but the underlying mechanisms have as yet not been identified. Using an in vitro system for oxidative-stress-induced T cell hyporesponsiveness we here report two sequential effects of oxidative stress on TCR signaling molecules: protein alterations and proteasomal degradation. We have identified the C-terminal part of TCR-zeta and the membrane-proximal domain of p56(lck) as potential targets for modifications induced by reactive oxygen species. Oxidative-stress-exposed proteins were differentially susceptible to proteasomal degradation: whereas modified TCR-zeta was relatively resistant, reactive oxygen species (ROS)-altered LAT and p56(lck) were much more susceptible. Importantly, we found that T cell hyporesponsiveness best correlated with ROS-dependent protein alteration since inhibition of proteasomal degradation did not restore function. Finally, our data provide an explanation for the paradox of reduced TCR-zeta signals combined with unaltered TCR-alphabeta and CD3-epsilon expression levels: the TCR-zeta chain in hyporesponsive T cells is still expressed but no longer detectable by certain mAb recognizing ROS-sensitive epitopes.
12496390 Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes. 2003 Jan 1 The predominance of autoimmune diseases among women suggests that estrogen may modulate immune function. Monocytes and macrophages are important in initiating, maintaining, and resolving inflammatory responses through cell-signaling molecules, which control immune cell survival. One important mechanism of cell survival is mediated by the Fas/Fas ligand (FasL) system. In this study, the link between estrogen, monocytes/macrophages, and the Fas/FasL system was investigated. Estrogen treatment increased FasL expression in monocytes through the binding of the estrogen receptors (ER) to the estrogen recognizing elements and AP-1 motifs present at the FasL promoter. Furthermore, estrogen induced apoptosis in monocytes expressing ERbeta, but not in monocyte-differentiated macrophages expressing ERalpha. The expression of either ERalpha or ERbeta and their response to estrogen in monocytes was found to be dependent on the their stage of cell differentiation. Previously, we have shown that estrogen replacement therapy in postmenopausal women decreased the number of circulating monocytes. In this study, we have characterized the molecular mechanism by which estrogen regulates monocytes homeostasis. These findings indicate that estrogen may regulate immune cell survival through the Fas/FasL system. There is biological relevance to these findings in view of studies showing that accumulation of activated monocytes is involved in the pathogenesis of conditions such as vasculititis, arteriosclerosis, and rheumatoid arthritis.
12172544 Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. 2002 Sep A general paradigm in signal transduction is ligand-induced feedback inhibition and the desensitization of signaling. We found that subthreshold concentrations of interferon-gamma (IFN-gamma), which did not activate macrophages, increased their sensitivity to subsequent IFN-gamma stimulation; this resulted in increased signal transducer and activator of transcription 1 (STAT1) activation and increased IFN-gamma#150;dependent gene activation. Sensitization of IFN-gamma signaling was mediated by the induction of STAT1 expression by low doses of IFN-gamma that did not effectively induce feedback inhibition. IFN-gamma signaling was sensitized in vivo after IFN-gamma injection, and STAT1 expression was increased after injection of lipopolysaccharide and in rheumatoid arthritis synovial cells. These results identify a mechanism that sensitizes macrophages to low concentrations of IFN-gamma and regulates IFN-gamma responses in acute and chronic inflammation.
11985705 Modeling alternative binding registers of a minimal immunogenic peptide on two class II ma 2002 Mar Several major histocompatibility complex class II (MHC II) complexes with known minimal immunogenic peptides have now been solved by X-ray crystallography. Specificity pockets within the MHC II binding groove provide distinct peptide contacts that influence peptide conformation and define the binding register within different allelic MHC II molecules. Altering peptide ligands with respect to the residues that contact the T-cell receptor (TCR) can drastically change the nature of the ensuing immune response. Here, we provide an example of how MHC II (I-A) molecules may indirectly effect TCR contacts with a peptide and drive functionally distinct immune responses. We modeled the same immunogenic 12-amino acid peptide into the binding grooves of two allelic MHC II molecules linked to distinct cytokine responses against the peptide. Surprisingly, the favored conformation of the peptide in each molecule was distinct with respect to the exposure of the N- or C-terminus of the peptide above the MHC II binding groove. T-cell clones derived from each allelic MHC II genotype were found to be allele-restricted with respect to the recognition of these N- vs. C-terminal residues on the bound peptide. Taken together, these data suggest that MHC II alleles may influence T-cell functions by restricting TCR access to specific residues of the I-A-bound peptide. Thus, these data are of significance to diseases that display genetic linkage to specific MHC II alleles, e.g. type 1 diabetes and rheumatoid arthritis.
11961173 In polymyalgia rheumatica serum prolactin is positively correlated with the number of typi 2002 Apr OBJECTIVES: Hyperprolactinaemia has been associated with the active phase of human systemic lupus erythematosus and rheumatoid arthritis. In the present study, we investigated the role of prolactin (PRL) in relation to the number of typical symptoms and serum markers of systemic inflammation in patients with polymyalgia rheumatica (PMR). METHODS: One hundred and two PMR patients presented with typical symptoms such as adynamia, bilateral muscular pain in shoulders, upper arms or neck, bilateral muscular pain in the pelvic girdle, headache, morning stiffness, arthralgia, symptoms of depression, fever, initial weight loss (>4 kg/month), and transient visual symptoms. If one of the mentioned symptoms was present, the corresponding item was scored with one point (maximum unweighted item points=10). PRL, interleukin-2 (IL-2), IL-6, IL-1 receptor antagonist (IL-1ra), tumour necrosis factor (TNF), soluble IL-2 receptor (sIL-2R), and soluble vascular cell adhesion molecule (sVCAM) were measured by enzyme-linked immunosorbent assay in patients and 31 age-matched healthy controls. RESULTS: Fifteen PMR patients with elevated PRL had a higher number of symptoms as compared with patients with normal levels (P=0.003). PRL was correlated with the number of symptoms (all PMR patients: r(rank)=+0.380, P<0.001) and duration of morning stiffness (all PMR patients: r(rank)=+0.335, P=0.002) irrespective of prior corticosteroid treatment. However, PRL did not correlate with markers of systemic inflammation such as erythrocyte sedimentation rate, C-reactive protein, serum IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM. CONCLUSION: The number of symptoms in PMR patients was positively correlated with PRL, but PRL was not correlated with serum markers of inflammation. This indicates that PRL is not a pro-inflammatory stimulus in patients with PMR. The inter-relationship between PRL and symptoms or duration of morning stiffness may be more a sign of central nervous system involvement, as it can be observed in people with depressed mood or under psychological stress.
11830590 Critical role of tumor necrosis factor-alpha and NF-kappa B in interferon-gamma -induced C 2002 Apr 19 CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 expression on antigen-presenting cells (including macrophages and microglia) is crucial for T-cell activation. Aberrant expression of CD40 has been associated with autoimmune inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. We have recently shown that the cytokine interferon (IFN)-gamma is the most potent inducer of CD40 expression in macrophages and microglia, and this induction is mediated by the IFN-gamma-activated transcription factor STAT-1alpha and constitutively expressed PU.1 and/or Spi-B. In this study, we have discovered that a major component of IFN-gamma-induced CD40 expression involves the endogenous production of the cytokine TNF-alpha. The inclusion of anti-TNF-alpha-neutralizing antibody significantly inhibits IFN-gamma-induced CD40 mRNA and CD40 promoter activity. IFN-gamma-induced CD40 protein expression is attenuated in TNF-alpha-deficient microglia and can be restored with exogenous TNF-alpha. Site-directed mutagenesis studies demonstrate that three of the four NF-kappaB elements in the CD40 promoter are required for IFN-gamma-induced CD40 promoter activity. IFN-gamma treatment leads to the activation of NF-kappaB in a time-dependent manner, which is inhibited in the presence of anti-TNF-alpha-neutralizing antibody. These results indicate that IFN-gamma-induced TNF-alpha production and subsequent NF-kappaB activation are integral parts of the mechanism of IFN-gamma-induced CD40 expression.
20642015 Cy5-Tat-Glu-Pro-Asp-acyloxymethyl ketone. 2004 Caspases are a group of cysteine proteases, which exist within cells as inactive zymogens, and are cleaved to form active enzymes after induction of apoptosis (1-3). There are two major pathways through which caspases are activated. One is the death signal–induced, death receptor–mediated extrinsic pathway, and the other is the stress-induced, mitochondria-directed intrinsic pathway (3, 4). Caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases. Caspase-8 and -9 act as initiators at the upper stream of this cascade, while caspase-3, -6, and -7 work as downstream executioners (1, 3, 4). Although physiological apoptosis takes place during embryonic development and in adult homeostasis, excessive apoptosis has been observed in some human diseases such as myocardial infarction, rheumatoid arthritis, ischemia, transplant rejection, and neurodegenerative disorders (Parkinson's and Alzheimer's) (5, 6). On the contrary, evading apoptosis is a hallmark of human cancer (7, 8). Many different molecular probes have been developed for imaging apoptosis both at the cellular level and in vivo (2, 5, 7, 9, 10). Of them, a large number of the probes are annexin V–based. Annexin V is a 36-kDa protein that binds to externalized phosphatidylserine residues in the presence of calcium ions on the surface of apoptotic cells (5). Radiolabeled annexin V derivatives have already been used for clinical imaging in many diseases, most notably for imaging myocardial dysfunction. A drawback of annexin V–based probes is their low specificity to apoptotic cells. Annexin V cannot distinguish apoptosis from necrosis (5). Phosphatidylserine externalization is also associated with inflammation and platelet activation, causing further challenges with annexin V specificity. During recent years, much work has focused on the development of probes for caspase-3 and -7. Thornberry et al. have observed that most caspases prefer a tetrapeptide motif with an aspartyl residue at P4 (11). Asp-Glu-Val-Asp (DEVD) is the peptide sequence optimal for caspase-3 and -7, while the Val-Glu-His-Asp (VEHD) sequence is preferred by caspase-6 (5). These sequence-based probes demonstrate high caspase specificity; however, most probes suffer from poor cellular uptake in the intact cell, a requirement for early detection. Edgington et al. developed a class of probes based on the acyloxymethyl ketone (AOMK) and the optimal sequence of caspase-3 and -7 (2). AB50-Cy5 is one of the probes, which contains a Glu-Pro-Asp-AOMK sequence labeled with the Cy5 fluorophore. This probe showed labeling of caspase-3 and legumain with no detectable cathepsin B labeling. To enhance the cell permeability of AB50-Cy5, the investigators synthesized the probe tAB50-Cy5, a version of the probe containing a tat peptide. For this probe, the tat peptide was used to increase the cell uptake of the probe through multiple positively charged amino acids, while AOMK was used to label caspases. This chapter summarized the synthesis and comparative analysis of tAB50-Cy5 and AB50-Cy5.
15328336 Modulation of effector cell functions in experimental autoimmune encephalomyelitis by lefl 2004 Nov Leflunomide inhibits de novo pyrimidine synthesis and is a novel, immunosuppressive agent that has been successfully used to treat rheumatoid arthritis. Here, we investigated the efficacy of leflunomide and its mode of action in experimental autoimmune encephalomyelitis (EAE), which is a T helper cell type 1 cell-borne disease model to simulate inflammatory aspects of multiple sclerosis and was induced in Lewis rats by adoptive transfer of myelin basic protein (MBP)-specific T line cells. Given in vivo for 7 days after cell transfer, leflunomide suppressed clinical signs of disease even in uridine-substituted animals. MBP-specific T line cells that had been antigen-activated in vitro in the presence of A77 1726 (active metabolite of leflunomide) produced less interferon-gamma, whereas interleukin (IL)-10 secretion had a tendency to be increased without changes in signal transducer and activator of transcription 6 trafficking. Furthermore, these T cells exhibited reduced chemotaxis and induced a significantly mitigated disease course upon transfer into naive rats. The effects of leflunomide on MBP-specific memory type T line cells in vitro may not be mediated by pyrimidine depletion, as they were not reversible by exogenous uridine. Moreover, A77 1726 led to increased expression of CD86 (B7-2) and secretion of IL-10 in cultured microglial cells in vitro, strengthening their down-modulatory impact on activated, autoantigen-specific T cells. In conclusion, our observations underline that the immunomodulatory potential of leflunomide in effector cells of EAE is clinically relevant and is not exclusively dependent on the depletion of cellular pyrimidine pools.
20641917 (68)Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[15-amino-4,7,10,13-tetraoxapentad 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). 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). 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. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (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 (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Liu et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[15-amino-4,7,10,13-tetraoxapentadecanoic acid-cyclo(RGDfK)](2) (P(4)-RGD2) to form ((68)Ga-NOTA-P(4)-RGD2) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
20641458 (68)Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[Gly-Gly-Gly-c(Arg-Gly-Asp-D-Phe-L 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). 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). 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. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (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 (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Li et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[Gly-Gly-Gly-cyclo(RGDfK)](2) (G(3)-RGD2) to form ((68)Ga-NOTA-G(3)-RGD2) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
20641262 (68)Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[c(Arg-Gly-Asp-D-Tyr-Lys)](2). 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). 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). 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) (50% inhibition concentration (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 and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Li et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[cyclo(RGDyK)](2) (RGD2) to form ((68)Ga-NOTA-RGD2) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma U87MG tumors.
23785729 (111)In-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-P 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. 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). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for use with the imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD (c(RGD)) peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled c(RGD) peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the evaluation of (111)In-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-Phe-Lys)](2) ((111)In-NODAGA-E-[c(RGDfK)](2)) for use with single-photon emission computed tomography (SPECT) imaging of α(v)β(3) in tumors.
21656983 Poly(ethylene glycol)-coated gold nanocages. 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets (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 a 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). Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality based on the photoacoustic effect. In PAI, non-ionizing optical pulses are delivered into biological tissues. Some of the delivered energy is absorbed and converted into heat, leading to transient thermoelastic expansion and thus ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission (i.e., the photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast and tissue structures. However, exogenous NIR contrast agents are necessary to overcome the intrinsic low tissue- and hemoglobin-absorption and scattering of tissue. On the other hand, these small molecules exhibit fast clearance, small optical absorption cross section, and non-targeted specificity. Therefore, there is a need for contrast agents with long blood circulation and targeted specificity. Gold (Au) nanoparticles have been studied as molecular imaging agents because of their bright NIR fluorescence emission around 700–900 nm and low toxicity (6, 7). They can be tuned to emit in a range of wavelengths by changing their sizes, shapes, and composition, thus providing broad excitation profiles and high absorption coefficients. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds for in vitro and in vivo studies. Au nanoparticles have been approved by the United States Food and Drug Administration for treatment of patients with rheumatoid arthritis. Au nanoparticles have been studied as contrast agents in X-ray/computed tomography, NIR optical coherence tomography, PAI, and photoacoustic tomography (PAT) (8). NIR Au nanocages (AuNCs) are biocompatible, have low toxicity, and are tunable to strong NIR absorption (9). They have an outer edge of ~50 nm and an inner edge of ~42 nm, with a wall thickness of ~4 nm. Yang et al. (10) performed PAT of the cerebral cortex of rats with poly(ethylene glycol)-coated AuNCs (PEG-AuNCs) as the optical contrast agent. The investigators observed an enhanced optical contrast in the vasculature in the cerebral cortex.