Osteopontin plays an important role in the development and perpetuation of rheumatoid arthritis (RA). Antibodies targeting osteopontin have shown promising therapeutic benefits against this disease. We have previously reported a novel anti-RA monoclonal antibody, namely, 23C3, and shown it capable of alleviating the symptoms of RA in a murine collagen-induced arthritis model, restoring the cytokine production profile in joint tissues, and reducing T-cell recall responses to collagen type II. We describe here the crystal structure of 23C3 in complex with its epitope peptide. Analyses of the complex structure reveal the molecular mechanism of osteopontin recognition by 23C3. The peptide folds into two tandem β-turns, and two key residues of the peptide are identified to be critical for the recognition by 23C3: TrpP43 is deeply embedded into a hydrophobic pocket formed by AlaL34, TyrL36, LeuL46, TyrL49, PheL91, and MetH102 and therefore has extensive hydrophobic interactions with 23C3, while AspP47 has a network of hydrophilic interactions with residues ArgH50, ArgH52, SerH53, and AsnH56 of the antibody. Besides the complementarity-determining region loops, the framework region L2 of 23C3 is also shown to interact with the epitope peptide, which is not common in the antibody-antigen interactions and thus could be exploited in the engineering of 23C3. These results not only provide valuable information for further improvement of 23C3 such as chimerization or humanization for its therapeutic application, but also reveal the features of this specific epitope of osteopontin that may be useful for the development of new antibody drugs against RA. 相似文献
Cellular retinoic acid binding protein II (CRABP-II) is overexpressed in a wide variety of cancers. Previously we have shown that CRABP-II expression levels are also elevated in neuroblastoma and Wilms tumors. To elucidate the molecular mechanisms underlying the abnormal expression of CRABP-II in Wilms tumor, we studied the expression of MycN and CRABP-II in these tumor samples. Our data revealed that CRABP-II is overexpressed in Wilms tumor compared to normal adjacent non-neoplastic tissue and its levels are even higher in late stage tumors. Its expression correlates with MycN expression in tumors. The tumors that do not express MycN have no CRABP-II expression. The expression of CRABP-II is also regulated by methylation and its promoter is unmethylated in tumors. Knockdown of MycN by small interfering RNA leads to downregulation of CRABP-II. Thus our results suggest that both MycN and DNA methylation are responsible for CRABP-II expression in pediatric tumors and demethylation of CRABP-II may be an early event in tumor development. 相似文献
Rituximab (Rit) was the first monoclonal antibody approved for therapeutic use in cancer patients. Rit is a chimeric mouse/human monoclonal antibody, consisting of the human IgG1 and k constant Fc region, and a mouse variable Fab region specific against the B-cell antigen CD20. Rit exerts its antilymphoma activity through many different mechanisms. Binding of antibody to CD20 antigen, provokes apoptosis through downstream signals that lead to caspase-3 activation. Complement activation by the Fc portion of the antibody results in complement-dependent cytotoxicity. However, the most effective mechanism of action seems to be antigen-dependent cellular cytotoxicity. Effector cytotoxic cells such as natural killer cells (NK) are activated after binding to the Fc portion of the anti-CD20 molecule. Activated NK cells kill the coated lymphoma cells with the use of granzyme-perforin system. More recently, pre-clinical data support the concept that Rituximab can provoke a vaccination-like effect. Finally in-vitro experiments and clinical trials have shown that co-administration of the antibody with cytotoxics confers a strong synergistic effect. The relative contribution of these mechanisms in vivo and in different lymphoma subtypes is not well known and remains to be further evaluated.
Among the different histological groups, follicular lymphoma (FL) has been proven to be the most sensitive to Rit when used as a single agent, with overall response rates of 80% and 50% in untreated and previously treated patients, respectively. Moreover, Rit in combination with chemotherapy is superior to chemotherapy alone in terms of response rate and event-free survival, while early data indicate a significant prolongation in overall survival as well. Similarly, the addition of Rit to standard chemotherapy improves the disease-free and overall survival of patients with diffuse large B-cell lymphoma. There is no doubt that Rit represents one of the greatest achievements of biotechnology engineering. However, we need to understand better the mechanisms of its action as well as the mechanisms of resistance to Rit, in order to design more effective treatment modalities. 相似文献
Objective: To identify research published on obesity in Canada, to explore the range of areas studied, and to identify gaps and areas that merit future research attention. Research Methods and Procedures: Medline and International Pharmaceutical Abstracts databases were searched from 1970 onwards. Original articles were identified and categorized by areas of interest. Results: A total of 1186 relevant articles were identified: 17, 136, 687, and 346 articles during the 1970s, 1980s, 1990s, and 2000 to 2003, respectively. Of the articles, 816 were considered original studies and accepted for this analysis. Twelve research areas were identified: basic science involving animal experiments (29%), human experiments (16%), populations surveys (14%), obesity‐related comorbidities (13%), diagnostic/surgical issues (11%), nonpharmacological approaches (7%), drug‐related issues (4%), anthropometrics (2%), impact of weight loss (2%), cost/healthcare use (1%), attitudes/perceptions (0.9%), and models/procedures (0.5%). Two‐thirds of all research was conducted in Quebec (34%) and Ontario (33%). Discussion: Given the multifactorial nature of obesity, Canadian obesity research covers a broad range of areas with a predominance of basic science but lesser emphasis on community and primary care studies. Furthermore, there was a paucity of research on either clinical management of medical conditions in obese patients or clinical aspects that go beyond weight loss. Thus, although Canada appears well represented in basic research, more attention to exploration of clinical issues and healthcare delivery for obese patients appears warranted. 相似文献
We have analyzed the importance of substrate methylation by S-adenosylmethionine-dependent methyltransferases for neuronal differentiation of P19 embryonal carcinoma cells. We show that treatment of cells with methyltransferase inhibitor adenosine dialdehyde (AdOx) interferes with neuronal differentiation. Retinoic acid (RA) and AdOx co-treated cells had a decreased number of neurites and a flattened morphology compared with cells differentiated by RA. Also, the amount of neuronal class III tubulin (Tuj1) decreased from 76% to 9.6% with AdOx-treatment. Gene expression levels of wnt-1, brn-2, neuroD, and mash-1 were also down-regulated by AdOx-treatment. But AdOx-treatment did not up-regulate BMP-4 and GFAP genes. Treatment of RA decreased E-cadherin expression during neuronal differentiation. However, in AdOx/RA co-treated cells, E-cadherin expression was restored to the control level. Also, mRNA expression of N-cadherin decreased with AdOx-treatment. Taken together, these data show that methylation reactions might influence the cell-fate decision and neuronal differentiation of P19 cells. 相似文献
The lesion of nucleus robustus archistriatalis (RA) has no effect on normal short calls in the bramble finch, but affects
significantly the temporal and acoustic features of learned long calls. It causes the principal frequency of basic sound in
monotone long calls to increase 500 cents, and to lose two upper partials. The lesion of RA not only results in the increased
sound length of loud-sound and shortened coda of variable-tone long calls by 13.4%–22.1% and 21.2%–24.2% on average, respectively,
but also makes the frequency rising coefficient (FRC) of even order partial tone in loud-sound drop 18.5%–25.8% on an average,
and the step-up rate decrease 22.7% –24.0% on an average with the increase of frequencies. These results show that the control
of temporal and frequency features of learned calls by RA matches to each other. Moreover, the lesion of bilateral RA can
confuse the vocal pattern, and the produced long call has the character of both the mono- and variable-tone long calls. The
prelude shows rising frequency, and the loud sound is monotone sound. 相似文献