1,395 research outputs found
Synthesis, Duplex-Forming Ability, and Enzymatic Stability of Oligonucleotides Modified with Amide-Linked Dinucleotides Containing a 3′,4′-Tetrahydropyran-Bridged Nucleic Acid
No full textOsawa T., Akino T., Obika S.. Synthesis, Duplex-Forming Ability, and Enzymatic Stability of Oligonucleotides Modified with Amide-Linked Dinucleotides Containing a 3′,4′-Tetrahydropyran-Bridged Nucleic Acid. Journal of Organic Chemistry 89, 269 (2024); https://doi.org/10.1021/acs.joc.3c02019.Replacement of a phosphodiester linkage with an amide linkage can improve the binding affinity of oligonucleotides to complementary RNA and their stability toward nucleases. In addition, restricting the conformation of the sugar moiety and the phosphate backbone in oligonucleotides effectively improves duplex stability. In this study, we designed amide-linked dinucleotides containing a 3′,4′-tetrahydropyran-bridged nucleic acid (3′,4′-tpBNA) with a constrained sugar conformation as well as a torsion angle ϵ. Phosphoramidites of the designed dinucleotides were synthesized and incorporated into oligonucleotides. Conformational analysis of the synthesized dinucleotides showed that the sugar conformation of the S-isomer of the amide-linked dinucleotide containing 3′,4′-tpBNA was N-type, which has the same conformation as that of the RNA duplex, while that of another R-isomer was S-type. Tm analysis indicated that the oligonucleotides containing the synthesized S-isomer showed RNA-selective hybridizing ability, although their duplex-forming ability was slightly inferior to that of natural oligonucleotides. Interestingly, the stability of the oligonucleotides toward endonucleases was significantly improved by modification with the two types of amide-linked dinucleotides developed in this study
Abstract 1397: Antisense oligo nucleotide of Annexin A4 improved platinum resistance in ovarian clear cell cancer
No full textAbstract
Introduction: Ovarian cancer in Japan are classified as clear cell carcinoma (CCC) more than 20 %, this percentage is higher than in Europe and United States. Besides, it is well known that CCC of ovary is highly resistant to cancer chemotherapy including carboplatin and paclitaxel treatment. We reported that Annexin A4 protein was overexpressed in ovarian CCC tissues by immunohistochemical analysis. Elevated Annexin A4 level has been detected in various epithelial cancer cell lines and have reported associating with chemoresistance to platinum-based cancer drugs. To overcome the platinum chemoresistance, we thought antisense oligonucleotides (ASOs) to be a good therapeutic option in a way of highly specific therapy for improving chemoresistance by suppressing the expression of Annexin A4 in cancer cells.
Methods: We generated ASO targeting Annexin A4 with 2’, 4’-bridged nucleic acid. And we analyzed suppression of Annexin A4 in ASO-transfected RMG-I cell line (CCC) in vitro using real time PCR and western blotting. In 16 types of ASOs targeting Annexin A4, 2 ASOs were eligible. Cells were seeded in 96-well plates (2,000 cells per well). Next day, cells were transfected with ASOs using lipofectamine 2000 and were exposed to various concentrations of cisplatin (0 - 100 μM) for 72 hr. Then, drug concentrations resulting in a 50% inhibition of cell growth (IC50 values) were calculated. Intracellular platinum accumulation in Annexin A4 overexpressing cells was analyzed. To assess the improvement of platinum resistance in vivo, we used ICR nu/nu mice xenografted subcutaneously with RMG-I cells. Intraperitoneal injection of cisplatin 3mg/kg after intratumoral administration of ASO 1mg/kg each twice a week were given to xenograft mice.
Results: By realtime PCR analysis, among strong 16 types of ASOs targeting Annexin A4, 2 ASOs showed strong knockdown efficiency (about 80% knockdown) compared to negative control ASOs. Western blotting analysis showing knockdown of Annexin A4 expression was observed in Annexin A4 ASO transfected cells compared to no treatment or control ASOs in vitro. ASO-transfected RMG-I cells was less resistant to cisplatin (IC50 = 3.3μM) compared with control cells (IC50 = 5.2μM) Same result were obtained with carboplatin. Platinum resistance was significantly improved in treated with Annexin A4 ASO and cisplatin compared to control ASO and cisplatin treated group in vivo.
Conclusion: By transfection of ASOs targeting Annexin A4, platinum resistance have improved in vivo and in vitro, Annexin A4 have associated with efflux of platinum anti-tumor drug. In conclusion, antisense oligonucleotides for Annexin A4 will be a therapeutic option for ovarian clear cell carcinoma with chemoresistance to platinum antitumor drug.
Citation Format: Reisa Kakubari, Satoshi Nakagawa, Tadashi Iwamiya, Eiji Kobayashi, Shinnya Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Yuya Kasahara, Satoshi Obika, Tadashi Kimura, Satoshi Serada, Tetsuji Naka, Minoru Fujimoto. Antisense oligo nucleotide of Annexin A4 improved platinum resistance in ovarian clear cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1397. doi:10.1158/1538-7445.AM2017-1397</jats:p
A successful model of regional healthcare information exchange in Japan: Case Study in Kagawa Prefecture
No full textIn this study, we focused on analysis of healthcare data exchange over the network. For the advance of broadband capability development, many governments expect online medical information exchange between medical institutions. Japanese government also has tried to deploy ICT in the healthcare field. In Japan, many healthcare ICT projects started, but almost of all the projects face many issues and failed to continue. This situation caused us to clarify the success factor of healthcare information exchange network. For inspecting the success factors, we analyzed information access of healthcare systems in Kagawa prefecture of Japan. Kagawa prefecture is one of the most advance areas for healthcare information technology. We analyzed four medical ICT projects in Kagawa prefecture: K-MIX, Critical Pathway for Diabetes, E-prescription, and PHR. In addition, we inspected characteristics of exchanged data in the network, and stakeholder involved in these projects. This analysis lets us find various types of healthcare ICT projects. Characteristic of data processed in the projects caused differences of characteristic of the projects. On the other hand, multiple systems process same data, though the project does not share the data itself. Considering various types of medical information exchanges projects, we propose classification and standard format of exchanged data according to their characteristic are critical for efficient business deployment. --e-Health,regional healthcare information exchange,EHR
Analysis for science librarians of the 2015 Nobel Prize in Physiology or Medicine: the life and work of William C. Campbell, Satoshi Ōmura, and Youyou Tu
No full textParasites affect humans worldwide with varying degrees of seriousness. Some of the most impactful parasitic infections affect millions of people, many of whom are already impoverished and struggling. The discoveries of the 2015 Nobel Laureates in Physiology of Medicine have changed the way some of these serious parasitic infections are treated, saving and improving the lives of countless people. These Laureates are William C. Campbell, Satoshi Ōmura, and Youyou Tu
Syntheses and Properties of Conformationally Restrained Nucleosides and Oligonucleotides Analogues
No full textChemInform Abstract: Syntheses and Properties of Conformationally Restrained Nucleosides and Oligonucleotides Analogues
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Effect of oligonucleotide structural difference on matrix‐assisted laser desorption/ionization in‐source decay in comparison with collision‐induced dissociation fragmentation
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