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Jian Y.,Indiana University - Purdue University Indianapolis | Ames D.M.,Indiana University - Purdue University Indianapolis | Ouyang H.,Preclinical Pharmacology | Li L.,Indiana University - Purdue University Indianapolis | Li L.,Indiana University
Organic Letters

Nucleoside/nucleotide/oligonucleotide photoreactions usually result in a number of products simultaneously due to a wide range of conformers existing at a given time. Such a complicated reaction pattern makes it difficult for one to focus on a single DNA photoproduct and elucidate the requirements for its formation. A rare example of thymidine photoreaction in microcrystals is reported, where 5-thyminyl-5,6-dihydrothymine, e.g.; the spore photoproduct (SP), is produced as the dominant species in ∼85% yield. This unprecedented high yield clears the major obstacle for future SP photochemistry studies in detail. © 2015 American Chemical Society. Source

Lin G.,Indiana University - Purdue University Indianapolis | Jian Y.,Indiana University - Purdue University Indianapolis | Ouyang H.,Preclinical Pharmacology | Li L.,Indiana University - Purdue University Indianapolis | Li L.,Indiana University
Organic Letters

Pyrimidine (6-4) pyrimidone photoproduct (6-4PP), a common DNA photolesion formed under solar irradiation, was indicated to hydrolyze under strong basic conditions, breaking the N3-C4 bond at the 5′-thymine. The reanalysis of this reaction revealed that the resulting water adduct may not be stable as previously proposed; it readily undergoes an esterification reaction induced by the 5-OH group at 6-4PP to form a five-membered ring, eliminating a molecule of ammonia. © 2014 American Chemical Society. Source

Zhong Z.,Imclone Systems | Carroll K.D.,Imclone Systems | Policarpio D.,Imclone Systems | Osborn C.,Imclone Systems | And 20 more authors.
Clinical Cancer Research

Purpose: Transforming growth factor β (TGFβ) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti-TGFβ receptor II (TGFβ RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models. Experimental Design: We generated neutralizing antibodies to TGFβ RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro. The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models. Results: Anti-TGFβ RII antibody blocked TGFβ RII binding to TGFβ 1, 2, and 3, and attenuated the TGFβ-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumorbearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis. Conclusions: These preclinical data provide a foundation to support using anti-TGFβ RII antibody as a therapeutic agent for TGFβ RIIβdependent cancer with metastatic capacity. ©2010 AACR. Source

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