Cytotoxic T Lymphocytes Regenerated from iPS Cells Have Therapeutic Efficacy in a Patient-Derived Xenograft Solid Tumor Model

Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR α/β genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors

A Comparison of Magnifying Chromoendoscopy Versus Narrow Band Imaging in the Diagnosis of Depth of Invasion for Early Colorectal Cancers

Although chromoendoscopy and narrow band imaging (NBI) are widely used in diagnosing the invasion depth of colorectal cancers, comparative studies of these modalities are lacking. This meta-analysis compared the performance of these two modalities in colorectal cancer diagnosis. MEDLINE, EMBASE, and Cochrane Library were searched for relevant original articles published up to December 20th, 2010. Major criteria for article inclusion were: (i) magnifying chromoendoscopy or NBI was used as a diagnostic modality and pit pattern or vascular pattern was used as a diagnostic classification; (ii) sensitivity and specificity were reported; (iii) absolute numbers of true-positive, false-positive, true-negative, and false-negative cases, or their equivalent, were provided; and (iv) pathology of biopsy, endoscopy, or surgical treatment was used as the reference standard. Sensitivity and specificity were pooled using a random effects model. Regression analysis was performed to compare the discriminatory power between chromoendoscopy and NBI by including a dummy variable. We made the assumption that a positive regression coefficient implied a better discriminatory power for NBI, and vice versa. Of 1846 screened articles, 16 fulfilled all inclusion criteria. Pooled sensitivity for chromoendoscopy and NBI was 0.85 (95% CI: 0.82-0.87) and 0.80 (0.76-0.85), respectively, and specificity was 0.98 (0.97-0.99) and 0.98 (0.97-0.99), respectively. The regression coefficient for chromoendoscopy versus NBI was -0.02 (95%CI: -1.18-1.71). These results indicate that chromoendoscopy and NBI may have similar power for the diagnostic assessment of colonic neoplasms. However, other factors such as convenience, time, and cost still must be taken into account in making the final diagnostic choice

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis