A modified mesenchymal stem cell (MSC) transplantation is a highly effective and precise treatment for inflammatory bowel disease (IBD), with a significant curative effect. Thus, we aim to examine the efficacy of hypoxia-inducible factor (HIF)–1α-overexpressing MSC (HIF-MSC) transplantation in experimental colitis and investigate the immunity regulation mechanisms of HIF-MSC through macrophages. A chronic experimental colitis mouse model was established using 2,4,6-trinitrobenzene sulfonic acid. HIF-MSC transplantation significantly attenuated colitis in weight loss rate, disease activity index (DAI), colon length, and pathology score and effectively rebuilt the local and systemic immune balance. Macrophage depletion significantly impaired the benefits of HIF-MSCs on mice with colitis. Immunofluorescence analysis revealed that HIF-MSCs significantly decreased the number of M1-like macrophages and increased the number of M2-like macrophages in colon tissues. In vitro, co-culturing with HIF-MSCs significantly decreased the expression of pro-inflammatory factors, C-C chemokine receptor 7 (CCR-7), and inducible nitric oxide synthase (INOS) and increased the expression of anti-inflammatory factors and arginase I (Arg-1) in induced M1-like macrophages. Flow cytometry revealed that co-culturing with HIF-MSCs led to a decrease in the proportions of M1-like macrophages and an increase in that of M2-like macrophages. HIF-MSCs treatment notably upregulated the expression of downstream molecular targets of phosphatidylinositol 3-kinase-γ (PI3K-γ), including HIF-1α and p-AKT/AKT in the colon tissue. A selected PI3K-γ inhibitor, IPI549, attenuated these effects, as well as the effect on M2-like macrophage polarization and inflammatory cytokines in colitis mice. In vitro, HIF-MSCs notably upregulated the expression of C/EBPβ and AKT1/AKT2, and PI3K-γ inhibition blocked this effect. Modified MSCs stably overexpressed HIF-1α, which effectively regulated macrophage polarization through PI3K-γ. HIF-MSC transplantation may be a potentially effective precision therapy for IBD.

Renal cell cancer is associated with the coagulation system. Long non-coding RNA (lncRNA) expression is closely associated with the development of clear cell renal cell carcinoma (ccRCC). The aim of this study was to build a novel lncRNA model to predict the prognosis and immunological state of ccRCC. The transcriptomic data and clinical data of ccRCC were retrieved from TCGA database, subsequently, the lasso regression and lambda spectra were used to filter prognostic lncRNAs. ROC curves and the C-index were used to confirm the predictive effectiveness of this model. We also explored the difference in immune infiltration, immune checkpoints, tumor mutation burden (TMB) and drug sensitivity between the high- and low-risk groups. We created an 8 lncRNA model for predicting the outcome of ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, and risk score are independent prognostic factors for ccRCC patients. ROC curve and C-index revealed the model had a good performance in predicting prognosis of ccRCC. GO and KEGG analysis showed that coagulation related genes were related to immune response. In addition, high risk group had greater TMB level and higher immune checkpoints expression. Sorafenib, Imatinib, Pazopanib, and etoposide had higher half maximal inhibitory concentration (IC₅₀₎ in the high risk group whereas Sunitinib and Bosutinib had lower IC₅₀. This novel coagulation-related long noncoding RNAs model could predict the prognosis of patients with ccRCC, and coagulation-related lncRNA may be connected to the tumor microenvironment and gene mutation of ccRCC.

This paper explores the role of institutional investors from a perspective of firm financialization by selecting listed companies in the Shanghai Stock Exchange and Shenzhen Stock Exchange as a sample for the study. We find that institutional investor ownership can reduce firm financialization. This result still holds after a series of robustness checks, such as the firm-year fixed effects model and additional control variables in the regression model. Additionally, the effect of institutional investors on financialization is more pronounced for firms with large size, which indicates that better corporate governance can provide support to the monitoring role of institutional investors. In all, our findings support strong insight on how regulators rationally lead institutional investors to adopt appropriate investment strategies and orient the finance industry to support the development of the real economy, consequently driving the revolution of the finance industry.

Prostate cancer is a heterogeneous disease, with multiple stages of cancer evident within an individual organ. Although some of the genetic changes necessary to initiate or advance prostate cancer have been identified, in order to develop effective therapies, it is critical to understand the different means by which this disease develops and progresses. Prostate Stem Cell Antigen (PSCA) is a GPI-anchored cell surface protein that is expressed in the normal epithelial cells of a restricted set of organs, including prostate, bladder, stomach, kidney and pancreas. Over-expression of PSCA is found in all stages of prostate cancer, from PIN to metastasis. We are investigating the biological function of PSCA in prostate tumorigenesis. We recently reported that deletion of PSCA increases metastasis of TRAMP-induced prostate tumors in mice, suggesting that PSCA may function as a tumor suppressor. To determine the effect of modulating PSCA dosage in the context of another oncogenic signal implicated in human prostate cancer development, we crossed PSCA knockout mice to prostate-specific Pten knockout mice, and analyzed the animals at 30 weeks of age. Pten −/−;PSCA +/− mice developed significantly larger prostate tumors than Pten −/− mice that are wild-type for PSCA. These results also suggest that PSCA may function as a tumor suppressor. In contrast, mice with deletion of both copies of the PSCA gene (Pten −/−; PSCA −/− mice) developed tumors similar in size to Pten −/−;PSCA +/+ animals, consistent with the possibility that PSCA function may contribute to the early stages of cancer development. Together, our results suggest that modulation of PSCA gene dosage affects cancer initiation and progression, indicating a putative dual role for PSCA in epithelial cancer. Our current experiments are designed to determine the molecular mechanism of PSCA function. Citation Information: Cancer Res 2009;69(23 Suppl):B37.

A significant number of patients develop castration-resistant prostate cancer, for which there is no cure. Our goal is to characterize the effector and inhibitory mechanisms which modulate prostate cancer progression. We have previously shown that CD8+ effector function is transiently increased following castration of prostate-specific Pten-/- mice. To determine inhibitory mechanisms responsible for the transient increase in effector function, we evaluated the role of myeloid cells in this model. We observed a heavy Gr-1+ cell infiltrate in the primary tumors which was markedly increased early after castration. Phenotypic profiling of tumor-infiltrating Gr-1+ cells from intact and castrated mice showed uniform CD11b+Ly6C+Ly6G+ marker expression and neutrophil morphology. To determine the functional importance of these tumor-associated neutrophils (TANs), we administered anti-Ly6G antibody to intact Pten-/- mice. We found that depletion of TANs slightly increased tumor burden prior to castration. In addition, the number of regulatory T cells was elevated in the tumor after neutrophil depletion, and the proportion of functional CD8+ T cells was unchanged. In contrast, concomitant castration and neutrophil depletion did not change tumor weight, early (2.5 wk) or late (5 wk) after castration. Although the total number of CD8+ T cells in the tumor was increased by neutrophil depletion early after castration, the proportion of functional CD8+ T cells was unchanged. A striking increase in regulatory T cell (Treg) numbers was also observed. In contrast, the number of CD8+ T cells and the percentage of functional cells were increased late after castration and neutrophil depletion. Furthermore, depletion of neutrophils decreased intratumoral Tregs at 5 weeks post-castration. These data suggest that TANs modulate the tumor microenvironment, rendering it increasingly immunosuppressive late after castration. We have found that castration increases systemic Tregs in Pten-/- mice. To determine whether Tregs regulate neutrophil function in prostate tumors, we administered α-CD25 antibody along with castration. Neutrophil numbers in castration-resistant prostate tumors increased, and expression of TNFα, IL4Rα, iNOS, Arg, IL-6 and IL-12 by the neutrophils was also augmented. Concomitantly, an increase in the proportion of functional CD8+ T cells was observed. Interestingly, depletion of neutrophils abrogated the augmentation of CD8+ CTL activation following Treg depletion, suggesting that cross-talk between neutrophils and Tregs regulates CD8 effector function. Thus, TANs in Pten-/- prostate tumors have anti-tumor potential and can modulate both CD8+ effector T cells and Tregs within the tumor. Our long-term goal is to understand how TANs control effector and inhibitory arms of the immune system in order to improve outcomes following immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3545. doi:1538-7445.AM2012-3545