Maspin, a unique member of the serpin family, is a secreted protein encoded by a class II tumor suppressor gene whose downregulation is associated with the development of breast and prostate cancers. Overexpression of maspin in breast tumor cells limits their growth and metastases in vivo. In this report we demonstrate that maspin is an effective inhibitor of angiogenesis. In vitro, it acted directly on cultured endothelial cells to stop their migration towards basic fibroblast growth factor and vascular endothelial growth factor and to limit mitogenesis and tube formation. In vivo, it blocked neovascularization in the rat cornea pocket model. Maspin derivatives mutated in the serpin reactive site lost their ability to inhibit the migration of fibroblasts, keratinocytes, and breast cancer cells but were still able to block angiogenesis in vitro and in vivo. When maspin was delivered locally to human prostate tumor cells in a xenograft mouse model, it blocked tumor growth and dramatically reduced the density of tumor-associated microvessels. These data suggest that the tumor suppressor activity of maspin may depend in large part on its ability to inhibit angiogenesis and raise the possibility that maspin and similar serpins may be excellent leads for the development of drugs that modulate angiogenesis.

Popular accounts of "lifestyle politics" and "culture wars" suggest that political and ideological divisions extend also to leisure activities, consumption, aesthetic taste, and personal morality. Drawing on a total of 22,572 pairwise correlations from the General Social Survey (1972-2010), the authors provide comprehensive empirical support for the anecdotal accounts. Moreover, most ideological differences in lifestyle cannot be explained by demographic covariates alone. The authors propose a surprisingly simplesolution to the puzzle of lifestyle politics. Computational experiments show how the self-reinforcing dynamics of homophily and influence dramatically amplify even very small elective affinities between lifestyle and ideology, producing a stereotypical world of "latte liberals" and "bird-hunting conservatives" much like the one in which we live.

Cranial bone defect remains a major challenge to craniofacial surgeons because of limited availability of autologous bone graft to repair the defects and the donor site defects secondary to tissue harvesting. In contrast, tissue-engineering technique can generate a large bone tissue using small amount of autologous cells and therefore avoid these problems. Bone Marrow Stromal Cells (MSCs) have the potential of multi-lineage (including osteogenic) differentiation. The objective of this study was to investigate the potential of using autologous MSCs to repair cranial bone defects by a tissue-engineering approach. Autologous MSCs were isolated from eight adult sheep respectively and were in vitro expanded and induced to become osteogenic cells. Bilateral full-thickness defects (20 mm in diameter) of parietal bones were created in animals and the bone defects were either repaired with the bone implants constituted with MSCs and calcium alginate at the experimental side (n = 8) or treated with calcium alginate only without MSCs (n = 4) or left unrepaired (n = 4) at the control side. New bone tissues were observed either grossly or histologically at the defects of experimental group as early as 6 weeks post-repairing, but not in control groups. The engineered bone tissue became more mature at 18 weeks post-repairing. Three-dimensional computerized tomography (CT) scan revealed an almost complete repair of the defect of experimental group at 18 weeks. This study may provide insight for future clinical repair of cranial defect.

Background:The role of STAT1 in promoting tumor progression is not well understood. Results: STAT1 activity is elevated in human and mouse breast cancers, and STAT1 promotes breast cancer progression. Conclusion: Tumor STAT1 transcription factor activity enhances breast tumor growth and immune suppression mediated by MDSCs. Significance: STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach.

BackgroundTumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression.Methodology/Principal FindingsIn this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d-dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors.Conclusions/SignificanceThe results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer.

Mammalian metallothionein (MT) genes are transcriptionally activated by the essential metal zinc as well as by environmental stresses, including toxic metal overload and redox fluctuations. In addition to playing a key role in zinc homeostasis, MT proteins can protect against metal-and oxidant-induced cellular damage, and may participate in other fundamental physiologic and pathologic processes such as cell survival, proliferation, and neoplasia. Previously, our group reported a requirement for metal-responsive transcription factor-1 (MTF-1) in hypoxia-induced transcription of mouse MT-I and human MT-IIA genes. Here, we provide evidence that the protumorigenic hypoxia-inducible transcription factor-1A (HIF-1A) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1A are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1A, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1A seems to function as a coactivator of MT-I gene transcription by interacting with MTF-1 during hypoxia. Coimmunoprecipitation studies suggest interaction between MTF-1 and HIF-1A, either directly or as mediated by other factors. It is proposed that association of these important transcription factors in a multiprotein complex represents a common strategy to control unique sets of hypoxia-inducible genes in both normal and diseased tissue. (Mol Cancer Res 2008;6(3):483 -90)

BackgroundThe objective of the study was to investigate the effect of different types of bile acids on proliferation of cholangiocarcinoma and the potential molecular mechanisms.MethodsPCR assay and Western blot were performed to detect the expression of farnesoid × receptor (FXR) in mRNA and protein level. Immunohistochemical analysis was carried out to monitor the expression of FXR in cholangiocarcinoma tissues from 26 patients and 10 normal controls. The effects on in vivo tumor growth were also studied in nude mouse model.ResultsFree bile acids induced an increased expression of FXR; on the contrary, the conjugated bile acids decreased the expression of FXR. The FXR effect has been illustrated with the use of the FXR agonist GW4064 and the FXR antagonist GS. More specifically, when the use of free bile acids combined with FXR agonist GW4064, the tumor cell inhibitory effect was even more pronounced. But adding FXR antagonist GS into the treatment attenuated the tumor inhibitory effect caused by free bile acids. Combined treatment of GS and CDCA could reverse the regulating effect of CDCA on the expression of FXR. Administration of CDCA and GW 4064 resulted in a significant inhibition of tumor growth. The inhibitory effect in combination group (CDCA plus GW 4064) was even more pronounced. Again, the conjugated bile acid-GDCA promoted the growth of tumor. We also found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth. And the characteristic and difference of FXR expressions were in agreement with previous experimental results in mouse cholangiocarcinoma tissues. There was also significant difference in FXR expression between normal and tumor tissues from patients with cholangiocarcinoma.ConclusionsThe imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma. FXR, a member of the nuclear receptor superfamily, may mediate the effects induced by the bile acids.

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