Mouse cancer models have consistently been used to qualify new anticancer drugs in the development of human clinical trials. Rodent tumour models currently being used and which include transgenic tumour models, and those generated by planting human tumour cell lines subcutaneously in immunodeficient mice, do not sufficiently represent clinical cancer characteristics, especially with regard to metastasis and drug sensitivity. The increasingly used patient-derived human tumour tissue (PDTT) xenografts models implanted subcutaneously or in subrenal capsule in immunodeficient mice, such as athymic nude mice or severe combined immunedeficient (SCID) mice, may provide a more accurate reflection of human tumour biological characteristics than tumour cell lines. The ability to passage patients' fresh tumour tissues into large numbers of immunodeficient mice provides possibilities for better preclinical testing of new therapies for the treatment and better outcome for cancer. In this review, we outline the methods of establishing xenograft models, discuss the biological stability of PDTT xenograft models and demonstrate their roles in developing new anticancer drugs and testing therapeutic regimens in cancer patients.

The gut and brain form the gut-brain axis through bidirectional nervous, endocrine, and immune communications. Changes in one of the organs will affect the other organs. Disorders in the composition and quantity of gut microorganisms can affect both the enteric nervous system and the central nervous system (CNS), thereby indicating the existence of a microbiota-gut-brain axis. Due to the intricate interactions between the gut and the brain, gut symbiotic microorganisms are closely associated with various CNS diseases, such as Parkinson's disease, Alzheimer's disease, schizophrenia, and multiple sclerosis. In this paper, we will review the latest advances of studies on the correlation between gut microorganisms and CNS functions & diseases.

The observation that delayed death of CAl neurons after global ischemia is inhibited by protein synthesis inhibitors suggests that the delayed death of these neurons is an active process that requires new gene expression. Delayed death in CAl has some of the characteristics of apoptotic death; however, candidate proapoptotic proteins have not been identified in the CAl after ischemia. We studied the expression of Bax protein and mRNA, a member of the bcl-2 family that is an effector of apoptotic cell death, after global ischemia in the fourvessel global ischemia model in the rat and compared these results with the expression of the antiapoptotic gene bcl-2. Bax mRNA and protein are both expressed in CAl before delayed death, whereas bcl-2 protein is not expressed. Bcl-2 protein expression, but not that of Bax, is increased in CA3, a region that is ischemic but less susceptible to ischemic injury. In the dentate gyrus, both Bax and bcl-2 proteins are expressed. The selective expression of Bax in CAl supports the hypothesis that Bax could contribute to delayed neuronal death in these vulnerable neurons by an independent mechanism or by forming heterodimers with gene family members other than bcl-2. Key Words: Apoptosis-Global ischemiabcl-2-Bax.

Background/Aims: Long non-coding RNAs (lncRNAs) have been reported to play pivotal roles in multiple tumors and can act as tumor biomarkers. In this study, we explored the association of the expression of an lncRNA, DGCR5 with clinicopathological features and prognosis in HCC. Methods: Expression levels of DGCR5 were detected by quantitative real-time PCR (qRT-PCR) and the clinical data was obtained, including basic information, data of clinicopathology and cancer specific survival rate. Receiver operating characteristic (ROC) curve, Kaplan-Meier methods and multivariable Cox regression models were used to analyze predictive efficiency, long-term survival outcomes and risk factors. Results: DGCR5 was found down-regulated in HCC tissues (P<0.001) and serum (P = 0.0035) and low expression of DGCR5 was correlated with a poor cancer specific survival (CSS) (P = 0.0019), as the overall 5-year CSS rates were 10.3% (low expression group) and 36.6% (high expression group), respectively. A stratified analysis demonstrated that low DGCR5 expression was an independent negative prognostic factor for HCC. In addition, the area under the ROC curve was 0.782 with a sensitivity of 0.633 and a specificity of 0.833. Conclusions: Our results suggest that DGCR5 may be a participator in HCC and can serve as potential biomarker for the diagnosis and prognosis in HCC.

Increasing evidence shows that the anti-tumor functions of tumor-infiltrating T lymphocytes (TILs) were inhibited significantly, but the underlying mechanisms remain not fully understood. In this study, we found that 14-3-3ζ expression was up-regulated in hepatocellular carcinoma (HCC) cells and in TILs. TILs with 14-3-3ζ high-expression (14-3-3ζhigh) exhibited impaired activation (CD69), proliferation (Ki67) and anti-tumor functions compared to 14-3-3ζ low expression (14-3-3ζlow) TILs. Flow cytometry assay showed that compared with 14-3-3ζlow CD8+T cells, 14-3-3ζhigh ones exhibited higher frequency of exhausted phenotypes as measured by inhibitory receptors such as PD-1, TIM-3, LAG3, and CTLA-4. 14-3-3ζ overexpression inhibited the activity and proliferation of peripheral blood CD3+ T cells, deviated the differentiation of naive T cells from effector T cells to regulatory T cells. Moreover, we found that 14-3-3ζ expression levels in TILs correlated positively with those in HCC cells. Naive T cells co-cultured with HCC cells or the visible components of culture medium of HCC cells exhibited increased 14-3-3ζ expression. Stochastic optical reconstruction microscopy (STORM) and confocal assay showed that 14-3-3ζ-containing exosomes derived from HCC cells could be swallowed by T cells, suggesting that 14-3-3ζ might be transmitted from HCC cells to TILs at least partially through exosomes. In conclusion, our study for the first time demonstrated that 14-3-3ζ is up-regulated in and inhibited the anti-tumor functions of tumor-infiltrating T cells in HCC microenvironment and that 14-3-3ζ might be transmitted from HCC cells to T cells at least partially through exosomes.

Acquired tamoxifen (TAM) resistance limits the therapeutic benefit of TAM in patients with hormone-dependent breast cancer. The switch from estrogen-dependent to growth factor-dependent growth is a critical step in this process. However, the molecular mechanisms underlying this switch remain poorly understood. In this study, we established a TAM resistant cell sub line (MCF-7/TAM) from estrogen receptor-α (ER-α66) positive breast cancer MCF-7 cells by culturing ER-α66-positive MCF-7 cells in medium plus 1 μM TAM over 6 months. MCF-7/TAM cells were then found to exhibit accelerated proliferation rate together with enhanced in vitro migratory and invasive ability. And the estrogen receptor-α36 (ER-α36), a novel 36-kDa variant of ER-α66, was dramatically overexpressed in this in vitro model, compared to the parental MCF-7 cells. Meanwhile, the expression of epidermal growth factor receptor (EGFR) in MCF-7/TAM cells was significantly up-regulated both in mRNA level and protein level, and the expression of ER-α66 was greatly down-regulated oppositely. In the subsequent studies, we overexpressed ER-α36 in MCF-7 cells by stable transfection and found that ER-α36 transfected MCF-7 cells (MCF-7/ER-α36) similarly exhibited decreased sensitivity to TAM, accelerated proliferative rate and enhanced in vitro migratory and invasive ability, compared to empty vector transfected MCF-7 cells (MCF-7/V). Real-time qPCR and Western blotting analysis revealed that MCF-7/ER-α36 cells possessed increased EGFR expression but decreased ER-α66 expression both in mRNA level and protein level, compared to MCF-7/V cells. This change in MCF-7/ER-α36 cells could be reversed by neutralizing anti-ER-α36 antibody treatment. Furthermore, knock-down of ER-α36 expression in MCF-7/TAM cells resulted in reduced proliferation rate together with decreased in vitro migratory and invasive ability. Decreased EGFR mRNA and protein expression as well as increased ER-α66 mRNA expression were also observed in MCF-7/TAM cells with down-regulated ER-α36 expression. In addition, blocking EGFR/ERK signaling in MCF-7/ER-α36 cells could restore the expression of ER-α66 partly, suggesting a regulatory function of EGFR/ERK signaling in down-regulation of ER-α66 expression. In conclusion, our results indicated for the first time a regulatory role of ER-α36 in up-regulation of EGFR expression and down-regulation of ER-α66 expression, which could be an underlying mechanism for the growth status switch in breast tumors that contribute to the generation of acquired TAM resistance. And ER-α36 could be considered a potential new therapeutic target in breast tumors which have acquired resistance to TAM.

Luteolin is a flavonoid, which has been extensively investigated due to its antitumor effects; however, the underlying mechanisms of its action remain largely unknown. The present study aimed to investigate the role of luteolin in breast cancer (BC), and explored how luteolin suppresses the growth and induces the apoptosis of BC cells. The MTS assay was used to determine the anticancer activity of luteolin. Colony formation and Transwell assays were performed to evaluate the effects of luteolin on cell growth and invasion. Cell cycle progression and apoptosis were analyzed by flow cytometry. In addition, western blotting was performed to analyze cellular apoptosis and signaling pathways elicited by luteolin. The present study revealed that the proliferation of the BC cell line MDA-MB-231 was effectively suppressed by luteolin in a dose-dependent manner. Additionally, luteolin was revealed to increase apoptotic rates in BC cells. Dose-dependent cell cycle arrest in S phase was observed following treatment with luteolin in MDA-MB-231 cells. Mechanistically, luteolin reduced telomerase levels in a dose-dependent manner. Additionally, luteolin inhibited phosphorylation of the nuclear factor-κB inhibitor α and its target gene c-Myc, to suppress human telomerase reverse transcriptase (hTERT) expression, which encodes the catalytic subunit of telomerase. Collectively, the results of the present study indicated that luteolin may inhibit BC cell growth by targeting hTERT, suggesting that the mechanism of hTERT regulation by luteolin may justify further study regarding its potential as a therapeutic target for BC treatment.

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