Abstract SARI (suppressor of AP‐1, regulated by IFN) impaired tumour growth by promoting apoptosis and inhibiting cell proliferation and tumour angiogenesis in various cancers. However, the role of SARI in regulating tumour‐associated inflammation microenvironment is still elusive. In our study, the colitis‐dependent and ‐independent primary model were established in SARI deficiency mice and immuno‐reconstructive mice to investigate the functional role of SARI in regulating tumour‐associated inflammation microenvironment and primary colon cancer formation. The results have shown that SARI deficiency promotes colitis‐associated cancer (CAC) development only in the presence of colon inflammation. SARI inhibited tumour‐associated macrophages (TAM) infiltration in colon tissues, and SARI deficiency in bone marrow cells has no observed role in the promotion of intestinal tumorigenesis. Mechanism investigations indicated that SARI down‐regulates p‐STAT1 and STAT1 expression in colon cancer cells, following inhibition of MCP‐1/CCR2 axis activation during CAC development. Inverse correlations between SARI expression and macrophage infiltration, MCP‐1 expression and p‐STAT1 expression were also demonstrated in colon malignant tissues. Collectively, our results prove the inhibition role of SARI in colon cancer formation through regulating TAM infiltration.
Abstract Within the oocytes of chicken preovulatory follicles, the engulfed yolk constitutes 99% of the oocyte content, while the small germinal disc (GD) (which contains the nucleus and 99% ooplasm) occupies only less than 1%. Relative to the position of the GD, the single granulosa cell layer surrounding the oocyte can be sub-divided into two sub-populations: granulosa cells proximal (named Gp cells) and distal (Gd cells) to the GD. It was reported that Gp cells and Gd cells differ in their morphology, proliferative rate and steroidogenic capacity, however, the underlying mechanism controlling granulosa cell heterogeneity remains unclear. Here we analyzed the transcriptomes of Gd and Gp cells of preovulatory (F5 and F1) follicles in chicken ovaries. We found that: (1) genes associated with cell cycle and DNA replication ( CDK1 , CCNB3 etc.) have comparatively higher expression levels in Gp cells than in Gd cells, while genes associated with steroidogenesis ( CYP51A1 , DHCR24 ) are highly expressed in Gd cells, indicating that Gp cells are likely more mitotic and less steroidogenic than Gd cells; (2) genes associated with extracellular matrix remodeling, cell adhesion and sperm binding (ZP3, ZP2) are differentially expressed in Gp and Gd cells; (3) Furthermore, signaling molecules (WNT4/IHH) and receptors for NGF (NGFR), epidermal growth factor (EGFR), gonadotropins (FSHR/LHR) and prostaglandin (PTGER3) are abundantly but differentially expressed in Gp and Gd cells. Taken together, our data strongly supports the notion that Gp and Gd cells of preovulatory follicles differ in their proliferation rate, steroidogenic activity, ECM organization and sperm binding capacity, which are likely controlled by gonadotropins and local ovarian factors, such as GD-derived factors.
Abstract Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer. In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation, although ageing does not affect the incidence of AOM-induced, sporadic non-inflammatory CRC. Mechanistically, reduced fibroblasts were observed in the colitis microenvironment of ageing mice. Through conditional lineage tracing, an important source of fibroblasts potentially derived from intestinal smooth muscle cells (ISMCs) was identified orchestrating intestinal wound healing and CAC initiation in young mice. However, the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice, accompanied by decreased intestinal wound healing and decreased CAC initiation. ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments. We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts. Meanwhile, the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice. Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment, decreased intestinal wound healing and decreased CAC initiation, similar to the phenotype of ageing mice. In addition, the data from intestine samples derived from inflammatory bowel disease (IBD) patients show that activation of YAP/TAZ also occurs in ISMCs from these patients. Collectively, our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation. Furthermore, our work also identified a potential source of fibroblasts involved in colitis and CAC.
Taking HYPERMESH as pre-processor, the modeling methods for a frame of the cab-over-engine medium bus in crash is expounded. Based on software LS-DYNA, the crash process is simulated with the crash regulations on M1 type bus. The deformations and energy absorbing for the parts and whole frame are analysised, especially for the invade distance and acceleration in crash. Based on these, the crash worthiness is estimated further for the medium bus.
A highly sensitive light-induced thermoelectric spectroscopy (LITES) sensor based on a multi-pass cell (MPC) with dense spot pattern and a novel quartz tuning fork (QTF) with low resonance frequency is reported in this manuscript. An erbium-doped fiber amplifier (EDFA) was employed to amplify the output optical power so that the signal level was further enhanced. The optical path length (OPL) and the ratio of optical path length to volume (RLV) of the MPC is 37.7 m and 13.8 cm-2, respectively. A commercial QTF and a self-designed trapezoidal-tip QTF with low frequency of 9461.83 Hz were used as the detectors of the sensor, respectively. The target gas selected to test the performance of the system was acetylene (C2H2). When the optical power was constant at 1000 mW, the minimum detection limit (MDL) of the C2H2-LITES sensor can be achieved 48.3 ppb when using the commercial QTF and 24.6 ppb when using the trapezoidal-tip QTF. An improvement of the detection performance by a factor of 1.96 was achieved after replacing the commercial QTF with the trapezoidal-tip QTF.
Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro . Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC.
DNA methylation plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). However, the global and temporal DNA methylation pattern during initiation and progression of colitis-associated cancer (CAC) are still unknown, including the potential therapeutic strategy of targeting methylation for CAC. In the present study, the global DNA methylation pattern was determined at different time points during CAC using DNA methylation sequencing, followed by the Starburst plot integrating alterations and potential functional prediction analysis. After demonstrating the regulatory role of DNA methyltransferases (DNMTs) on the expression of hub-genes in CRC cells, DNMT inhibitors were administered to treat CAC mice. Our results indicated that 811 genes were hypermethylated at different time points during initiation and progression of CAC. Genes that were downregulated and hypermethylated during CAC, including hub-genes BAD and inositol polyphosphate phosphatase-like 1 (INPPL1), were involved in MAPK signaling pathways, kit receptor signaling pathways, apoptosis and EGF/EGFR signaling pathways. Upregulated DNMTs (DNMT1, DNMT3A and DNMT3B) mediated downregulation and hypermethylation of BAD and INPPL1 in CAC and CRC cells. Low doses of DNMT inhibitors (decitabine (DAC) and azacitidine (AZA)) exerted efficient antitumor effects in CAC, accompanied with upregulation of BAD and INPPL1 expression, and apoptosis induction. In summary, the present study demonstrates the temporal DNA methylation pattern during CAC and provides a novel therapeutic strategy for treating this disease.
Objective To investigate the relationship between postmortem interval(PMI) and porcine vitreous potassium and hypoxanthine in death due to acute massive hemorrhage under different environmental conditions.Methods 192 porcine eyes from pigs die of acute massive hemorrhage were divided randomly into group A and group B,which were put in the dark environment with(15±2)℃,(50±5)% humidity or kept in double distilled water from 2h to 96h,and the concentration of potassium,sodium,chlorine and hypoxanthine were analyzed by automatic analyzer and Ultra Performance Liquid Chromatography(UPLC).The data were statistically processed by SPSS13.0 software.Results Regression analysis showed that concentration of vitreous potassium and hypoxanthine of porcine eyes kept in air were positively correlated with PMI,and the regression equations was PMI=-11.467+1.954[K+]-0.017 [K+]2+ 0.511[Hx](R2=0.858);however,the concentration of vitreous sodium and chlorine of porcine eyes kept in double distilled water were positively correlated with PMI,and the regression equations was PMI=144.439-1.636[Na+] +0.007 [Na+]2-0.961 [Cl-]+0.005 [Cl-]2(R2=0.622).Conclusion Vitreous potassium and hypoxanthine of corpses kept in air may be used as relatively objective parameter for PMI estimation,and the vitreous sodium and chlorine may be used for estimating PMI after corpses hurled in fresh water.
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