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Individuals with inflammatory bowel disease are at high risk of developing colitis‐associated cancer (CAC). Strategies to block the process from inflammatory bowel disease to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane and dextran sodium sulphate‐induced CAC in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of 35 C57BL/6 mice were collected and examined for the degree of inflammation and tumorigenesis. Comparative 16S rRNA sequencing was carried out to observe Bifico‐target alterations in gene expression and microbiota structure. We found that pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including CXCL1, CXCL2, CXCL3, and CXCL5, which are all ligands of C‐X‐C motif receptor 2 (CXCR2). The 16S rRNA sequencing showed that Bifico decreased the abundance of genera Desulfovibrio, Mucispirillum, and Odoribacter, and a bloom of genus Lactobacillus was detected. Notably, we found that an abundance of these Bifico‐target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies indicate that Bifico, given orally, can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus, and CXCR2 signaling. Bifico capsules have a great effect in restraining colonic tumorigenesis in mice. In addition, we performed cDNA microarray and 16s rRNA sequencing of the colon tissues and demonstrated that bacterial groups Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus and CXCR2 ligand genes were involved in the chemoprevention of Bifico, which providing a novel insight into mechanism of probiotics treatment.

Radioactive gas signatures from underground nuclear explosions (UNEs) result from gas-migration processes occurring in the subsurface. The processes considered in this study either drive or retard upward migration of gases from the detonation cavity. The relative importance of these processes is evaluated by simulating subsurface transport in a dual-permeability medium for the multi-tracer Noble Gas Migration Experiment (NGME) originally intended to study some aspects of transport from a UNE. For this experiment, relevant driving processes include weak two-phase convection driven by the geothermal gradient, over pressuring of the detonation cavity, and barometric pumping while gas sorption, dissolution, radioactive decay, and usually diffusion represent retarding processes. From deterministic simulations we found that over-pressuring of the post-detonation chimney coupled with barometric pumping produced a synergistic effect amplifying the tracer-gas reaching the surface. Bounding simulations indicated that the sorption and dissolution of gases, tending to retard transport, were much smaller than anticipated by earlier laboratory studies. The NGME observations themselves show that differences in gas diffusivity have a larger effect on influencing upward transport than do the combined effects of tracer-gas sorption and dissolution, which is consistent with a Sobol’ sensitivity analysis. Both deterministic simulations and those considering parametric uncertainties of transport-related properties predict that the excess in concentration of SF 6 compared to 127 Xe as might be captured in small volumetric samples should be much smaller than the order-of-magnitude contrast found in the large-volume gas samples taken at the site. While extraction of large-volume subsurface gas samples is shown to be capable of distorting in situ gas compositions, the highly variable injection rate of SF 6 into the detonation cavity relative to that of 127 Xe at the start of the field experiment is the most likely explanation for the large difference in observed concentrations.

Background Nicotine, an active ingredient in tobacco, can promote epithelial-to-mesenchymal transition (EMT) processes that enhance the aggressiveness of a number of human cancers. In the present study, we investigated whether cigarette smoke/nicotine drives EMT in pancreatic ductal adenocarcinoma (PDAC). Methods Quantitative real-time PCR, western blot, immunohistochemistry, and immunofluorescence assays were used to evaluate Yes-associated protein 1 (YAP1) expression associated with cigarette smoking in human PDAC tissue samples and with nicotine exposure in PDAC cell lines. Bioinformatics, loss- and gain- of- function experiments, luciferase reporter assays, chromatin immunoprecipitation (ChIP), and murine tumor xenograft models were performed to examine the function of YAP1 in PDAC and to identify potential mechanisms of action. Results Exposure to smoking or nicotine promoted EMT and tumor growth in PDAC cells and in xenograft tumors. Functional studies revealed that YAP1 might drive nicotine-stimulated EMT and oncogenic activity in vitro and in vivo. In human PDAC tissues, upregulation of YAP1 was associated with “ever smoking” status and poor overall survival. In term of mechanism, hypoxia inducible factor (HIF)1A promoted YAP1 nuclear localization and YAP1 transactivation by directly binding to the hypoxia responsive elements of the YAP1 promoter upon nicotine treatment. Nicotine stimulated HIF1A and YAP1 expression by activating cholinergic receptor nicotinic alpha7 (CHRNA7). In addition, YAP1 increased and sustained the protein stability of HIF1A. Conclusions These data demonstrate that YAP1 enhances nicotine-stimulated EMT and tumor progression of PDAC through a HIF1A/YAP1 positive feedback loop. Developing inhibitors that specifically target YAP1 may provide a novel therapeutic approach to suppress PDAC growth, especially in PDAC patients who have a history of smoking.

In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency ( DICAR +/− ) mice, whereas the DCM was alleviated in DICAR-overexpressed DICAR Tg mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.

Hysteretic sorption and desorption of water is observed from 0 to 95% relative humidity and 298–333 K on a glassy polyurethane foam. It is postulated that sorption-induced swelling of the glassy polyurethane increases the concentration of accessible hydrogen-bonding adsorption sites for water. The accessibility of sites is kinetically controlled due to the restricted thermal motions of chains in the glassy polymer, causing a difference in accessible site concentrations during sorption and desorption. This discrepancy leads to hysteresis in the sorbed concentrations of water. A coupled chemo-mechanical model relating volumetric strain, adsorption site concentration, and sorbed water concentration is employed to describe water sorption hysteresis in the glassy polyurethane. This model not only describes the final mass uptake for each relative humidity step, but also captures the dynamics of water uptake, which exhibit diffusion and relaxation rate-controlled regimes.

Type 2 diabetes mellitus (T2DM), a chronic condition commonly observed in adults, particularly among the elderly, is characterized by a dysfunctional insulin response that impairs blood glucose regulation, resulting in persistent hyperglycemia. Ginseng, a medicinal plant with significant economic value and a longstanding history of therapeutic use in Asia, has shown efficacy against various diseases. Extensive clinical and experimental studies highlight ginsenosides, its primary bioactive compounds, for their multiple therapeutic effects across a range of conditions, including endocrine, cardiovascular, and central nervous system disorders. Various ginsenoside types have demonstrated potential in lowering blood glucose levels, reducing insulin resistance, and alleviating complications through the modulation of key protein targets and signaling pathways. This review consolidates the pharmacological actions and mechanisms of distinct ginsenosides in managing diabetes and its complications, offering a theoretical foundation for further pharmacological research and novel drug development for T2DM treatment, while also providing robust theoretical support for future clinical applications.

BackgroundArtificial intelligence (AI) performed variously among test sets with different diversity due to sample selection bias, which can be stumbling block for AI applications. We previously tested AI named ENDOANGEL, diagnosing early gastric cancer (EGC) on single-center videos in man–machine competition. We aimed to re-test ENDOANGEL on multi-center videos to explore challenges applying AI in multiple centers, then upgrade ENDOANGEL and explore solutions to the challenge.MethodsENDOANGEL was re-tested on multi-center videos retrospectively collected from 12 institutions and compared with performance in previously reported single-center videos. We then upgraded ENDOANGEL to ENDOANGEL-2022 with more training samples and novel algorithms and conducted competition between ENDOANGEL-2022 and endoscopists. ENDOANGEL-2022 was then tested on single-center videos and compared with performance in multi-center videos; the two AI systems were also compared with each other and endoscopists.ResultsForty-six EGCs and 54 non-cancers were included in multi-center video cohort. On diagnosing EGCs, compared with single-center videos, ENDOANGEL showed stable sensitivity (97.83% vs. 100.00%) while sharply decreased specificity (61.11% vs. 82.54%); ENDOANGEL-2022 showed similar tendency while achieving significantly higher specificity (79.63%, p < 0.01) making fewer mistakes on typical lesions than ENDOANGEL. On detecting gastric neoplasms, both AI showed stable sensitivity while sharply decreased specificity. Nevertheless, both AI outperformed endoscopists in the two competitions.ConclusionsGreat increase of false positives is a prominent challenge for applying EGC diagnostic AI in multiple centers due to high heterogeneity of negative cases. Optimizing AI by adding samples and using novel algorithms is promising to overcome this challenge.

Moisture uptake and outgassing can be detrimental to a system by altering the chemical and mechanical properties of materials within the system over time. In this work, we conducted isotherm experiments to investigate dynamic moisture sorption and desorption in markedly different materials, i.e., a polymeric material, Sylgard-184 and a ceramic aluminosilicate material, Zircar RS-1200, at different temperatures (30 °C–70 °C) by varying the water activity (0.0–0.90). Sylgard-184 showed a linear sorption and outgassing behavior with no-hysteresis over the entire temperature and water activity range considered here. Whereas, the sorption and outgassing of Zircar RS-1200 was highly non-linear with significant hysteresis, especially at higher water activities, at all temperatures considered here. The type of hysteresis suggested the presence of mesopores in Zircar RS-1200, whereas the lack of hysteresis in Sylgard-184 indicates that it has a nonporous structure. A diffusion model coupled with a dynamic, triple-mode sorption (Langmuir, Henry, and pooling modes) model employed in this study matched our experimental data very well and provides mechanistic insight into the processes. Our triple-mode sorption model was adaptive enough to (1) model these distinctly different materials and (2) predict sorption and outgassing under conditions that are distinctly different from the parameterization experiments.

Many studies have shown that programmed cell death protein 1 (PD-1) and its ligand, PD-L1, are expressed in advanced gastric cancer. Furthermore, detection of these proteins is associated with infiltrating CD8+ T-cells, indicating that an adaptive immune resistance mechanism occurs in advanced gastric cancer. However, PD-L1 and PD-1 expression in gastric intraepithelial neoplasia and early-stage gastric cancer (EGC) has yet to be elucidated. Fifty-four resections of low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and EGC were stained by immunohistochemistry for PD-1, PD-L1, and CD8. CD8+ T-cell densities both within tumors and in the tumor-stromal interface were analyzed. Flow cytometry (FACS) was used to analyze the PD-1 expression in tumor tissues and peripheral blood mononuclear cells. Furthermore, the relationship between Helicobacter pylori (Hp) infection and PD-1 and PD-L1 was also evaluated. We demonstrated that PD-L1 expression was significantly increased in HGIN and EGC compared with LGIN, and both PD-1 and PD-L1 showed similar expression patterns, being mainly detected in infiltrating immune cells. FACS also showed that PD-1 was expressed on both CD4+ and CD8+ T-cells. However, no difference was found in CD8+ T-cell infiltration between LGIN and HGIN+EGC, and this was not not found to be associated with PD-L1 or PD-1 expression. However, Hp infection was significantly associated with expression of PD-L1 and PD-1. The PD-1/PD-L1 checkpoint is involved in intraepithelial neoplasia and EGC, but an adaptive immune resistance mechanism does not occur. Expression of PD-1/PD-L1 is also associated with Hp infection, and so Hp infection may be an important initiating factor. This study was approved by the Institutional Review Board of Ruijin Hospital and written informed consent was obtained from all patients.

Protein inhibitor of activated STAT-1 (PIAS1) is a novel modulator of the JAK/STAT signaling pathway that negatively regulates the inflammatory response. It has been also reported to be downregulated in a variety of human cancer cell lines. However, the role of PIAS1 in gastric cancer remains unclear. In this study, we investigated the prognostic value of PIAS1 expression and its regulated mechanisms in gastric cancer cell metastasis. Therefore, the expression of PIASI was explored in gastric cancer tissues and adjacent tissues of gastric cancer with 31 cases of patients, and the prognostic value was analyzed. In addition, the growth and invasion in SGC7901 cells were investigated in the restoration of PIAS1 expression with Ad5/F35-PIAS1 or Ad5/F35-vector or PBS treatment, and the activity of P38MAPK, P-P38MAPK, JNK/SAPK, P-JNK/SAPK, ERK and P-ERK, were detected by western blotting. The tumor migratory factors MMP-9, MMP-2 and ICAM-1 were analyzed by western blotting. The results demonstrated that 22 of 31 (70.9%) gastric cancer specimens showed low levels of PIAS1 expression from immunohistochemistry staining using tissue microarrays. Statistical analysis suggested that the downregulation of PIAS1 was significantly correlated with tumor staging. Furthermore, we found that the restoration of PIAS1 expression mediated by Ad5/F35 virus suppressed cell proliferation and invasion accompanied by the inhibition of P38MAPK and ERK protein expression and activity, but not JNK/SAPK protein. Notably, PIAS1 restoration with the transfection of Ad5/F35-PIAS1 robustly decreased the expression of tumor migratory factors including MMP-9, MMP-2 and ICAM-1 compared to Ad5/F35-vector. These data suggest that PIAS1 may function as a tumor suppressor to regulate gastric cancer cell metastasis by targeting the MAPK signaling pathway.