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The endometrium plays a critical role in embryo implantation and pregnancy, and a thin uterus is recognized as a key factor in embryo implantation failure. Umbilical cord mesenchymal stem cells (UC-MSCs) have attracted interest for the repair of intrauterine adhesions. The current study investigated the repair of thin endometrium in rats using the UC-MSCs and the mechanisms involved. Rats were injected with 95% ethanol to establish a model of thin endometrium. The rats were randomly divided into normal, sham, model, and UC-MSCs groups. Endometrial morphological alterations were observed by hematoxylin–eosin staining and Masson staining, and functional restoration was assessed by testing embryo implantation. The interaction between UC-MSCs and rat endometrial stromal cells (ESCs) was evaluated using a transwell 3D model and immunocytochemistry. Microarray mRNA and miRNA platforms were used for miRNA-mRNA expression profiling. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed to identify the biological processes, molecular functions, cellular components, and pathways of endometrial injury and UC-MSCs transplantation repair and real-time quantitative reverse transcription PCR (qRT-PCR) was performed to further identify the expression changes of key molecules in the pathways. Endometrium thickness, number of glands, and the embryo implantation numbers were improved, and the degree of fibrosis was significantly alleviated by UC-MSCs treatment in the rat model of thin endometrium. In vitro cell experiments showed that UC-MSCs migrated to injured ESCs and enhanced their proliferation. miRNA microarray chip results showed that expression of 45 miRNAs was downregulated in the injured endometrium and upregulated after UC-MSCs transplantation. Likewise, expression of 39 miRNAs was upregulated in the injured endometrium and downregulated after UC-MSCs transplantation. The miRNA-mRNA interactions showed the changes in the miRNA and mRNA network during the processes of endometrial injury and repair. GO and KEGG analyses showed that the process of endometrial injury was mainly attributed to the decomposition of the extracellular matrix (ECM), protein degradation and absorption, and accompanying inflammation. The process of UC-MSCs transplantation and repair were accompanied by the reconstruction of the ECM, regulation of chemokines and inflammation, and cell proliferation and apoptosis. The key molecules involved in ECM-receptor interaction pathways were further verified by qRT-PCR. Itga1 and Thbs expression decreased in the model group and increased by UC-MSCs transplantation, while Laminin and Collagen expression increased in both the model group and MSCs group, with greater expression observed in the latter. This study showed that UC-MSCs transplantation could promote recovery of thin endometrial morphology and function. Furthermore, it revealed the expression changes of miRNA and mRNA after endometrial injury and UC-MSCs transplantation repair processed, and signaling pathways that may be involved in endometrial injury and repair.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with extremely poor prognosis. Gemcitabine resistance is a major challenge in the treatment of PDAC. Here, we showed that LINC00460 was associated with the response to gemcitabine both in PDAC patients and PDAC‐PDX. After knocking down LINC00460 in PDAC tumor cells, results of RNA sequencing followed by gene ontology analysis indicated that LINC00460 influenced the activity of growth factors and modified the extracellular matrix. FISH showed that LINC00460 is mostly located in the cytoplasm. Results of RNA pull‐down, LC–MS/MS, RIP, and immunoblotting confirmed that LINC00460 could directly bind to PDAP1. Furthermore, we demonstrated that LINC00460 mediated the cellular communication of PDAC tumor cells and CAFs by PDAP1/PDGFA/PDGFR signaling pathway and regulated the gemcitabine‐resistance function of CAFs, which could be reversed by treatment with a PDGFR inhibitor (crenolanib). PDAC‐PDX tumors with lower expression of LINC00460 showed a better response to gemcitabine plus crenolanib treatment. Our finding supported the application of LINC00460 in precision medicine that uses gemcitabine plus crenolanib to treat PDAC with low expression of LINC00460. LINC00460 regulates the gemcitabine chemotherapy‐resistance function of CAFs via the PDAP1/PDGFA/PDGFR pathway, which could be attenuated by treatment with a PDGFR inhibitor (crenolanib).PDAC with low expressed LINC00460 is an indicator to apply treatment therapy of gemcitabine combine with crenolanib.

Background Repair deficiency after endometrial injury is an important reason for intra-uterine adhesions, amenorrhea, and infertility in females. Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is effective in repairing the damaged endometrium. However, the possibility of using umbilical cord-derived MSCs (UC-MSCs) to treat endometrial injury is rarely reported. Methods Ethanol (95%) was injected into rat uterus to establish a model of endometrial injury. UC-MSCs were injected through the tail vein, either as a single, twice, or thrice administration. Functional restoration of the uterus was assessed by testing embryo implantation rates. Endometrial morphological alteration was observed by hematoxylin and eosin staining. Endometrial fibrosis, markers of epithelial and stromal cells of endometrium, cell proliferation and angiogenesis, and inflammatory factors were detected using immunohistochemistry, Western blotting, and quantitative reverse-transcription polymerase chain reaction. Results Endometrial morphology and embryo implantation rates were significantly improved on day 8 of transplantation among single-, twice-, or thrice-administered rats. Moreover, UC-MSCs could alleviate fibrosis in general, and reduced the expression of fibrosis markers, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β. The cell proliferation marker Ki-67 had a positive expression in the injured endometrium after UC-MSC transplantation. The endometrial stromal marker vimentin and epithelial marker cytokeratin-19 (CK-19) expressions were visibly increased. The expression of vascular markers CD31, vascular endothelial growth factor (VEGF)A, and matrix metalloprotein (MMP)9 was generally upregulated. Proinflammatory factors interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2 were significantly downregulated in the rats administered UC-MSCs twice and thrice. Conclusions UC-MSC transplantation contributed to the repair of endometrial injury and restoration of fertility, likely through the suppression of excessive fibrosis and inflammation, and enhancement of endometrial cell proliferation and vascular remodeling.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fourth leading cause of cancer‐related death worldwide. Our previous study showed that EYA4 functioned by suppressing growth of HCC tumor cells, but its molecular mechanism is still not elucidated. Based on the results of gene microassay, EYA4 was inversely correlated with MYCBP and was verified in human HCC tissues by immunohistochemistry and western blot. Overexpressed and KO EYA4 in human HCC cell lines confirmed the negative correlation between EYA4 and MYCBP by qRT‐PCR and western blot. Transfected siRNA of MYCBP in EYA4 overexpressed cells and overexpressed MYCBP in EYA4 KO cells could efficiently rescue the proliferation and G2/M arrest effects of EYA4 on HCC cells. Mechanistically, armed with serine/threonine‐specific protein phosphatase activity, EYA4 reduced nuclear translocation of β‐catenin by dephosphorylating β‐catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by β‐catenin/LEF1 binding to the promoter of MYCBP. Clinically, HCC patients with highly expressed EYA4 and poorly expressed MYCBP had significantly longer disease‐free survival and overall survival than HCC patients with poorly expressed EYA4 and highly expressed MYCBP. In conclusion, EYA4 suppressed HCC tumor cell growth by repressing MYCBP by dephosphorylating β‐catenin S552. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC. Our previous studies showed that EYA4 suppressed hepatocellular carcinoma (HCC) tumor cells growth. Nevertheless, the functional involvement of EYA4 in HCC is not clearly understood. In the present study, we reported that EYA4 suppressed HCC tumor cell growth by reducing the nuclear translocation of β‐catenin by dephosphorylating β‐catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by β‐catenin/LEF1 binding to the promoter of MYCBP. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC.

Background Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. Results In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes ( e.g. CCL4 , CXCL10 , TNF and IL-1β ) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. Conclusions We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Increasing evidence highlights the role of bacteria in promoting tumorigenesis. The underlying mechanisms may be diverse and remain poorly understood. Here, we report that Salmonella infection leads to extensive de/acetylation changes in host cell proteins. The acetylation of mammalian cell division cycle 42 (CDC42), a member of the Rho family of GTPases involved in many crucial signaling pathways in cancer cells, is drastically reduced after bacterial infection. CDC42 is deacetylated by SIRT2 and acetylated by p300/CBP. Non-acetylated CDC42 at lysine 153 shows an impaired binding of its downstream effector PAK4 and an attenuated phosphorylation of p38 and JNK, consequently reduces cell apoptosis. The reduction in K153 acetylation also enhances the migration and invasion ability of colon cancer cells. The low level of K153 acetylation in patients with colorectal cancer (CRC) predicts a poor prognosis. Taken together, our findings suggest a new mechanism of bacterial infection-induced promotion of colorectal tumorigenesis by modulation of the CDC42-PAK axis through manipulation of CDC42 acetylation.

Background Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. Methods This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. Results Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32–0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20–0.79), respectively. Calcium channel blockers, diuretics, and β-blockers didn’t show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2–34.4); OS, 24.8 months (16.5–42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1–24.1); OS, 14.6 months (10.6–28.4)). The 1 year, 2 years, and 3 years’ survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). Conclusions RASis usage improves the survival of patients with CCA and hypertension concurrently.

Background Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. The dismal outcome of ICC patients is due to lack of early diagnosis, the aggressive biological behavior of ICC and the lack of effective therapeutic options. Early diagnosis and prognosis of ICC by non-invasive methods would be helpful in providing valuable information and developing effective treatment strategies. Methods Expression of microfibrillar-associated protein 5 (MFAP5) in the serum of ICC patients was detected by ELISA. Human ICC specimens were immunostained by MFAP5 antibodies. The growth rate of human ICC cell lines treated with MFAP5 or MFAP5 shRNAs was examined by CCK8 and colony formation assays. Cell cycle analysis was performed with PI staining. The effect of MFAP5 inhibition was assessed by xenograft models in nude mice. RNA-seq and ATAC-seq analyses were used to dissect the molecular mechanism by which MFAP5 promoted ICC aggressiveness. Results We identified MFAP5 as a biomarker for the diagnosis and prognosis of ICC. Upregulated MFAP5 is a common feature in aggressive ICC patients’ tissues. Importantly, MFAP5 level in the serum of ICC patients and healthy individuals showed significant differential expression profiles. Furthermore, we showed that MFAP5 promoted ICC cell growth and G1 to S-phase transition. Using RNA-seq expression and ATAC-seq chromatin accessibility profiling of ICC cells with suppressed MFAP5 secretion, we showed that MFAP5 regulated the expression of genes involved in the Notch1 signaling pathway. Furthermore, FLI-06, a Notch signaling inhibitor, completely abolished the MFAP5-dependent transcriptional programs. Conclusions Raised MFAP5 serum level is useful for differentiating ICC patients from healthy individuals, and could be helpful in ICC diagnosis, prognosis and therapies.

Acute ischemic stroke (AIS) may trigger a spectrum of cardiac complications spanning arrhythmias, troponin elevation, Takotsubo cardiomyopathy, heart failure, and myocardial fibrosis and other acute or chronic cardiac lesions. These complications seriously affect the prognosis of patients. Existing studies have shown that the excessive excitation of the sympathetic neural network after cerebral ischemic injury leads to an increase in catecholamine levels, which may be a key factor triggering neurogenic cardiac damage after AIS. Therefore, evaluating the trigger areas of sympathetic nerve excitation and monitoring related cardiac damage indicators play a key role in patient management. Inhibiting excessive excitation of the sympathetic nerve, alleviating inflammatory responses and oxidative stress, is expected to become the core strategy for the prevention and treatment of neurogenic cardiac injury after AIS. Future research still needs to deeply explore the mechanism of cardiotoxicity mediated by the sympathetic neuro-catecholamine system after AIS, and at the same time promote clinical trials targeting the mechanism to verify treatment paradigms through translational models. This review aims to provide a useful reference direction for subsequent in-depth research.

Background Alveolar cleft is a type of cleft lip and palate that seriously affects the physical and mental health of patients. In this study, a model of the alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (HUC-MSCs) on the repair of alveolar cleft bone defects. Methods A model of alveolar clefts in rabbits was established by removing the incisors on the left side of the upper jaw bone collagen particles combined with HUC-MSCs that were then implanted in the defect area. Blood biochemical analysis was performed 3 months after surgery. Skull tissues were harvested for gross observation, and micro-focus computerised tomography (micro-CT) analysis. Tissues were harvested for histological and immunohistochemical staining. The experiments were repeated 6 months after surgery. Results Bone collagen particles and HUC-MSCs showed good biocompatibility. Bone collagen particles combined with HUC-MSCs were markedly better at inducing bone repair and regeneration than bone collagen particles alone. Conclusions Combining HUC-MSCs with bone collagen particles provides a simple, rapid and suitable method to fill a bone defect site and treat of alveolar cleft bone defects.