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The endometrium is essential to the development of embryos and pregnancy. Human umbilical cord mesenchymal stem cells (HUCMSCs) are promising stem cell sources. HUCMSCs self-renew quickly and are painless to collect. Spermidine is an inherent polyamine needed for cellular and molecular processes that regulate physiology and function. HUCMSCs and spermidine (SN) may heal intrauterine adhesions. HUCMSCs were investigated for endometrial repair in rats. Composite hydrogels are used for medical exosome implantation, including their materials, properties, and embedding procedures. This study examined whether bioengineered hydrogel-loaded exosomes from HUCMSCs and spermidine prenatally improved conception rates in mice with poor endometrial lining. The data show that HUCMSC and SN provide a good experimental base for HUCMSC safety and intrauterine treatment in rats. Western blots, exosome structural analysis, pregnancy outcomes, flow cytometry, H&E staining, immunohistochemistry, and immunofluorescence labelling found and recovered the aberrant area. HUCM-derived stem cells and spermidine-derived exosomes biophysically match. These traits strengthen and prolong endometrial function. Pregnant rats with HUCMSC and SN had thinner endometrium. Hydrogel-incorporated HEHUCMSC and SN exosomes may improve IUI in rats with thin endometrium.

Cervical cancer (CC) is a malignant tumor of the female reproductive system that typically occurs in cervical cells and has high incidence and mortality rates, strong metastatic ability, and poor prognosis. Asiatic acid (AA) exhibits anti-inflammatory, anti-depressant, and anti-tumor effects. However, the molecular targets and mechanisms underlying AA-mediated inhibition of CC metastasis remain unclear. AA affects the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) process of CC cell lines. MTT experiments verified that AA inhibited the proliferation ability of CC cells, and the effect of AA on the lateral and longitudinal migration ability of CC was evaluated through wound healing and Transwell assays. Western blotting was used to explore whether AA inhibits EMT process in HeLa and C33a cells. Currently, targeting the PI3K/AKT/mTOR pathway as a strategy for cancer treatment remains an evolving field. However, the molecular mechanism by which AA inhibits CC via the PI3K/AKT/mTOR pathway remains unclear and requires further investigation.

Background: Ulcerative colitis (UC) is a common and progressive inflammatory bowel disease primarily affecting the colon and rectum. Prolonged inflammation can lead to colitis-associated colorectal cancer (CAC). While the exact cause of UC remains unknown, this study aims to investigate the role of the TWIST1 gene in UC.Methods: Second-generation sequencing data from adult UC patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, and characteristic genes were selected using machine learning and Lasso regression. The Receiver Operating Characteristic (ROC) curve assessed TWIST1’s potential as a diagnostic factor (AUC score). Enriched pathways were analyzed, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA). Functional mechanisms of marker genes were predicted, considering immune cell infiltration and the competing endogenous RNA (ceRNA) network.Results: We found 530 DEGs, with 341 upregulated and 189 downregulated genes. TWIST1 emerged as one of four potential UC biomarkers via machine learning. TWIST1 expression significantly differed in two datasets, GSE193677 and GSE83687, suggesting its diagnostic potential (AUC = 0.717 in GSE193677, AUC = 0.897 in GSE83687). Enrichment analysis indicated DEGs associated with TWIST1 were involved in processes like leukocyte migration, humoral immune response, and cell chemotaxis. Immune cell infiltration analysis revealed higher rates of M0 macrophages and resting NK cells in the high TWIST1 expression group, while TWIST1 expression correlated positively with M2 macrophages and resting NK cell infiltration. We constructed a ceRNA regulatory network involving 1 mRNA, 7 miRNAs, and 32 long non-coding RNAs (lncRNAs) to explore TWIST1’s regulatory mechanism.Conclusion: TWIST1 plays a significant role in UC and has potential as a diagnostic marker. This study sheds light on UC’s molecular mechanisms and underscores TWIST1’s importance in its progression. Further research is needed to validate these findings in diverse populations and investigate TWIST1 as a therapeutic target in UC.

Abstract Background The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial. Methods We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1. Results We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage. Conclusion Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies. Video Abstract

Abstract Background Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. P21 activated kinase 4 (PAK4) and Breast cancer anti-estrogen resistance 3 (BCAR3) have been reported to be involved in numerous aspects in tumorous progression. In this study, we propose to screen multi-targeted microRNAs. (miRNAs), which simultaneously inhibit neoplastic evolution through suppressing the transcription of target genes. Methods MTT and Colony formation assays measured cell’s viability and proliferation. Scratch wound and Transwell assays detected the ability in migration and invasion for SW116 cells. The multi-targeted microRNAs of PAK4 and BCAR3 were predicted using bioinformatics analysis and verified by conducting dual luciferase reporter assay, western blot and qRT-PCR that could detect the expression levels of miR-199a/b-3p. Results The knockdown of PAK4 significantly impeded proliferation and colony formation of SW1116 cells when the knockdown of BCAR3 hindered migration and invasion of SW1116 cells. MiR-199a/b-3p directly targeted the 3'-UTR of PAK4 and BCAR3, further effected proliferation, colony formation, migration, and invasion of SW1116 cells. PAK4 or BCAR3 overexpression could partially reversed inhibitory effects of miR-199a/b-3p. Conclusions These results provided a new multi-targeted cite for cancerous suppressant to improve the prognosis of CRC inpatients.

Higher cyclin-dependent kinase (CDK7) expression is a character of breast cancer and indicates poor prognosis. Inhibiting CDK7 exhibited effective cancer cell suppression which implies the potential of CDK7 inhibition to be a method for anti-cancer treatment. Our study aimed to explore a novel mechanism of CDK7 inhibition for suppressing breast cancer cell survival. Here, we proved inhibiting CDK7 repressed breast cancer cell proliferation and colony formation and increased the apoptotic cell rate, with p53 and GSDME protein level elevation. When p53 was suppressed in MCF-7 cells, the decline of GSDME expression and associated stronger proliferation and colony formation could be observed. Since downregulation of GSDME was of benefit to breast cancer cells, p53 inhibition blocked the elevation of GSDME induced by CDK7 inhibition and retrieved cells from the tumor suppressive effect of CDK7 inhibition. Therefore, CDK7 inhibition exerted a negative effect on breast cancer cell proliferation and colony formation in a p53–GSDME dependent manner. These results revealed the CDK7–p53–GSDME axis could be a pathway affecting breast cancer cell survival.

Abstract Background The prevalence of ischaemic heart failure (HF) continues to increase. Diabetes mellitus (DM) concomitant with ischaemic HF increases the risk of major adverse cardiovascular events (MACEs). As a promising predictor for cardiovascular diseases, the predictive value of the monocyte to high-density lipoprotein cholesterol ratio (MHR) for MACE in the ischaemic HF with DM cohort has never been investigated before. Objective We aimed to investigate the MHR as a predictor for MACE in ischaemic HF patients with DM who underwent percutaneous coronary intervention (PCI). Methods This observational study enrolled 1049 patients with ischaemic HF and DM undergoing PCI from June 2017 to June 2019. The baseline data were collected. MACEs, including all-cause mortality, nonfatal myocardial infarction, and any revascularization, were recorded within the 36-month follow-up. The characteristics and incidence of MACE were analysed in four groups stratified by the quartiles of MHR. The hazard ratio for MACE was analysed with Cox regression models. The incidence of MACE in the four groups was evaluated by Kaplan‒Meier survival analysis. Restricted cubic spline analysis was performed to determine the nonlinear correlation between the MHR and MACE. Results After the 36-month follow-up, 407 patients (38.8%) experienced MACEs. The incidence of MACE was significantly higher among patients in the upper MHR quartile than among those in the lower MHR quartiles (23.4% vs. 36.0% vs. 41.4% and 54.6%; P 0.05). Conclusion The MHR was a significant and independent predictor of MACEs in ischaemic HF patients with DM undergoing PCI.

Zinc (Zn) has antioxidant effect in different types of organs and is closely associated with human health. Endometrial receptivity is one of the most important factors in the embryo implantation and development. However, the regulatory mechanism of Zn in endometrium tissue is still unclear. In the study, we found that plasma Zn level is significantly associated with female infertility, which severely affects female reproductive health. Primary endometrial stromal cells were isolated from female endometrium and cultured in the laboratory. Zn chelator TPEN treatment reduced the expression of stem cell markers CD73, CD90, and CD105 and generated reactive oxygen species in endometrial stromal cells. However, pre treatment of Zn (zinc sulfate) is able to prevent TPEN induced oxidative stress in vitro. By transcriptional profiling and gene ontology analysis, we found that Zn increased the cellular pluripotency signaling and extracellular matrix-receptor interaction, but reduced autophagy, endocytosis, and the nitrogen metabolism pathway. We further discovered the antioxidant function of Zn through the peroxisome proliferator-activated receptor gamma coactivator 1/ nuclear factor erythroid-2-related factor signaling pathway in endometrial stromal cells. Zn supplementation may open up an effective therapeutic approach for patients with oxidative stress-related endometrial diseases. [ABSTRACT FROM AUTHOR]

T cells are one of the most important effector cells in cancer immunotherapy. Various T cell-dependent bispecific antibody (TDB) drugs that engage T cells for targeted cancer cell lysis are being developed. Here, we describe supra-molecular T-cell redirecting antibody fragment-anchored liposomes (TRAFsomes) and report their immune modulation and anti-cancer effects. We found that TRAFsomes containing different copies of anti-CD3 fragments displayed different T cell modulation profiles, showing that optimization of surface density is needed to define the therapeutic window for potentiating cancer cell-specific immune reactions while minimizing nonspecific side effects. Moreover, small molecular immunomodulators may also be incorporated by liposomal encapsulation to drive CD8 + T cell biased immune responses. In vivo studies using human peripheral blood mononuclear cell reconstituted mouse models showed that TRAFsomes remained bounded to human T cells and persisted for more than 48 hours after injection. However, only TRAFsomes containing a few anti-CD3 (n = 9) demonstrated significant T cell-mediated anti-cancer activities to reverse tumor growth. Those with more anti-CD3s (n = 70) caused tumor growth and depletion of human T cells at the end of treatments. These data suggested that TRAFsomes can be as potent as traditional TDBs and the liposomal structure offers great potential for immunomodulation and improvement of the therapeutic index.Abbreviation: Chimeric antigen receptor T cells (CAR-T cells), Cytokine release syndrome (CRS) Cytotoxic T cell (CTL) Effector: target ratios (E:T ratios), Heavy chain (HC) Immune-related adverse events (irAE), Large unilamellar vesicle (LUV), Peripheral blood mononuclear cells (PBMCs, Single-chain variable fragment (scFv), T cell-dependent bispecific antibody (TDB), T cell redirecting antibody fragment-anchored liposomes (TRAFsomes), Methoxy poly-(ethylene glycol) (mPEG)

Wall thinning, as one of the key defects in tube bending determined the forming quality and limit, is more easily to occur due to the specific properties of high strength 0Cr21Ni6Mn9N stainless steel tube (0Cr21Ni6Mn9N-HS tube). To achieve tube accuracy numerical control (NC) bending forming, the wall thinning characteristics of the 0Cr21Ni6Mn9N-HS tube should be clarified. An analytical model was proposed to reveal the essential relation between tube parameters and wall thickness distribution. Considering the varied elastic modulus, a finite element (FE) model was applied to explore the wall thinning under different geometrical and process parameters. Using the modified multi-parameter sensitivity analysis method combined with FE simulation, the sensitivity of the wall thinning to geometrical and process parameters was carried out. The experiments of NC tube bending were conducted to validate the analytical and simulate results. The results show that the varied elastic modulus can enhance the wall thinning degree, but has no obvious effect on wall thinning characteristics. The wall thinning characteristics under different geometrical and process parameters are revealed and the reasonable parameters ranges for the 0Cr21Ni6Mn9N-HS tube in NC bending are obtained. The most sensitive parameter on wall thinning is the relative bending radius, while the bending angle is the least one.

In order to screen drug rapidly and effectively in vivo, the approach of the establishment for mouse melanoma model with primary cell from melanin solid tumor tissue of mouse is studied. The primary cell and the cultured B16 cells in vitro are implanted into two groups of C57BL/6 mice by hypodermic, respectively. The appearing time and the growth rate of tumor in two groups of mouse are investigated. The results show that when the inoculation is 0.2 mL for each one (the cell concentration of 5.0×106/mL), the tumor formation rates of the primary tumor cells of mouse melanoma and in vitro cultured B16 cells are 100% and 80%, respectively, and it takes about 3 and 8 days respectively that the tumor sizes become about 4 mm3. The preliminary evaluation of two models are carried out with taxol, showing that the primary B16 cell model is a feasible and effective method for screening and evaluating the antitumor activity of specific compounds in vivo compared with the B16 cell model cultured in vitro, and it has shorter tumor forming time, higher tumor forming rate and less error in the obtained experimental data, which provides a new way for the development and research of related drug evaluation models.