Abstract Aims/Introduction Gastric cancer, one of the most common malignant tumors worldwide, is affected by insulin resistance. The triglyceride glucose (TYG) index is considered a surrogate indicator of insulin resistance; however, its prognostic value in patients with gastric cancer remains obscure. This study aimed to determine whether the TYG index could predict the long‐term prognosis of patients with gastric cancer after radical resection gastrectomy. Materials and Methods We retrospectively analyzed patients with gastric cancer who underwent radical resection gastrectomy. The preoperative TYG index was calculated using the patients' laboratory data. Patients were divided into two groups based on a high or low TYG index. We observed overall survival and evaluated the clinical application value of the index using Cox proportional hazards regression to calculate independent parameters. A prediction model was also established. Results In total, 822 patients with gastric cancer were included. The high and low TYG index groups comprised 353 and 469 patients, respectively. The overall survival time was significantly longer in the high‐index group than in the low‐index group. In the multivariate analysis, TYG index, preoperative age, surgical procedure, tumor node metastasis (TNM) stage, N stage, and postoperative complications (all p < 0.01) were considered independent prognostic predictors. Based on the multivariate analysis, the riglyceride glucose (TYG) index hazard ratio was 0.70 (95% confidence interval, 0.54–0.89, p = 0.004). Conclusions We established a model with a high clinical application value and clinical practice relevance to predict the prognosis of gastric cancer. In this model, TYG was an independent protective factor for gastric cancer prognosis.

Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington’s disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.

To investigate the impact of Sufentanil on the progression of endometrial cancer (EC), including its proliferation, migration, epithelial-mesenchymal transition and underlying mechanism. The effects of Sufentanil on EC cell growth were evaluated using Cell counting kit-8 (CCK-8) and colony formation assays, while wound healing and transwell assays were performed to assess the influence on motility. In addition, immunoblot assays were performed to determine its role in EC cell epithelial-mesenchymal transition (EMT) and the associated underlying mechanism. Sufentanil demonstrated the ability to inhibit EC cell growth, migration, invasion and EMT process through the inhibition of the Protein Kinase B (AKT)/nuclear factor kappa-B (NF-KB) axis, thereby contributing to the repression of EC progression. Sufentanil effectively inhibited the proliferation, migration and EMT of endometrial cancer, demonstrating a potentially effective approach against EC.

BACKGROUND:The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism.METHODS:Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML.RESULTS:We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients.CONCLUSIONS:Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.

Human organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single-cell RNA sequencing (scRNA-seq) technology and genome-wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait-relevant cell types or states. Here, we constructed a computational framework to integrate atlas-level organoid scRNA-seq data, GWAS summary statistics, expression quantitative trait loci, and gene-drug interaction data for distinguishing critical cell populations and drug targets relevant to coronavirus disease 2019 (COVID-19) severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID-19 outcomes. Notably, subset of lung mesenchymal stem cells increased proximity with fibroblasts predisposed to repair COVID-19-damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID-19, and this cell subset showed a notable increase in cell-to-cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID-19 in a cell-type-specific manner. Overall, our results showcase that host genetic determinants have cellular-specific contribution to COVID-19 severity, and identification of cell type-specific drug targets may facilitate to develop effective therapeutics for treating severe COVID-19 and its complications.

OIP5-AS1, a conserved lncRNA, has been reported to be involved in several biological and pathological processes, including oncogenesis. OIP5-AS1 exerts its oncogenic or antitumor functions via regulation of different miRNAs in various cancer types. In this review, we describe the dysregulation of OIP5-AS1 expression in a variety of human cancers. Moreover, we discuss the multiple functions of OIP5-AS1 in cancer, including in proliferation, apoptosis, autophagy, ferroptosis, cell cycle, migration, metastasis, invasion, epithelial to mesenchymal transition, angiogenesis, cancer stem cells and drug resistance. Furthermore, we provide a future perspective for OIP5-AS1 research. We conclude that targeting OIP5-AS1 might be a promising cancer therapy approach.

Objective To determine whether gut microbiota, fatty metabolism and cytokines were associated with immune thrombocytopenia (ITP). Methods In total, 29 preliminarily diagnosed ITP patients and 33 healthy volunteers were enrolled. Fecal bacterial were analyzed based on 16S rRNA sequencing. Plasma cytokines and motabolites were analyzed using flow cytometry and liquid chromatography-mass spectrometry (LC-MS), respectively. Results Bacteroides, Phascolarctobacterium, and Lactobacillus were enriched at the genus level in ITP patients, while Ruminococcaceae UCG-002, Eubacterium coprostanoligeues, Megamonas, and Lachnospiraceae NC2004 were depleted. At the phylum level, the relative abundance of Proteobacteria and Chloroflexi increased in ITP patients, while Firmicutes, Actinobacteria, and the Firmicutes/Bacteroidetes ratio decreased. Plasma levels of 5-hydroxyeicosatetraenoic acid (5-HETE), 6-trans-12-epi-leukotriene B4 (6t,12e-LTB4), and resolvin D2 (RvD2) were upregulated, and stachydrine, dowicide A, dodecanoylcarnitine were downregulated in ITP patients. Furthermore, RvD2 is positively correlated with order Bacteroidetes VC2.1 Bac22, 5-HETE is positively correlated with genus Azospirillum, and 6t,12e-LTB4 is positively correlated with genus Cupriavidus. In addition, stachydrine is positively correlated with family Planococcaceae, dowicide A is positively correlated with class MVP-15, and dodecanoylcarnitine is positively correlated with order WCHB1-41. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were upregulated in ITP patients. Conclusion Our study revealed a relationship between microbiota and fatty metabolism in ITP. Gut microbiota may participate in the pathogenesis of ITP through affecting cytokine secretion, interfering with fatty metabolism.

BACKGROUND:The aim of this research was to estimate the expression of interleukin-10 in acute lymphoblastic leukemia (ALL) patients before and after chemotherapy in order to evaluate its role as a marker of disease progression. METHODS:Flow cytometry was used to detect the serum IL-10 levels in ALL patients before and during chemotherapy. Patients were divided into either complete remission (CR) group and non-remission (NR) group, before chemotherapy group and during chemotherapy group, B-ALL group and T-ALL group, WT-1 positive group and BCR-ABL1 positive group. The changes in serum IL-10 concentration before and during the chemotherapy were analyzed. RESULTS:IL-10 serum levels were significantly elevated in ALL patients at the onset of disease, and it was also more elevated in the NR group compared to the CR group. There is a significant reduction in IL-10 serum levels in ALL patients after effective chemotherapy. There was no significant difference between the before chemotherapy group and during chemotherapy group. Regardless of chemotherapy, the IL-10 levels of patients whose bone marrow achieved complete remission were lower than the patients who have not (p < 0.05). The same result can be seen in B or T-ALL groups. There was no significant difference in IL-10 serum levels between the group with WT-1(+) or BCR-ABL1(+) and the group with WT-1(-) or BCR-ABL1(-) (p > 0.05). In some ALL patients, increased IL-10 concentrations may be correlated to the number of peripheral blood leukemic cells. CONCLUSIONS:The increase of serum IL-10 level may be a possible marker of disease progression in ALL.

Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.

Ovarian cancer is one of the most lethal gynecologic tumors in women and has a poor prognosis. The purpose of our study was to identify new prognostic markers in ovarian cancer. We examined the prognostic roles of mRNA expression of the chromobox (CBX) family in patients with ovarian cancer utilizing the Kaplan-Meier plotter database. The prognostic values and expression levels of CBX members associated with prognosis were further evaluated using KM plotter in diverse subgroups and immunohistochemistry (IHC) analysis in ovarian carcinoma. The results revealed that elevated CBX1-3 mRNA expression may predict poor overall survival (OS) and progression-free survival (PFS) outcomes in patients with ovarian cancer. Notably, in women with ovarian cancer, increased CBX1 mRNA expression was linked to a short OS in all stages and in the grade II and grade III subgroups. Additionally, CBX2 and CBX3 were strongly related to short OS in stage III+IV patients, and a link between high CBX3 mRNA expression and unfavorable OS in grade II patients was observed. High expression levels of CBX1 and CBX3 were significantly associated with chemotherapy resistance in ovarian cancer patients. IHC staining showed that the CBX1-3 proteins were upregulated in serous ovarian carcinoma tissues compared with normal ovarian tissues. Therefore, our results indicated that CBX1-3 could be attractive biomarkers for predicting poor prognosis of ovarian cancer.

This study investigated the effect of isoflurane on the proliferation of squamous cervical cancer cells, with focus on histone deacetylase 6 that is closely related to carcinogenesis. Squamous cervical cancer cells SiHa and Caski were exposed to 1%, 2%, or 3% isoflurane for 2 h, respectively. Cell proliferation was measured with the cell counting kit (CCK-8) assay and determined by BrdU assay. Expression of histone deacetylase 6, phospho-AKT, phospho-mTOR, and proliferating cell nuclear antigen (PCNA) was assessed by Western blot. In order to block the histone deacetylase 6 (HDAC6) expression, siRNA transfection was performed. Isoflurane significantly promoted the proliferation of both SiHa and Caski cells, accompanied by upregulation of PCNA protein expression. Isoflurane increased the level of histone deacetylase 6 protein expression in both cells, and knockdown of histone deacetylase 6 attenuated the pro-proliferation effects of isoflurane. Additionally, activation of AKT/mTOR was found after isoflurane treatment, and mTOR inhibition abolished isoflurane-induced histone deacetylase 6 expression. However, inhibition of AKT phosphorylation had no effect on the expression of histone deacetylase 6 mediated by isoflurane. In conclusion, Isoflurane enhanced proliferation of cervical cancer cells through upregulation of histone deacetylase 6, which was associated with mTOR-dependent pathway, but not AKT-mediated pathway.

BACKGROUND: MicroRNA (miRNA) expression has been implicated in leukaemia. In recent years, miRNAs have been under investigation for their potential as non-invasive biomarkers in acute promyelocytic leukaemia (APL). We investigated whether miR-638 in circulating leukaemia cells is a non-invasive biomarker in diagnosis, assessment of the treatment response and minimal residual disease (MRD) surveillance of APL. METHODS: Sixty cases of acute myeloid leukaemia (AML), including 30 cases of APL and 30 cases of non-APL AML, were selected. Thirty healthy controls were also selected. Bone marrow (BM) and peripheral blood (PB) samples were collected from APL patients at diagnosis and post-induction. Microarray analysis and quantitative real-time PCR (qRT-PCR) were performed for miRNA profiling and miR-638 expression analysis, respectively. For statistical analysis, Mann-Whitney U test, Wilcoxon Signed Rank test, receiver operating characteristic (ROC) curve analysis and Spearman’s rho correlation test were used. RESULTS: Both microarray and qRT-PCR data showed that miR-638 was significantly upregulated in BM after APL patients received induction therapy. Moreover, miR-638, which is specifically downregulated in APL cell lines, was upregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation. Receiver operating characteristic (ROC) curve analyses revealed that miR-638 could serve as a valuable biomarker for differentiating APL from controls or non-APL AML. Furthermore, miR-638 expression was sharply increased after induction therapy and complete remission (CR). An inverse correlation was observed between miR-638 and PML-RARα transcripts levels in BM samples, while a positive correlation was revealed between PB miR-638 and BM miR-638 levels in APL patients after induction therapy. CONCLUSIONS: Our study suggested that miR-638 may serve as a potential APL biomarker for diagnosis and assessment of the response to targeted therapy, and PB miR-638 could be used for non-invasive MRD surveillance in APL.

The existence of Th17 cells and IL-17 was recently shown in several types of infectious diseases, but their distribution and functions in cervical lesions with high-risk human papillomavirus (HPV) infection have not been fully elucidated. In this study, the frequency of Th17 cells in peripheral blood samples obtained from 28 cervical squamous cell carcinoma patients, 26 CIN1 patients, 30 CIN2 patients, 29 CIN3 patients, 25 high-risk HPV-infected women with normal cervical cytology, and 30 healthy controls was determined by flow cytometry. Besides, the levels of IL-17 in peripheral blood samples as well as in supernatant of cervical tissue homogenate were assessed by enzyme-linked immunosorbent assay (ELISA) simultaneously. We found that during the disease progression of cervical lesions, the proportion of Th17 cells in the total CD4+ cells showed a gradually increased tendency compared with the controls (P < 0.05). Moreover, levels of IL-17 in serum and supernatant of cervical tissue homogenate showed the same tendency as the proportion of Th17 cells (P < 0.05). When compared in pairs, the levels of IL-17 in supernatant differed significantly among the study groups and the control group (P < 0.05), but no significant difference was observed in serum (P > 0.05). In conclusions, the results indicate that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV especially in the cervical microenvironment, which contribute to the disease progression of its associated cervical lesions.