Assessment of Immune Status in Patients with Mismatch Repair Deficiency Endometrial Cancer.

Objective: This study introduced a novel subtype classification method for endometrial cancer (EC) with mismatch repair deficiency (MMRd) by employing immune status and prognosis as the foundational criteria. The goal was to enhance treatment guidance through precise subtype delineation. Methods: Study Cohort: This study encompassed a cohort of 119 patients diagnosed with MMRd-EC between 2015 and 2022. Analyses using t-tests and Mann-Whitney U-tests were performed to assess prognostic markers and peripheral blood immune cell profiles in patients with MutS deficiency (MutS-d) versus those with MutL deficiency (MutL-d). Logistic regression analysis was used to identify independent risk factors. Bioinformatics Analysis: An online database was used to assess the prognostic implications, immune cell infiltration, and immune checkpoint involvement associated with the deficiency of MutS versus MutL in EC. Results: Patients with MutL-d exhibited heightened risk factors, including elevated cancer grade and increased myometrial invasion, leading to poorer prognosis and shorter overall survival and progression-free survival. Regarding systemic immune status, patients with MutL-d demonstrated decreased peripheral blood lymphocyte percentage, lymphocyte count, and CD8+ T cell percentage. For local immunity, the infiltration of natural killer cells, CD8+ T cells, and cytotoxic T lymphocytes in the tumor tissue was reduced in patients with MutL-d. Additionally, patients with MutL-d exhibited lower expression of immune checkpoint markers. The composition of immune subtypes and survival outcomes also indicate that patients with MutL-d have a poorer immune status and prognosis than the patients with MutS-d. Conclusion: Patients with MMRd-EC can be subclassified according to MutS or MutL deficiency. Patients with MutS-d exhibited better immune status, prognosis, and immunotherapy benefits than those with MutL-d. These results can help guide patients to a more precise treatment.

ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer.

BACKGROUND: Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. METHODS: The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. RESULTS: Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. CONCLUSIONS: ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.

Comparative study on plant growth-promoting bacterial inoculation by irrigation and spraying for promoting Bidens pilosa L. phytoremediation of cadmium-contaminated soil.

A field study was conducted to compare FM-1 inoculation by irrigation and spraying for promoting Bidens pilosa L. phytoremediation of cadmium (Cd)-contaminated soil. Cascading relationships between bacterial inoculation by irrigation and spraying and soil properties, plant growth-promoting traits, plant biomass and Cd concentrations in Bidens pilosa L. were explored based on the partial least squares path model (PLS-PM). The results indicated that inoculation with FM-1 not only improved the rhizosphere soil environment of B. pilosa L. but also increased the Cd extracted from the soil. Moreover, Fe and P in leaves play vital roles in promoting plant growth when FM-1 is inoculated by irrigation, while Fe in leaves and stems plays a vital role in promoting plant growth when FM-1 is inoculated by spraying. In addition, FM-1 inoculation decreased the soil pH by affecting soil dehydrogenase and oxalic acid in cases with irrigation and Fe in roots in cases with spraying. Thus, the soil bioavailable Cd content increased and promoted Cd uptake by Bidens pilosa L. To address Cd-induced oxidative stress, Fe in leaves helped to convert GSH into PCs, which played a vital role in ROS scavenging when FM-1 was inoculated by irrigation. The soil urease content effectively increased the POD and APX activities in the leaves of Bidens pilosa L., which helped alleviate Cd-induced oxidative stress when FM-1 was inoculated by spraying. This study compares and illustrates the potential mechanism by which FM-1 inoculation can improve the phytoremediation of Cd-contaminated soil by Bidens pilosa L., suggesting that FM-1 inoculation by irrigation and spraying is useful in the phytoremediation of Cd-contaminated sites.

ERRα Up-Regulates Invadopodia Formation by Targeting HMGCS1 to Promote Endometrial Cancer Invasion and Metastasis.

Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERRα and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERRα/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERRα and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERRα and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERRα and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERRα and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERRα promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial-mesenchymal transition pathway. Our findings suggest that ERRα and HMGCS1 are potential targets to suppress EC progression.

A modified diatomite additive alleviates cadmium-induced oxidative stress in Bidens pilosa L. by altering soil microbial communities.

In the present study, a modified silicon adsorbent (MDSA) was used as a passivator, and we explored the mechanism by which the MDSA helps B. pilosa L. alleviate Cd-induced oxidative stress and its effect on the rhizosphere microbial community. Therefore, a field study was conducted, and MDSA was applied at four levels (control (0 mg m-2), A1 (100 mg m-2), A2 (200 mg m-2), and A3 (400 mg m-2)). The application of MDSA significantly increased the soil pH and decreased the acid-soluble Cd content, which decreased by 30.3% with A3 addition. The addition of MDSA increased the relative abundance of Sordariomycetes due to the increased invertase activity and total nitrogen (TN) and total phosphorus (TP) contents, and the increased soil pH led to increased relative abundances of Alphaproteobacteria and Thermoleophilia. Meanwhile, MDSA addition significantly decreased the Cd concentrations in leaves and stems, which decreased by 19.7 to 39.5% in stems and 24.6 to 43.2% in leaves. All MDSA additions significantly decreased the translocation factor (TF) values of Cd, which decreased by 30.5% (A1), 50.9% (A2), and 52.7% (A3). Moreover, peroxidase (POD) from the antioxidant enzyme system and glutathione (GSH) from the nonenzymatic system played vital roles in scavenging reactive oxygen intermediates (ROIs) such as H2O2 and ⋅O2- in leaves, thereby helping B. pilosa L. alleviate Cd-induced oxidative stress and promote plant growth. Hence, our study indicated that MDSA application improved the rhizosphere soil environment, reconstructed the soil microbial community, helped B. pilosa L. alleviate Cd-induced oxidative stress, and promoted plant growth.

Depletion of circPDSS1 inhibits ITGA11 production to confer cisplatin sensitivity through miR-515-5p in gastric cancer.

Chemoresistance limits cisplatin (DDP)-mediated treatment for gastric cancer (GC). Circular RNA (circRNA) acts an important role in chemoresistance. However, the underlying mechanism of circPDSS1 regulating DDP sensitivity in GC remains unclear. The expression patterns of circPDSS1, miR-515-5p and integrin subunit alpha 11 (ITGA11) were analyzed by qRT-PCR. Protein expression was checked by Western blotting analysis. Cell viability was investigated by 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell proliferation was evaluated by colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. The analysis of cell apoptosis, migration and invasion was performed by flow cytometry analysis and transwell assays. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to identify the associations among circPDSS1, miR-515-5p and ITGA11. In vivo assay was implemented using a xenograft mouse model assay. CircPDSS1 and ITGA11 expression were significantly upregulated, whereas miR-515-5p was downregulated in DDP-resistant GC tissues and cells in comparison with controls. CircPDSS1 depletion reduced DDP resistance, cell proliferation, migration and invasion but induced cell apoptosis in DDP-resistant GC cells. CircPDSS1 directly bound to miR-515-5p. CircPDSS1-mediated actions were dependent on the regulation of miR-515-5p. Besides, miR-515-5p was associated with ITGA11, and circPDSS1 regulated ITGA11 expression by binding to miR-515-5p. Overexpression of miR-515-5p improved DDP sensitivity owing to the downregulation of ITGA11. Further, circPDSS1 mediated DDP sensitivity by regulating miR-515-5p and ITGA11 in vivo. CircPDSS1 conferred DDP resistance through the miR-515-5p/ITGA11 axis in GC cells.

Simultaneous mitigation of arsenic and cadmium accumulation in rice grains by foliar inhibitor with ZIF-8@Ge-132.

Simultaneous mitigation of Arsenic (As) and Cadmium (Cd) in rice grains is hardly achieved with conventional soil treatments due to their opposite chemical behaviors in paddy soils. This study evaluates the effectiveness of a novel foliar inhibitor with germanium (Ge) -modified zeolitic imidazolate framework (ZIF-8@Ge-132) in cooperative mitigation of As and Cd in rice grains in a As and Cd co-contaminated paddy field, and the effecting mechanisms are elucidated by a series of advanced techniques. The results showed that the grains inorganic As and Cd was remarkably decreased by 45 % and 66 % by the foliar spay of ZIF-8@Ge-132, respectively. ZIF-8@Ge-132 also reduced the As and Cd contents in rice tissues, except for Cd in leaves, where Cd content increased by 148 %. The image-based measurement of plant phenotypic traits and the elements of image analysis using Laser Ablation-ICP-MS (LA-ICP-MS) and Laser Scanning Confocal Microscopy (LSCM) revealed that the possible mechanisms for the reduction of As and Cd in rice grains were as follows: (i) the thickening of the xylem in roots significantly retarded As and Cd absorption by rice plants. (ii) co-accumulation of Ge and Cd in the leaf vascular system likely contributed to the high Cd retention in rice leaves. (iii) antagonistic effects of Zn suppressed the uptake and transport of As in roots/leaves, resulting a lower As accumulation in rice grains.

Mechanism underlying how a chitosan-based phosphorus adsorbent alleviates cadmium-induced oxidative stress in Bidens pilosa L. and its impact on soil microbial communities: A field study.

In the present study, field experiments were conducted in Side village, Yangshuo, Guilin, Guangxi Province, China, using four C-BPA application levels (control (0 mg m-2), T1 (100 mg m-2), T2 (200 mg m-2) and T3 (400 mg m-2)) to clarify the mechanism by which a chitosan-based phosphorus adsorbent (C-BPA) applied as a passivator helps Bidens pilosa L. (B. pilosa L.) alleviate cadmium (Cd)-induced oxidative stress in Cd-contaminated soil. In the aqueous phase, C-BPA successfully adsorbed Cd2+ on the surface primarily via ion exchange, and C-BPA has potential Cd2+ adsorption capacity, enabling its use as a passivator in real Cd-contaminated environments. In Cd-contaminated soils, under C-BPA application at the T3 level, the pH value increased by 11.2%, and the acid-soluble form of Cd decreased by 26.5%. Additionally, the application of C-BPA improved the rhizosphere soil environment and impacted the soil microbial community diversity and structure. Among soil microbes, the soil fungal community was more sensitive than bacteria to C-BPA application. Dehydrogenase, acetic acid, soil pH and Eurotiomycetes or Dothideomycetes significantly impacted Cd accumulation in the leaves of B. pilosa L.; Cd accumulation in leaves was decreased by 68.1% under C-BPA application at the T3 level. Additionally, the variation of increased catalase (CAT) and peroxidase (POD) jointly promoted plant growth; the plant weight was increased by 112.7% under the C-BPA application at the T3 level. Notably, the production of CAT and POD by B. pilosa L. was more effective than the synthesis of glutathione (GSH) in helping B. pilosa L. eliminate excess reactive oxygen species (ROS). Therefore, our findings demonstrated that the application of C-BPA to Cd-contaminated soil can greatly improve the rhizosphere soil environment, help B. pilosa L. eliminate ROS and promote plant growth.

Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression.

BACKGROUND: Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. The transcription factor EB (TFEB)-ERRα axis induces lipid reprogramming to promote progression of EC was explored in this study. METHODS: TFEB and ERRα were analyzed and validated by RNA-sequencing data from the Cancer Genome Atlas (TCGA). The TFEB-ERRα axis was assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the TFEB-ERRα-related lipid metabolism pathway. Pseudopods were observed by scanning electron microscope. Furthermore, immunohistochemistry and lipidomics were performed in clinical tissue samples to validate the ERRα-related lipids. RESULTS: TFEB and ERRα were highly expressed in EC patients and correlated to EC progression. ERRα is the direct target of TFEB to mediate EC lipid metabolism. TFEB-ERRα axis mainly affected glycerophospholipids (GPs) and significantly elevated the ratio of phosphatidylcholine (PC)/sphingomyelin (SM), which indicated the enhanced membrane fluidity. TFEB-ERRα axis induced the mitochondria specific phosphatidylglycerol (PG) (18:1/22:6) + H increasing. The lipid reprogramming was mainly related to mitochondrial function though combining lipidomics and proteomics. The maximum oxygen consumption rate (OCR), ATP and lipid-related genes acc, fasn, and acadm were found to be positively correlated with TFEB/ERRα. TFEB-ERRα axis enhanced generation of pseudopodia to increase the invasiveness. Mechanistically, our functional assays indicated that TFEB promoted EC cell migration in an ERRα-dependent manner via EMT signaling. Consistent with the in vitro, higher PC (18:1/18:2) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (18:1/18:2) + HCOO was an independent risk factor positively related to ERRα for lymph node metastasis. CONCLUSION: Lipid reprogramming induced by the TFEB-ERRα axis increases unsaturated fatty acid (UFA)-containing PCs, PG, PC/SM and pseudopodia, which enhance membrane fluidity via EMT signaling to promote EC progression. PG (18:1/22:6) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.

Construction and Validation of a Ferroptosis-Related Prognostic Model for Gastric Cancer.

BACKGROUND: Gastric cancer (GC), an extremely aggressive tumor with a very different prognosis, is the third leading cause of cancer-related mortality. We aimed to construct a ferroptosis-related prognostic model that can be distinguished prognostically. METHODS: The gene expression and the clinical data of GC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). The ferroptosis-related genes were obtained from the FerrDb. Using the "limma" R package and univariate Cox analysis, ferroptosis-related genes with differential expression and prognostic value were identified in the TCGA cohort. Last absolute shrinkage and selection operator (LASSO) Cox regression was applied to shrink ferroptosis-related predictors and construct a prognostic model. Functional enrichment, ESTIMATE algorithm, and single-sample gene set enrichment analysis (ssGSEA) were applied for exploring the potential mechanism. GC patients from the GEO cohort were used for validation. RESULTS: An 8-gene prognostic model was constructed and stratified GC patients from TCGA and meta-GEO cohort into high-risk groups or low-risk groups. GC patients in high-risk groups have significantly poorer OS compared with those in low-risk groups. The risk score was identified as an independent predictor for OS. Functional analysis revealed that the risk score was mainly associated with the biological function of extracellular matrix (ECM) organization and tumor immunity. CONCLUSION: In conclusion, the ferroptosis-related model can be utilized for the clinical prognostic prediction in GC.

Development of Prognostic Indicator Based on Autophagy-Related lncRNA Analysis in Colon Adenocarcinoma.

There were no systematic researches about autophagy-related long noncoding RNA (lncRNA) signatures to predict the survival of patients with colon adenocarcinoma. It was necessary to set up corresponding autophagy-related lncRNA signatures. The expression profiles of lncRNAs which contained 480 colon adenocarcinoma samples were obtained from The Cancer Genome Atlas (TCGA) database. The coexpression network of lncRNAs and autophagy-related genes was utilized to select autophagy-related lncRNAs. The lncRNAs were further screened using univariate Cox regression. In addition, Lasso regression and multivariate Cox regression were used to develop an autophagy-related lncRNA signature. A risk score based on the signature was established, and Cox regression was used to test whether it was an independent prognostic factor. The functional enrichment of autophagy-related lncRNAs was visualized using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Ten prognostic autophagy-related lncRNAs (AC027307.2, AC068580.3, AL138756.1, CD27-AS1, EIF3J-DT, LINC01011, LINC01063, LINC02381, AC073896.3, and SNHG16) were identified to be significantly different, which made up an autophagy-related lncRNA signature. The signature divided patients with colon adenocarcinoma into the low-risk group and the high-risk group. A risk score based on the signature was a significantly independent factor for the patients with colon adenocarcinoma (HR = 1.088, 95%CI = 1.057 - 1.120; P < 0.001). Additionally, the ten lncRNAs were significantly enriched in autophagy process, metabolism, and tumor classical pathways. In conclusion, the ten autophagy-related lncRNAs and their signature might be molecular biomarkers and therapeutic targets for the patients with colon adenocarcinoma.

Construction of a 13-microRNA-based signature and prognostic nomogram for predicting overall survival in patients with hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) is a common malignancy associated with a poor prognosis due to difficulties in reliably estimating overall survival (OS). MicroRNAs (miRNAs) play critical roles in HCC initiation, progression, and metastasis and are highly correlated with patient prognosis. Thus, miRNA-based risk signatures and nomograms are urgently required for predicting OS in patients with HCC. METHODS: We constructed a 13-miRNA-based signature and prognostic nomogram using 408 HCC samples and 58 normal tissues with miRNA sequencing data and clinical data from 323 patients downloaded from The Cancer Genome Atlas. A total of 195 patients were assigned as the internal validation cohort for verification and testing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis was applied to investigate pathway enrichment for the signature. RESULTS: We identified and validated a 13-miRNA risk signature highly associating with the OS of HCC patients. The signature showed good performances by calculating C-index, area under the curve, and calibration curves. After verification and testing using an internal validation cohort, the results yielded a miRNA-based signature and a prognostic nomogram with reliable predictive accuracy. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that various genes and multiple pathways were closely related to the mechanisms of HCC proliferation and metastasis. CONCLUSION: We successfully identified a 13-miRNA-based signature and prognostic nomogram that are capable of predicting OS in patients with HCC.