Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aß1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-ß in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of ß-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.

Construction of exosome-related genes risk model in kidney cell carcinoma predicts prognosis and immune therapy response.

Renal cell carcinoma (RCC) is one of the most prevalent types of urological cancer. Exosomes are vesicles derived from cells and have been found to promote the development of RCC, but the potential biomarker and molecular mechanism of exosomes on RCC remain ambiguous. Here, we first screened differentially expressed exosome-related genes (ERGs) by analyzing The Cancer Genome Atlas (TCGA) database and exoRBase 2.0 database. We then determined prognosis-related ERGs (PRERGs) by univariate Cox regression analysis. Gene Dependency Score (gDS), target development level, and pathway correlation analysis were utilized to examine the importance of PRERGs. Machine learning and lasso-cox regression were utilized to screen and construct a 5-gene risk model. The risk model showed high predictive accuracy for the prognosis of patients and proved to be an independent prognostic factor in three RCC datasets, including TCGA-KIRC, E-MTAB-1980, and TCGA-KIRP datasets. Patients with high-risk scores showed worse outcomes in different clinical subgroups, revealing that the risk score is robust. In addition, we found that immune-related pathways are highly enriched in the high-risk group. Activities of immune cells were distinct in high-/low-risk groups. In independent immune therapeutic cohorts, high-risk patients show worse immune therapy responses. In summary, we identified several exosome-derived genes that might play essential roles in RCC and constructed a 5-gene risk signature to predict the prognosis of RCC and immune therapy response.

N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling. Increasing evidence indicates that endothelial-to-mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs) is a pivotal trigger initiating this remodeling. However, the regulatory mechanisms underlying EndMT in PH are still not fully understood. METHODS: Cytokine-induced hPAECs were assessed using RNA methylation quantification, qRT-PCR, and western blotting to determine the involvement of N6-methyladenosine (m6A) methylation in EndMT. Lentivirus-mediated silencing, overexpression, tube formation, and wound healing assays were utilized to investigate the function of METTL3 in EndMT. Endothelial-specific gene knockout, hemodynamic measurement, and immunostaining were performed to explore the roles of METTL3 in pulmonary vascular remodeling and PH. RNA-seq, RNA Immunoprecipitation-based qPCR, mRNA stability assay, m6A mutation, and dual-luciferase assays were employed to elucidate the mechanisms of RNA methylation in EndMT. RESULTS: The global levels of m6A and METTL3 expression were found to decrease in TNF-α- and TGF-ß1-induced EndMT in human PAECs (hPAECs). METTL3 inhibition led to reduced endothelial markers (CD31 and VE-cadherin) and increased mesenchymal markers (SM22 and N-cadherin) as well as EndMT-related transcription factors (Snail, Zeb1, Zeb2, and Slug). The endothelial-specific knockout of Mettl3 promoted EndMT and exacerbated pulmonary vascular remodeling and hypoxia-induced PH (HPH) in mice. Mechanistically, METTL3-mediated m6A modification of kruppel-like factor 2 (KLF2) plays a crucial role in the EndMT process. KLF2 overexpression increased CD31 and VE-cadherin levels while decreasing SM22, N-cadherin, and EndMT-related transcription factors, thereby mitigating EndMT in PH. Mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, subsequently diminishing its protective effect against EndMT. Furthermore, KLF2 modulates SM22 expression through direct binding to its promoter. CONCLUSIONS: Our findings unveil a novel METTL3/KLF2 pathway critical for protecting hPAECs against EndMT, highlighting a promising avenue for therapeutic investigation in PH.

Single-cell and bulk RNA-sequence identified fibroblasts signature and CD8+ T-cell - fibroblast subtype predicting prognosis and immune therapeutic response of bladder cancer, based on machine-learning bioinformatics retrospective study.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are found in primary and advanced tumours. They are primarily involved in tumour progression through complex mechanisms with other types of cells in the tumour microenvironment. However, essential fibroblasts-related genes (FRG) in bladder cancer still need to be explored, and there is a shortage of an ideal predictive model or molecular subtype for the progression and immune therapeutic assessment for bladder cancer, especially muscular-invasive bladder cancer based on the FRG. MATERIALS AND METHODS: CAF-related genes of bladder cancer were identified by analyzing single-cell RNA sequence datasets, and bulk transcriptome datasets and gene signatures were used to characterize them. Then, ten types of machine learning algorithms were utilized to determine the hallmark FRG and construct the FRG index (FRGI) and subtypes. Further molecular subtypes combined with CD8+ T-cells were established to predict the prognosis and immune therapy response. RESULTS: 54 BLCA-related FRG were screened by large-scale scRNA-sequence datasets. The machine learning algorithm established a 3-genes FRG index (FRGI). High FRGI represented a worse outcome. Then, FRGI combined clinical variables to construct a nomogram, which shows high predictive performance for the prognosis of bladder cancer. Furthermore, the BLCA datasets were separated into two subtypes - fibroblast hot and cold types. In five independent BLCA cohorts, the fibroblast hot type showed worse outcomes than the cold type. Multiple cancer-related hallmark pathways are distinctively enriched in these two types. In addition, high FRGI or fibroblast hot type shows a worse immune therapeutic response. Then, four subtypes called CD8-FRG subtypes were established under the combination of FRG signature and activity of CD8+ T-cells, which turned out to be effective in predicting the prognosis and immune therapeutic response of bladder cancer in multiple independent datasets. Pathway enrichment analysis, multiple gene signatures, and epigenetic alteration characterize the CD8-FRG subtypes and provide a potential combination strategy method against bladder cancer. CONCLUSIONS: In summary, we established a novel FRGI and CD8-FRG subtype by large-scale datasets and organized analyses, which could accurately predict clinical outcomes and immune therapeutic response of BLCA after surgery.

Tumor Supplying Artery Injection of Liposome@Sunitinib Could Effectively Inhibit the Progression of Kidney Tumor.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system and is not sensitive to chemotherapy or radiotherapy in its advanced stages. Sunitinib is recommended as a first-line target drug for unresectable and metastatic RCC by targeting tyrosine kinase-related signaling pathways, but its therapeutic effect is unsatisfactory. Recently, nanomaterials have shown great prospects in the medical field because of their unique physicochemical properties. Particularly, liposomes are considered as ideal drug delivery systems due to their biodegradability, biocompatibility, and ideal drug-loading efficiency. Considering that tumor supplying artery injection can directly distribute drugs into tumor tissues, in this study, liposomes were employed to encapsulate water-insoluble sunitinib to construct the liposome@sunitinib (Lipo@Suni) complex, so that the drug could directly target and distribute into tumor tissue, and effectively trapped in tumor tissues after tumor supplying artery injection for the advantage of the physicochemical properties of liposomes, thereby achieving a better therapeutic effect on advanced RCC. Here, we found that compared with the peripheral intravenous administration, trans-renal arterial administration increases the content and prolongs the retention time of liposomes in tumor tissues; accordingly, more sunitinib is dispersed and retained in tumor tissues. Ultimately, trans-renal arterial administration of Lipo@Suni exerts a better suppressive effect on RCC progression than peripheral intravenous administration, even better than the conventional oral administration of sunitinib.

Classification of multi-feature fusion ultrasound images of breast tumor within category 4 using convolutional neural networks.

BACKGROUND: Breast tumor is a fatal threat to the health of women. Ultrasound (US) is a common and economical method for the diagnosis of breast cancer. Breast imaging reporting and data system (BI-RADS) category 4 has the highest false-positive value of about 30% among five categories. The classification task in BI-RADS category 4 is challenging and has not been fully studied. PURPOSE: This work aimed to use convolutional neural networks (CNNs) for breast tumor classification using B-mode images in category 4 to overcome the dependence on operator and artifacts. Additionally, this work intends to take full advantage of morphological and textural features in breast tumor US images to improve classification accuracy. METHODS: First, original US images coming directly from the hospital were cropped and resized. In 1385 B-mode US BI-RADS category 4 images, the biopsy eliminated 503 samples of benign tumor and left 882 of malignant. Then, K-means clustering algorithm and entropy of sliding windows of US images were conducted. Considering the diversity of different characteristic information of malignant and benign represented by original B-mode images, K-means clustering images and entropy images, they are fused in a three-channel form multi-feature fusion images dataset. The training, validation, and test sets are 969, 277, and 139. With transfer learning, 11 CNN models including DenseNet and ResNet were investigated. Finally, by comparing accuracy, precision, recall, F1-score, and area under curve (AUC) of the results, models which had better performance were selected. The normality of data was assessed by Shapiro-Wilk test. DeLong test and independent t-test were used to evaluate the significant difference of AUC and other values. False discovery rate was utilized to ultimately evaluate the advantages of CNN with highest evaluation metrics. In addition, the study of anti-log compression was conducted but no improvement has shown in CNNs classification results. RESULTS: With multi-feature fusion images, DenseNet121 has highest accuracy of 80.22 ± 1.45% compared to other CNNs, precision of 77.97 ± 2.89% and AUC of 0.82 ± 0.01. Multi-feature fusion improved accuracy of DenseNet121 by 1.87% from classification of original B-mode images (p < 0.05). CONCLUSION: The CNNs with multi-feature fusion show a good potential of reducing the false-positive rate within category 4. The work illustrated that CNNs and fusion images have the potential to reduce false-positive rate in breast tumor within US BI-RADS category 4, and make the diagnosis of category 4 breast tumors to be more accurate and precise.

Deguelin and Paclitaxel Loaded PEG-PCL Nano-Micelles for Suppressing the Proliferation and Inducing Apoptosis of Breast Cancer Cells.

BACKGROUND: Deguelin (DGL) is a natural flavonoid reported to exhibit antitumor effects in breast cancer (BC). PEG-PCL (Polyethylene Glycol- Polycaprolactone), as polymeric micelles, has biodegradability and biocompatibility. The aim of this study was to investigate whether the nanoparticular delivery system, PEG-PCL could improve the bioavailability of DGL for suppressing proliferation of BC cells. METHODS: PEG-PCL polymers were first prepared by ring-opening polymerization, and DGL and paclitaxel (PTX)-loaded PEG-PCL nano-micelles were formulated via the film dispersion method. The composition and molecular weight of PEG-PCL were analyzed by nuclear magnetic resonance and fourier Transform infrared spectroscopy (FTIR) spectra. Particle size, surface potential and hemolytic activity of micelles were assessed by dynamic light scattering, transmission electron microscopy and hemolysis assay, respectively. Then proliferation and apoptosis of MDA-MB-231 and MDA-MB-468 cells were tested with Edu staining, CCK-8, TUNEL staining, and Flow cytometer. Caspase 3 expression was also assessed by Western blot. RESULTS: Our results first indicated that PEG2000-PCL2000 was successfully synthesized. DGL and PTX-loaded PEG-PCL nano-micelles were rounded in shape with a particle size of 35.78 ± 0.35 nm and a surface potential of 2.84 ± 0.27 mV. The micelles had minimal hemolytic activity. Besides, we proved that DGL and PTX-loaded PEG-PCL nano-micelles could suppress proliferation and induce apoptosis in BC cells. The DGL and PTX-loaded PEG-PCL nano-micelles constructed in this study had a prominent inhibitory role on proliferation and a remarkable promotional role on apoptosis in BC cells. CONCLUSIONS: This study proposes that nano-micelles formed by PEG-PCL can enhance the cytotoxicity of Paclitaxel against breast cancer cells, and concurrently, the loading of Deguelin may further inhibit cell proliferation. This presents a potential for the development of a novel therapeutic strategy.

Safety and Effectiveness of Robotic-Arm Assisted Total Knee Arthroplasty.

OBJECTIVE: We investigated the advantages of robotic arm-assisted total knee arthroplasty (raTKA) over conventional manual TKA (cmTKA) by comprehensively comparing patients who received raTKA and cmTKA in terms of postoperative pain, function, imaging assessment, and trauma to the body. This study investigated the efficacy and safety of raTKA in patients using the YUANHUA-TKA system. METHODS: In a prospective, randomized single-blind trial, 60 patients undergoing primary unilateral TKA from October 2020 to December 2020 were randomly assigned to either raTKA or cmTKA. Clinical evaluation, including the time of osteotomy and prosthesis model testing, the total operation time, the visual analogue scale at rest, VAS in motion, opioid consumption, white blood cell count, neutrophil ratio, erythrocyte sedimentation rate, C-reactive protein (CRP), passive and active range of motion (pROM, aROM), Western Ontario and McMaster Universities Arthritis Index (WOMAC [stiffness, pain, and function]) score, gait analysis, keen society score (KSS), adverse events, and blood loss were collected by the project nurse, as well as the imaging evaluation, including the lateral tibia component angle (LTC), frontal femoral component angle, frontal tibia component angle (FTC), lateral femoral component angl, and hip-knee-ankle angle (HKA). The student t-test (or the Wilcoxon signed-rank test) and the χ2-test (or the Fisher exact test) were used to determine differences in categorical variables. RESULTS: No significant difference was found between the two groups in pain throughout the whole follow-up period. On the third day postoperatively, the erythrocyte sedimentation rate in the cmTKA group was significantly higher (p = 0.02), as well as the CRP (p = 0.04). No significant difference was found in the WOMAC stiffnes score or pROM. However, the aROM and the flexion range when walking (FRW) were significantly better in the raTKA group throughout the trial (p < 0.05). The KSS at the 1-month follow-up and the WOMAC function score at the 1-year follow-up were both significantly better in the raTKA group (p < 0.05). The HKA and the LTC in the raTKA group closer to the ideal angle, and the difference between the groups was significant (p < 0.05). The total operation time of the raTKA group was significantly longer (p = 0.001). The intraoperative blood loss had no significant difference in the two groups. CONCLUSION: Compared with cmTKA, raTKA with the YUANHUA robot not only avoids extra pain and trauma in patients but promises better functional recovery and improves the accuracy of the prosthesis position and axial alignment reconstruction.

Efficacy and adverse events of immune checkpoint inhibitors in esophageal cancer patients: Challenges and perspectives for immunotherapy.

Esophageal cancer (EC) is the seventh most common cancer worldwide. Patients with EC have a generally poor prognosis mainly due to the lack of effective treatments. Cancer immunotherapy is a promising novel treatment option for EC. This literature review investigated the clinical efficacy of immunotherapy either alone or in combination with chemotherapy or targeted therapy. In addition, we analyzed the adverse events associated with immune checkpoint inhibitors (ICIs). In conclusion, ICIs increase the efficacy of EC treatments, thereby improving the outcomes of EC patients. The findings of this study may help enhance the response to immunotherapy, diminish toxicity, and thus eventually improve medical care for patients with EC.

A novel tumor purity and immune infiltration-related model for predicting distant metastasis-free survival in prostate cancer.

BACKGROUND: umor cells, immune cells and stromal cells jointly modify tumor development and progression. We aim to explore the potential effects of tumor purity on the immune microenvironment, genetic landscape and prognosis in prostate cancer (PCa). METHODS: Tumor purity of prostate cancer patients was extracted from The cancer genome atlas (TCGA). Immune cellular proportions were calculated by the CIBERSORT. To identify critical modules related to tumor purity, we used weighted gene co-expression network analysis (WGCNA). Using STRING and Cytoscape, protein-protein interaction (PPI) networks were constructed and analyzed. A Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Disease Ontology (DO), and Gene Set Enrichment Analysis (GSEA) enrichment analysis of identified modules was conducted. To identify the expression of key genes at protein levels, we used the Human Protein Atlas (HPA) platform. RESULTS: A model of tumor purity score (TPS) was constructed in the gene expression omnibus series (GSE) 116,918 cohort. TCGA cohort served as a validation set and was employed to validate the TPS. TPS model, as an independent prognostic factor of distant metastasis-free survival (DMFS) in PCa. Patients had higher tumor purity and better prognosis in the low-TPS group. Tumor purity was related to the infiltration of mast cells and macrophage cells positively, whereas related to the infiltration of dendritic cells, T cells and B cells negatively in PCa. The nomogram based on TPS, Age, Gleason score and T stage had a good predictive value and could evaluate the prognosis of PCa metastasis. GO and KEGG enrichment analyses showed that hub genes mainly participate in T cell activation and T-helper lymphocytes (TH) differentiation. Hub genes were mainly enriched in primary immunodeficiency disease, according to DO analysis. SLAMF8 was identified as the most critical gene by Cytoscape and HPA analysis. CONCLUSIONS: Dynamic changes in the immune microenvironment associated with tumor purity could correlate with a poor DMFS of low-purity PCa. The TPS can predict the DMFS of PCa. In addition, prostate cancer metastases may be related to immunosuppression caused by a disorder of the immune microenvironment.

A prognostic risk model for programmed cell death and revealing TRIB3 as a promising apoptosis suppressor in renal cell carcinoma.

Programmed cell death (PCD), a common modality of cell death, affects tumor development and acts as a target for tumor therapeutics. Many modalities of PCD regulate genesis, progression and metastasis of cancers, thus affecting the patients' prognosis, but the comprehensive molecular mechanisms of PCD in tumors are lacking, especially in renal cancer. Here, seventeen PRPCDGs were identified from 1257 genes associated with thirteen PCD modalities, which were highly differentially expressed and significantly affected patients' prognosis. Then, LASSO regression analysis of these PRPCDGs screened the 9-gene PRPCDGs risk signature in TCGA-KIRC database. The PRPCDGs risk signature was closely associated with the patients' prognosis and presented stable prediction efficacy for 5- and 7-year overall survival (OS) in three different cohorts of renal cancer. Immune cell infiltration, immune checkpoint expression and pathway enrichment (including GO, KEGG pathway, tumor-associated pathways and metabolism-associated pathways) were significantly different in the high- or low-PRPCDGs-risk group. Finally, we illustrated that TRIB3 might be a protumor factor responsible for the elevated proliferation and invasion capacities of renal cell carcinoma (RCC) cells. In summary, the PRPCDGs risk signature was developed and showed stable prediction efficacy for the prognosis of patients and that (such as TRIB3) could be a potential target for RCC management.

Tex10 interacts with STAT3 to regulate hepatocellular carcinoma growth and metastasis.

Testis expression 10 (Tex10) is reported to be associated with tumorigenesis in several types of cancer types, but its role in hepatocellular carcinoma (HCC) metastasis has not been investigated. In this study, the expression of Tex10 in the HCC cell line and tissue microarray was determined by Western blot and immunohistochemistry (IHC), respectively. RNA sequencing-based transcriptome analysis was performed to identify the Tex10-mediated biological process. Cell Counting Kit-8, colony formation, transwell assays, xenograft tumor growth, and lung metastasis experiments in nude mice were applied to assess the effects of Tex10 on cell proliferation, migration, invasion, and metastasis. The underlying mechanisms were further investigated using dual-luciferase reporter, co-immunoprecipitation, immunofluorescence, and chromatin immunoprecipitation assays. We found that Tex10 was upregulated in HCC tumor tissues compared to adjacent normal tissues, with its expression correlated with a poor prognosis. Gene ontology function enrichment analysis revealed alterations in several biological processes in response to Tex10 knockdown, especially cell motility and cell migration. Functional studies demonstrated that Tex10 promotes HCC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Moreover, Tex10 was shown to regulate invasion and epithelial-mesenchymal transition via signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, Tex10 was found to interact with STAT3 and promote its transcriptional activity. In addition, we found that Tex10 promotes p300-mediated STAT3 acetylation, while p300 silencing abolishes Tex10-enhanced STAT3 transcriptional activity. Together, these findings indicate that Tex10 functions as an oncogene by upregulating STAT3 activity, thus suggesting that Tex10 may serve as a prognostic biomarker and/or therapeutic target for HCC patients.

METTL14­mediated RNA methylation in digestive system tumors.

N6­methyladenosine (m6A) RNA methylation is one of the most common post­transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of the mRNA life cycle, specifically regulating its stability, splicing, export and translation. Methyltransferase­like 14 (METTL14) is a particularly important m6A methylation 'writer' that can recognize RNA substrates. METTL14 has been documented to improve the activity and catalytic efficiency of METTL3. However, as individual proteins they can also regulate different biological processes. Malignancies in the digestive system are some of the most common malignancies found in humans, which are typically associated with poor prognoses with limited clinical solutions. METTL14­mediated methylation has been implicated in both the potentiation and inhibition of digestive system tumor growth, cell invasion and metastasis, in addition to drug resistance. In the present review, the research progress and regulatory mechanisms of METTL14­mediated methylation in digestive system malignancies were summarized. In addition, future research directions and the potential for its clinical application were examined.

Mesenchymal Stem Cell-Derived Exosomal Noncoding RNAs as Alternative Treatments for Myocardial Ischemia-Reperfusion Injury: Current Status and Future Perspectives.

Ischemic cardiomyopathy is treated mainly with thrombolytic drugs, percutaneous coronary intervention, and coronary artery bypass grafting to recanalize blocked vessels. Myocardial ischemia-reperfusion injury (MIRI) is an unavoidable complication of obstructive revascularization. Compared with those of myocardial ischemic injury, few effective therapeutic options are available for MIRI treatment. The pathophysiological mechanisms of MIRI involve the inflammatory response, the immune response, oxidative stress, apoptosis, intracellular Ca2+ overload, and cardiomyocyte energy metabolism. These mechanisms exacerbate MIRI. Mesenchymal stem cell-derived exosomes (MSC-EXOs) can alleviate MIRI through these mechanisms and, to some extent, prevent the limitations caused by direct MSC administration. Therefore, using MSC-EXOs instead of MSCs to treat MIRI is a potentially beneficial cell-free treatment strategy. In this review, we describe the mechanism of action of MSC-EXO-derived noncoding RNAs in the treatment of MIRI and discuss the advantages and limitations of this strategy, as well as possible future research directions.

Inhibition of Annexin A10 Contributes to ZNF281 Mediated Aggressiveness of Hepatocellular Carcinoma.

Objective: To investigate the involvement and transcriptional targets of zinc finger protein 281 (ZNF281) in the progression of hepatocellular carcinoma (HCC). Methods: The expression of ZNF281 in HCC was detected in tissue microarray and cell lines. The role of ZNF281 in aggressiveness of HCC was examined using wound healing, matrigel transwell, pulmonary metastasis model and assays for expression of EMT markers. RNA-seq was used to find potential target gene of ZNF281. Chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (Co-IP) were employed to uncover the mechanism of the transcriptional regulation of ZNF281 on the target gene. Results: ZNF281 was increased in tumor tissues and positively correlated with vascular invasion in HCC. Knockdown of ZNF281 suppressed the migration and invasion with significant alteration of EMT marker expression in HLE and Huh7 HCC cell lines. RNA-seq screening showed that the tumor suppressor gene Annexin A10 (ANXA10) was a most up-regulated gene in response to ZNF281 depletion and responsible for the attenuation of aggressiveness. Mechanistically, ZNF281 interacted with the ANXA10 promoter region harboring ZNF281 recognition sites, and recruited components of nucleosome remodeling and deacetylation (NuRD) complex. By knocking down such components like HDAC1 or MTA1, ANXA10 was released from transcriptional repression by ZNF281/NuRD, and in turn reversed the EMT, invasion and metastasis driven by ZNF281. Conclusion: ZNF281 drives invasion and metastasis of HCC partially through transcriptional repression of tumor suppressor gene ANXA10 by recruiting NuRD complex.

Advances in holliday junction recognition protein (HJURP): Structure, molecular functions, and roles in cancer.

Oncogenes are increasingly recognized as important factors in the development and progression of cancer. Holliday Junction Recognition Protein (HJURP) is a highly specialized mitogenic protein that is a chaperone protein of histone H3. The HJURP gene is located on chromosome 2q37.1 and is involved in nucleosome composition in the mitotic region, forming a three-dimensional crystal structure with Centromere Protein A (CENP-A) and the histone 4 complex. HJURP is involved in the recruitment and assembly of centromere and kinetochore and plays a key role in stabilizing the chromosome structure of tumor cells, and its dysfunction may contribute to tumorigenesis. In the available studies HJURP is upregulated in a variety of cancer tissues and cancer cell lines and is involved in tumor proliferation, invasion, metastasis and immune response. In an in vivo model, overexpression of HJURP in most cancer cell lines promotes cell proliferation and invasiveness, reduces susceptibility to apoptosis, and promotes tumor growth. In addition, upregulation of HJURP was associated with poorer prognosis in a variety of cancers. These properties suggest that HJURP may be a possible target for the treatment of certain cancers. Various studies targeting HJURP as a prognostic and therapeutic target for cancer are gradually attracting interest and attention. This paper reviews the functional and molecular mechanisms of HJURP in a variety of tumor types with the aim of providing new targets for future cancer therapy.

MicroRNA-30e-3p reduces coronary microembolism-induced cardiomyocyte pyroptosis and inflammation by sequestering HDAC2 from the SMAD7 promoter.

This study investigates the mechanism by which microRNA (miR)-30e-3p reduces coronary microembolism (CME)-induced cardiomyocyte pyroptosis and inflammation. Cardiac function tests, histological staining, and transmission electron microscopy were performed on CME-model rats injected with adeno-associated viral vectors. Cardiomyocytes were transfected 24 h before a cellular model of pyroptosis was established via treatment with 1 µg/mL lipopolysaccharide (LPS) for 4 h and 5 mM ATP for 30 min. Pyroptosis, inflammation, and Wnt/ß-catenin signaling in cardiomyocytes were detected. Dual-luciferase reporter assays and/or RNA pull-down assays were performed to verify the binding of miR-30e-3p to HDAC2 mRNA or HDAC2 to the SMAD7 promoter. Chromatin immunoprecipitation was used to assess the level of H3K27 acetylation at the SMAD7 promoter. miR-30e-3p and SMAD7 expression levels were downregulated and HDAC2 expression was upregulated with CME. The overexpression of miR-30e-3p restored cardiac functions in CME-model rats and reduced serum cTnI, IL-18, and IL-1ß levels, microinfarcts, inflammatory cell infiltration, apoptosis, collagen content, and GSDMD-N, cleaved caspase-1, and NLRP3 expression in the myocardium, but these effects were reversed by SMAD7 knockdown. The overexpression of miR-30e-3p or knockdown of HDAC2 reduced LDH, IL-18, and IL-1ß secretion, propidium iodide intake, and GSDMD-N, NLRP3, cleaved caspase-1, Wnt3a, Wnt5a, and ß-catenin expression in the cardiomyocyte model. miR-30e-3p inhibited the expression of HDAC2 by binding HDAC2 mRNA. HDAC2 repressed the expression of SMAD7 by catalyzing H3K27 deacetylation at the SMAD7 promoter. miR-30e-3p, by binding HDAC2 to promote SMAD7 expression, reduces CME-induced cardiomyocyte pyroptosis and inflammation.

A novel clinical tool to predict cancer-specific survival in patients with primary pelvic sarcomas: A large population-based retrospective cohort study.

BACKGROUND: Primary osseous sarcoma of the pelvis is rare and has a particularly sinister outcome. This study aims to identify independent prognostic factors of cancer-specific survival (CSS) in patients with primary pelvic sarcoma (PS) and develop a nomogram to predict 3-, 5-, and 10-year probability of CSS in these patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 416 patients with primary PS, who were divided into two groups: a training cohort and a validation cohort. Univariate and multivariate Cox analyses were used to screen independent prognostic factors in patients with primary PS. Based on these independent prognostic factors, a prognostic nomogram was developed to predict 3-, 5-, and 10-year probability of CSS. The nomogram's predictive performance and clinical value were evaluated using the calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Finally, a mortality risk stratification system was developed. RESULTS: Tumor size, tumor stage, histological type, surgery, and chemotherapy were identified as independent prognostic factors for the CSS of primary PS patients. Based on these factors, a nomogram was created to predict the 3-, 5-, and 10-year probability of CSS in these patients. The calibration curve, ROC, and DCA indicated that the nomogram performed well and was appropriate for clinical use, with 3-, 5-, and 10-year areas under ROC curve all higher than 0.800. Furthermore, the nomogram-based mortality risk stratification system could effectively divide these patients into three risk subgroups. CONCLUSIONS: The nomogram constructed in this study could accurately predict 3-, 5-, and 10-year probability of CSS in patients with primary PS. Clinicians can use the nomogram to categorize these patients into risk subgroups and provide personalized treatment plans.