Dihydroartemisinin restores the immunogenicity and enhances the anticancer immunosurveillance of cisplatin by activating the PERK/eIF2α pathway.

BACKGROUND: Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice. METHODS: Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo. RESULTS: Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo. CONCLUSIONS: We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Sodium Tanshinone IIA Sulfonate alleviates vascular senescence in diabetic mice by modulating the A20-NFκB-NLRP3 inflammasome-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.

CDPK5 and CDPK13 play key roles in acclimation to low oxygen through the control of RBOH-mediated ROS production in rice.

CALCIUM-DEPENDENT PROTEIN KINASE (CDPK) stimulates reactive oxygen species (ROS)-dependent signaling by activating RESPIRATORY BURST OXIDASE HOMOLOG (RBOH). The lysigenous aerenchyma is a gas space created by cortical cell death that facilitates oxygen diffusion from the shoot to the root tips. Previously, we showed that RBOHH is indispensable for the induction of aerenchyma formation in rice (Oryza sativa) roots under low-oxygen conditions. Here, we showed that CDPK5 and CDPK13 localize to the plasma membrane where RBOHH functions. Mutation analysis of the serine at residues 92 and 107 of RBOHH revealed that these residues are required for CDPK5- and CDPK13-mediated activation of ROS production. The requirement of Ca2+ for CDPK5 and CDPK13 function was confirmed using in vitro kinase assays. CRISPR/Cas9-based mutagenesis of CDPK5 and/or CDPK13 revealed that the double knockout almost completely suppressed inducible aerenchyma formation, whereas the effects were limited in the single knockout of either CDPK5 or CDPK13. Interestingly, the double knockout almost suppressed the induction of adventitious root formation, which is widely conserved in vascular plants, under low-oxygen conditions. Our results suggest that CDPKs are essential for the acclimation of rice to low-oxygen conditions, and also for many other plant species conserving CDPK-targeted phosphorylation sites in RBOH homologues.

Mechanism of PTPN18 for regulating the migration and invasion of endometrial cancer cells via the MYC/PI3K/AKT pathway.

OBJECTIVE: Endometrial cancer (EC) is a prevalent gynecologic malignancy. The critical role of PTPN18 in EC has been reported, while its role in the aerobic glycolysis of EC cells remains unclear. Our current study focused on the mechanism of PTPN18 in the regulation of aerobic glycolysis in EC. METHODS: PTPN18 expression levels in endometrial stromal cells (KC02-44D) and EC cells (KLE, HEC-1-A, HEC-1B, and HEC-50) were determined. Following transfection of sh-PTPN18 in HEC-1-A cells, the changes in cell migratory and invasive abilities were assessed by the Transwell assay, and the changes in glucose consumption, lactic acid secretion, and ATP levels were detected using kits. The expression levels of glycolysis-related proteins HIF-1α, PKM2, and LDHA and the activation of the MYC/PI3K/AKT pathway were detected by Western blot. Additionally, sh-PTPN18 and pcDNA3.1-MYC were transfected into HEC-1-A cells to further explore their roles in the changes in aerobic glycolysis, migration, and invasion ability of EC cells. RESULTS: Expression of PTPN18 in EC cells was up-regulated (HEC-1-A>HEC-1B>HEC-50>KLE). PTPN18 knockdown suppressed EC cell migration and invasion. Additionally, PTPN18 knockdown reduced glucose consumption, lactate production, ATP levels, and glycolysis-related protein levels (HIF-1α, PKM2, LDHA). PTPN18 knockdown inhibited the activation of the MYC/PI3K/AKT pathway in EC cells. MYC overexpression partially annulled the inhibitory effects of PTPN18 knockdown on aerobic glycolysis, migration, and invasion of EC cells. CONCLUSION: Our present study provided evidence that the knockdown of PTPN18 inhibited the aerobic glycolysis, migration, and invasion of EC cells by suppressing the MYC/PI3K/AKT pathway.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Integrating spatial and single-cell transcriptomics reveals tumor heterogeneity and intercellular networks in colorectal cancer.

Single cell RNA sequencing (scRNA-seq), a powerful tool for studying the tumor microenvironment (TME), does not preserve/provide spatial information on tissue morphology and cellular interactions. To understand the crosstalk between diverse cellular components in proximity in the TME, we performed scRNA-seq coupled with spatial transcriptomic (ST) assay to profile 41,700 cells from three colorectal cancer (CRC) tumor-normal-blood pairs. Standalone scRNA-seq analyses revealed eight major cell populations, including B cells, T cells, Monocytes, NK cells, Epithelial cells, Fibroblasts, Mast cells, Endothelial cells. After the identification of malignant cells from epithelial cells, we observed seven subtypes of malignant cells that reflect heterogeneous status in tumor, including tumor_CAV1, tumor_ATF3_JUN | FOS, tumor_ZEB2, tumor_VIM, tumor_WSB1, tumor_LXN, and tumor_PGM1. By transferring the cellular annotations obtained by scRNA-seq to ST spots, we annotated four regions in a cryosection from CRC patients, including tumor, stroma, immune infiltration, and colon epithelium regions. Furthermore, we observed intensive intercellular interactions between stroma and tumor regions which were extremely proximal in the cryosection. In particular, one pair of ligands and receptors (C5AR1 and RPS19) was inferred to play key roles in the crosstalk of stroma and tumor regions. For the tumor region, a typical feature of TMSB4X-high expression was identified, which could be a potential marker of CRC. The stroma region was found to be characterized by VIM-high expression, suggesting it fostered a stromal niche in the TME. Collectively, single cell and spatial analysis in our study reveal the tumor heterogeneity and molecular interactions in CRC TME, which provides insights into the mechanisms underlying CRC progression and may contribute to the development of anticancer therapies targeting on non-tumor components, such as the extracellular matrix (ECM) in CRC. The typical genes we identified may facilitate to new molecular subtypes of CRC.

FGF21 overexpression alleviates VSMC senescence in diabetic mice by modulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-ß-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-ß-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.

The Combination of circEPSTI1 and MIF Offers Diagnostic Value for Endometrial Cancer.

Background: Circular RNAs (circRNAs) exhibit unique patterns of expression and high levels of stability in patient plasma samples such that they represent ideal non-invasive biomarkers that can be leveraged to detect a wide array of diseases including endometrial cancer (EC). This study was designed to identify circRNAs with potential diagnostic utility in serum samples from EC patients while also evaluating the utility of macrophage migration inhibitory factor (MIF) as a biomarker when screening for this form of cancer in the clinic. Methods: Levels of circEPSTI1 and MIF were assessed in the plasma of EC patients and healthy subjects (n=186 each) through qPCR and ELISAs. The diagnostic utility of these biomarkers was assessed with receiver operating characteristic curve (ROC) analyses. Results: Relative to healthy subjects, EC patient serum contained significantly elevated circEPSTI1 and MIF. An association was noted between circEPSTI1 expression in stages, histologic grade, and residual tumor. ROC curves confirmed that serum circEPSTI1 levels distinguished between controls and patients with EC with an Area of 0.835 and serum MIF levels distinguished between controls and patients with EC with an Area of 0.6646. When instead diagnosing patients based on the combination of MIF and circEPSTI1, the Area further rose to 0.8604. Conclusion: Assessing the combination of circEPSTI1 and MIF may be a viable approach to reliably diagnosing EC.

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells.

Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.

The effect of varicella-zoster virus reactivation on the long-term outcomes of patients undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND: A virus infection may lead the body to produce more immune cells of particular types or stimulate the production of new ones, both of which may have anti-leukemic effects. There has been no research on whether immune cells stimulated by varicella-zoster virus (VZV) infection have anti-leukemic effects. The objective of this investigation is to assess the impact of VZV infection on patients' long-term survival following allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: This retrospective study investigated the association between varicella-zoster virus (VZV) reactivation and outcomes in 219 individuals who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the Sun Yat-sen University's First Affiliated Hospital. According to being diagnosed with VZV infection or not, these patients were grouped into two groups. The comparison of cumulative incidence of relapse, non-recurrent mortality, and overall survival (OS) was conducted between the two groups. RESULTS: Analyzing multivariate data, VZV reactivation was linked to lower relapse incidence in the group containing all individuals (hazard ratio [HR] = 0.27; 95% confidence interval [CI], 0.12-0.64), patients suffering from acute myeloid leukaemia (HR = 0.10; 95% CI, 0.01-0.83), and patients suffering from acute lymphoblastic leukaemia (HR = 0.25; 95% CI, 0.08-0.77). Moreover, VZV reactivation was linked with decreased non-relapse mortality in all individuals (HR = 0.20; 95% CI, 0.05-0.79), but no statistical significance was found for any disease subgroup. Further, VZV reactivation was an independent predictor for improved OS in the group containing all individuals (HR = 0.10; 95% CI, 0.03-0.29), patients suffering from acute myeloid leukaemia (HR = 0.09; 95% CI, 0.01-0.66), and patients suffering from acute lymphoblastic leukaemia (HR = 0.16; 95% CI, 0.04-0.68). CONCLUSION: This is the first study to show that VZV reactivation following allo-HSCT is an independent predictor for lower relapse rates and improved OS, providing novel therapeutic approaches to improve patients' long-term survival following allo-HSCT.

Isorhapontigenin (ISO) inhibits malignant cell transformation, migration, and invasion through MEG3/NEDD9 signaling in Cr(VI)-transformed cells.

Cr(VI) compounds are confirmed human carcinogens. Maternally expression 3 (MEG3) is the first long non-coding RNA to be identified as a tumor suppressor. MEG3 is frequently downregulated or lost in various primary human tumor tissues and cancer cell lines. Downregulation of MEG3 is associated with cancer initiation, progression, and metastasis. Our previous study has revealed that MEG3 was lost and NEDD9 was upregulated in Cr(VI)-transformed cells compared to those in passage-matched normal BEAS-2B cells. Overexpression of MEG3 reduced NEDD9. ß-Catenin was activated in Cr(VI)-transformed cells, overexpression of MEG3 or knockdown of NEDD9 inhibited the activation of ß-Catenin. The results from the present study showed that isorhapontigenin (ISO) treatment is able to suppress cell proliferation, migration, and invasion of Cr(VI)-transformed cells. Further study showed that ISO treatment in Cr(VI)-transformed cells decreases the levels of Ki67, a biomarker for cell proliferation, and of cyclin D1, a regulator for the cell cycle. ISO elevated the MEG3 expression level in Cr(VI)-transformed cells. The DNA methylation transferases DNMT3a, DNMT3b, and DNMT1 levels were reduced upon ISO treatment. ISO treatment decreased both mRNA and protein levels of NEDD9. In addition, ISO treatment reduced the activation of ß-catenin. Slug was upregulated and E-Cadherin was downregulated in Cr(VI)-transformed cells, treatment with ISO decreased Slug and increased E-Cadherin. This study demonstrated that ISO is a potent therapeutical agent against lung cancer induced by Cr(VI).

Loss of MEG3 contributes to the enhanced migration and invasion in arsenic-induced carcinogenesis through NQO1/FSCN1 pathway.

Arsenic ranks at the top among all toxic metals and poses a serious threat to human health. Inorganic arsenite and arsenate compounds have been classified as human carcinogens in various types of cancers. Maternally expressed gene 3 (MEG3), a tumor suppressor that is commonly lost in cancer, was investigated in this study for its role in the migration and invasion of arsenic-transformed cells. Our results showed that MEG3 was downregulated in both arsenic-transformed cells (As-T) and cells treated with low doses of arsenic for three months (As-treated). The analysis using TCGA dataset revealed that MEG3 expression was significantly reduced in the tumor tissues from human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) compared to normal lung tissues. The results from the methylation-specific PCR (MSP) assay demonstrated enhanced methylation in the MEG3 promoters in both As-T and As-treated cells, indicating that increased methylation of the MEG3 promoter caused MEG3 downregulation in these cells. Moreover, As-T cells displayed increased migration and invasion and higher levels of NAD(P)H quinone dehydrogenase 1 (NQO1) and fascin actin-bundling protein 1 (FSCN1). Consistently, the results from immunohistochemistry staining showed that both NQO1 and FSCN1 are highly expressed in human lung squamous cell carcinoma tissues compared to those in normal lungs. Knockdown of MEG3 in normal BEAS-2B cells also led to increased migration and invasion, along with elevated levels of NQO1 and FSCN1. The negative regulation of MEG3 on FSCN1 was restored by NQO1 overexpression in both As-T and BEAS-2B cells. The results from immunoprecipitation assays confirmed the direct binding of NQO1 to FSCN1. Overexpression of NQO1 increased migration and invasion abilities in BEAS-2B cells, while knockdown of NQO1 by its shRNA reduced these two hallmarks of cancer. Interestingly, the reduced migration and invasion by NQO1 knockdown were restored by FSCN1. Collectively, the loss of MEG3 upregulated NQO1, which in turn stabilized FSCN1 protein through its direct binding, resulting in elevated migration and invasion in arsenic-transformed cells.

GPR Clutter Removal Based on Weighted Nuclear Norm Minimization for Nonparallel Cases.

Ground-penetrating radar (GPR) is an effective geophysical electromagnetic method for underground target detection. However, the target response is usually overwhelmed by strong clutter, thus damaging the detection performance. To account for the nonparallel case of the antennas and the ground surface, a novel GPR clutter-removal method based on weighted nuclear norm minimization (WNNM) is proposed, which decomposes the B-scan image into a low-rank clutter matrix and a sparse target matrix by using a non-convex weighted nuclear norm and assigning different weights to different singular values. The WNNM method's performance is evaluated using both numerical simulations and experiments with real GPR systems. Comparative analysis with the commonly used state-of-the-art clutter removal methods is also conducted in terms of the peak signal-to-noise ratio (PSNR) and the improvement factor (IF). The visualization and quantitative results demonstrate that the proposed method outperforms the others in the nonparallel case. Moreover, it is about five times faster than the RPCA, which is beneficial for practical applications.

IGFBP­rP1 affects the proliferation, apoptosis and macrophage polarization of endometrial cancer cells by regulating the PI3K/AKT pathway.

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor suppressor gene in a variety of cancers including colorectal cancer and breast cancer. However, its role and the potential mechanism in endometrial carcinoma (EC) are still unclear. The purpose of this study was to explore the effect of IGFBP-rP1 on EC cell proliferation and apoptosis and its underlying mechanism. Western blot analysis and reverse transcription-quantitative PCR were used to assess protein and gene expression levels of IGFBP-rP1 in EC cells. Overexpression of IGFBP-rP1 and/or AKT serine/threonine kinase was used to analyze their effects on cell proliferation and apoptosis of the EC cells. Co-immunoprecipitation and glutathione S transferase pull-down assays were used to analyze the interaction between IGFBP-rP1 and AKT. The expression of IGFBP-rP1 in EC cells was downregulated. Overexpression of IGFBP-rP1 inhibited the proliferation and induced apoptosis of EC cells, which were abolished by the overexpression of AKT. In addition, IGFBP-rP1 directly interacted with AKT to inhibit PI3K/AKT signaling. Additionally, M0 macrophages were induced by EC cells to differentiate into M2 macrophages, which was reversed by IGFBP-rP1. Overexpression of AKT in EC cells abolished the inhibitory effect of IGFBP-rP1 on M2 polarization. IGFBP-rP1 as an oncogenic factor inhibits M2 polarization of TAMs through PI3K/AKT signaling pathway and may be a potentially valuable target for EC therapy.

Effects of escitalopram oxalate plus low-dose trazodone on psychological state and quality of life in patients with treatment-refractory depression.

OBJECTIVE: To analyze the effect of escitalopram oxalate (ESC) plus low-dose (LD) trazodone (TRA) on the psychological state and quality of life (QOL) of patients with treatment-refractory depression (TRD). METHODS: In this retrospective study, we selected 111 TRD patients treated in the People's Hospital of Oedos Dongsheng District between February 2019 and February 2021; 54 patients who were treated with ESC were assigned to the control group (the Con) and the remaining 57 patients treated with ESC + LD-TRA were placed into the research group (the Res). The scores of Hamilton Anxiety/Depression Scale (HAMA, HAMD), Generic Quality of Life Inventory (GQOLI), Pittsburgh Sleep Quality Index Scale (PSQI), and Treatment Emergent Signs and Symptoms (TESS), as well as the levels of brain-derived neurotrophic factor (BDNF), S-100B protein (S-100B), and neuron-specific enolase (NSE) were determined before and after intervention. Besides, the curative effect and incidence of adverse reactions were compared. Furthermore, the risk factors affecting treatment ineffectiveness in TRD patients were analyzed by the multivariate Logistic model. RESULTS: Evident reductions were observed in the Res in terms of HAMA, HAMD and PSQI scores and S-100B and NSE levels after intervention. Eight weeks after intervention, the TESS score was significantly reduced in the Res but not significantly different from the Con; while the scores of various dimensions of the GQOIL and the BDNF level were elevated markedly in the Res that were higher than those of the Con. Moreover, the Res presented with an evidently higher overall response rate than the Con. The two groups had no statistical significance in the overall incidence of adverse reactions (fever, irritability, insomnia, nausea, etc.). Based on the multivariate Logistic model analysis, HAMA, HAMD, PSQI, TESS, BDNF, S-100B, NSE, and treatment modality were not independent risk factors for treatment ineffectiveness in TRD patients. CONCLUSIONS: ESC + LD-TRA can significantly improve the psychological status, QOL, sleep quality and neurological function of patients with TRD while improving efficacy and ensuring patient safety.

Correction: Zhu et al. A Feedback Loop Formed by ATG7/Autophagy, FOXO3a/miR-145 and PD-L1 Regulates Stem-like Properties and Invasion in Human Bladder Cancer. Cancers 2019, 11, 349.

In the original article [...].

Long Non-Coding RNA MEG3 in Metal Carcinogenesis.

Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.

Advances in Sorptive Removal of Hexavalent Chromium (Cr(VI)) in Aqueous Solutions Using Polymeric Materials.

Sorptive removal of hexavalent chromium (Cr(VI)) bears the advantages of simple operation and easy construction. Customized polymeric materials are the attracting adsorbents due to their selectivity, chemical and mechanical stabilities. The mostly investigated polymeric materials for removing Cr(VI) were reviewed in this work. Assembling of robust functional groups, reduction of self-aggregation, and enhancement of stability and mechanical strength, were the general strategies to improve the performance of polymeric adsorbents. The maximum adsorption capacities of these polymers toward Cr(VI) fitted by Langmuir isotherm model ranged from 3.2 to 1185 mg/g. Mechanisms of complexation, chelation, reduction, electrostatic attraction, anion exchange, and hydrogen bonding were involved in the Cr(VI) removal. Influence factors on Cr(VI) removal were itemized. Polymeric adsorbents performed much better in the strong acidic pH range (e.g., pH 2.0) and at higher initial Cr(VI) concentrations. The adsorption of Cr(VI) was an endothermic reaction, and higher reaction temperature favored more robust adsorption. Anions inhibited the removal of Cr(VI) through competitive adsorption, while that was barely affected by cations. Factors that affected the regeneration of these adsorbents were summarized. To realize the goal of industrial application and environmental protection, removal of the Cr(VI) accompanied by its detoxication through reduction is highly encouraged. Moreover, development of adsorbents with strong regeneration ability and low cost, which are robust for removing Cr(VI) at trace levels and a wider pH range, should also be an eternally immutable subject in the future. Work done will be helpful for developing more robust polymeric adsorbents and for promoting the treatment of Cr(VI)-containing wastewater.

DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells.

The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3'-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients.