Cholesteryl ester transfer protein knock-down in conjunction with a cholesterol-depleting agent decreases tamoxifen resistance in breast cancer cells.

The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock-down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor-positive' (ER+; Michigan Cancer Foundation-7 (MCF7) breast cancer cells) and 'triple-negative' breast cancer (TNBC; MDA-MB-231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 µM) and acetyl plumbagin (a cholesterol-depleting agent) (5 µM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT2 Profiler PCR array (Qiagen, Germany)-based gene expression analysis revealed an overall downregulation of genes associated in cholesterol biosynthesis, lipid signalling and drug resistance in MCF7 cells post-CETP knock-down. On the contrary, resistance in MDA-MB-231 cells was reduced through increased expression in cholesterol efflux genes and the expression of targetable surface receptors by endocrine therapy. The pilot xenograft mice study substantiated CETP's role as a cancer survival gene as knock-down of CETP stunted the growth of TNBC tumour by 86%. The principal findings of this study potentiate CETP as a driver in breast cancer growth and aggressiveness and thus targeting CETP could limit drug resistance via the reduction in cholesterol accumulation in breast cancer cells, thereby reducing cancer aggressiveness.

Advances in systemic immune inflammatory indices in non-small cell lung cancer: A review.

Lung cancer is one of the most prevalent cancers globally, with non-small cell lung cancers constituting the majority. These cancers have a high incidence and mortality rate. In recent years, a growing body of research has demonstrated the intricate link between inflammation and cancer, highlighting that inflammation and cancer are inextricably linked and that inflammation plays a pivotal role in cancer development, progression, and prognosis of cancer. The Systemic Immunoinflammatory Index (SII), comprising neutrophil, lymphocyte, and platelet counts, is a more comprehensive indicator of the host's systemic inflammation and immune status than a single inflammatory index. It is widely used in clinical practice due to its cost-effectiveness, simplicity, noninvasiveness, and ease of acquisition. This paper reviews the impact of SII on the development, progression, and prognosis of non-small cell lung cancer.

The role of tumor parenchyma and brain cortex signal intensity ratio in differentiating solitary fibrous tumors and meningiomas.

BACKGROUND: Solitary fibrous tumors (SFT) and meningiomas (MA) have similar clinical and radiographic presentations but require different treatment approaches and have different prognoses. This emphasizes the importance of a correct preoperative diagnosis of SFT versus MA. OBJECTIVE: In this study, investigated the differences in imaging characteristics between SFT and MA to improve the accuracy of preoperative imaging diagnosis of SFT. METHODS: The clinical and imaging data of 26 patients with SFT and 104 patients with MA who were pathologically diagnosed between August 2017 and December 2022, were retrospectively analyzed. The clinical and imaging differences between SFT and MA, as well as between the various pathological grades of SFT, were analyzed. RESULTS: Age, gender, cystic change, flow void phenomenon, yin-yang sign, lobulation, narrow base, tumor/cortex signal ratio (TCSR) > 1.0 in T1-weighted imaging (T1WI), TCSR ≥ 1.1 in T2-weighted imaging (T2WI), peritumoral edema, and absence of dural tail sign varied between SFT and MA. As per the receiver operating characteristic (ROC) curve analysis, TCSR > 1 in T1WI has the maximum diagnostic accuracy for SFT. Cranial or venous sinus invasion had a positive effect on SFT (Grade III, World Health Organization (WHO) grading). CONCLUSION: Among the many radiological and clinical distinctions between SFT and MA, TCSR ≥ 1 exhibits the highest predictive efficacy for SFT; while cranial or venous sinus invasion may be a predictor of WHO grade III SFT.

Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer.

Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces immune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients. PUM1 positively regulates PD-L1 expression and PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1. PUM1 inhibits the anti-tumor activity of T cells through the PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy.

Imaging and pathological characteristics, treatment, and prognosis of pulmonary sequestration-A retrospective study of 13 cases.

OBJECTIVE: This study aimed to summarize and analyze the characteristics of pulmonary sequestration to improve our understanding of this disease. METHODS: Between January 2019 and April 2023, the clinical data of 13 patients with pulmonary sequestration underwent surgical treatment at the First Affiliated Hospital of Gannan Medical University. RESULTS: The male-to-female ratio was 4:9, the age was 0.5 to 60 years, and the average age was 38 ± 19 years. There were 10 and 3 cases of intralobar and extralobar pulmonary sequestration, respectively. Chest enhanced computed tomography (CT) and three-dimensional vascular reconstruction showed that the abnormal blood vessels were derived from the descending thoracic aorta in nine cases and from other blood vessels in four cases. Three patients underwent thoracoscopic lobectomy, two underwent thoracoscopic segmentectomy, and eight underwent thoracoscopic wedge resection. All the patients successfully completed the surgery and were discharged postoperatively. CONCLUSIONS: Some patients with pulmonary sequestration exhibit no obvious symptoms. Patients with clinical symptoms are easily confused for pneumonia, bronchial cysts, lung abscesses, and lung tumors; therefore, patients with pulmonary sequestration are prone to missed diagnosis and misdiagnosis. Currently, enhanced chest CT combined with three-dimensional vascular reconstruction can accurately show the course, branches, and relationship with the mass of the feeding artery. Routine pathological examination is helpful to further clarify the diagnosis of pulmonary sequestration. Minimally invasive thoracoscopic surgery is the preferred treatment for patients with pulmonary sequestration. Surgical resection is safe and feasible, and satisfactory results are typically obtained.

PUM1 Promotes Tumor Progression by Activating DEPTOR-Meditated Glycolysis in Gastric Cancer.

RNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.

Interplay between the renin angiotensin system and oxidative stress contributes to alcohol addiction by stimulating dopamine accumulation in the mesolimbic pathway.

The brain renin-angiotensin system (RAS) has recently been implicated in the development of substance abuse and addiction. However, the integrative roles of the two counter-regulating RAS arms, including the ACE1/Ang II/AT1R axis and the ACE2/Ang(1-7)/MasR axis, in alcohol addiction remain unclear. Using the 20% ethanol intermittent-access two-bottle-choice (IA2BC) paradigm, we observed significant alcohol preference and addictive behaviors in rats. Additionally, we observed significant disruption in the RAS and redox homeostasis in the ventral tegmental area (VTA), as indicated by upregulation of ACE1 activities, Ang II levels, AT1R expression, and glutathione disulfide contents, as well as downregulation of ACE2 activities, Ang(1-7) levels, MasR expression and glutathione content. Moreover, dopamine accumulated in the VTA and nucleus accumbens of IA2BC rats. Intra-VTA infusion of the antioxidant tempol substantially attenuated RAS imbalance and addictive behaviors. Intra-VTA infusion of the ACE1 inhibitor captopril significantly reduced oxidative stress, alcohol preference, addictive behaviors, and dopamine accumulation, whereas intra-VTA infusion of the ACE2 inhibitor MLN4760 had the opposite effects. The anti-addictive effects of the ACE2/Ang(1-7)/MasR axis were further observed using intra-VTA infusion of Ang(1-7) and a MasR-specific antagonist A779. Therefore, our findings suggest that excessive alcohol intake causes RAS imbalance via oxidative stress, and that a dysregulated RAS in the VTA contributes to alcohol addiction by stimulating oxidative stress and dopaminergic neurotransmission. Breaking the vicious cycle of RAS imbalance and oxidative stress using brain-permeable antioxidants, ACE1 inhibitors, ACE2 activators, or Ang(1-7) mimetics thus represents a promising strategy for combating alcohol addiction.

Discovery of therapeutic targets of quercetin for endometrial carcinoma patients infected with COVID-19 through network pharmacology.

Purpose: Aimed to identify the anti-uterine corpus endometrial carcinoma (UCEC) function and characterize the mechanism of quercetin in the treatment of patients infected with COVID-19 via integrated in silico analysis. Methods: The Cancer Genome Atlas and Genotype Tissue Expression databases were applied to obtain differentially expressed genes of UCEC and non-tumor tissue. Several in silico methods such as network pharmacology, functional enrichment analysis, Cox regression analyses, somatic mutation analysis, immune infiltration and molecular docking were used to investigate and analysis the biological targets, functions and mechanisms of anti-UCEC/COVID-19 of quercetin. Multiple methods such as CCK8 assay, Transwell assay and western blotting were performed to test proliferation, migration, and protein level of UCEC (HEC-1 and Ishikawa) cells. Results: Functional analysis disclosed that quercetin against UCEC/COVID-19 mainly by 'biological regulation', 'response to stimulus', and 'regulation of cellular process'. Then, regression analyses indicated that 9 prognostic genes (including ANPEP, OAS1, SCGB1A1, HLA-A, NPPB, FGB, CCL2, TLR4, and SERPINE1) might play important roles in quercetin for treating UCEC/COVID-19. Molecular docking analysis revealed that the protein products of 9 prognostic genes were the important anti-UCEC/COVID-19 biological targets of quercetin. Meanwhile, the proliferation and migration of UCEC cells were inhibited by quercetin. Moreover, after treatment with quercetin, the protein level of ubiquitination-related gene ISG15 was decreased in UCEC cells in vitro. Conclusions: Taken together, this study provides new treatment option for UCEC patients infected with COVID-19. Quercetin may work by reducing the expression of ISG15 and participating in ubiquitination-related pathways.

APOC1 predicts a worse prognosis for esophageal squamous cell carcinoma and is associated with tumor immune infiltration during tumorigenesis.

Background: Esophageal carcinoma (ESCA), a common malignant tumor of the digestive tract with insidious onset, is a serious threat to human health. Despite multiple treatment modalities for patients with ESCA, the overall prognosis remains poor. Apolipoprotein C1 (APOC1) is involved in tumorigenesis as an inflammation-related molecule, and its role in esophageal cancer is still unknown. Methods: We downloaded documents and clinical data using The Cancer Genome Atlas (TCGA)and Gene Expression Omnibus (GEO) databases. We also conducted bioinformatics studies on the diagnostic value, prognostic value, and correlation between APOC1 and immune infiltrating cells in ESCA through STRING (https://cn.string-db.org/), the TISIDB (http://cis.hku.hk/TISIDB/) website, and various other analysis tools. Results: In patients with ESCA, APOC1 was significantly more highly expressed in tumor tissues than in normal tissues (p < 0.001). APOC1 could diagnose ESCA more accurately and determine the TNM stage and disease classification with high accuracy (area under the curve, AUC≥0.807). The results of the Kaplan-Meier curve analysis showed that APOC1 has prognostic value for esophageal squamous carcinoma (ESCC) (p = 0.043). Univariate analysis showed that high APOC1 expression in ESCC was significantly associated with worse overall survival (OS) (p = 0.043), and multivariate analysis shows that high APOC1 expression was an independent risk factor for the OS of patients with ESCC (p = 0.030). In addition, the GO (gene ontology)/KEGG (Kyoto encyclopedia of genes and genomes) analysis showed a concentration of gene enrichment in the regulation of T-cell activation, cornification, cytolysis, external side of the plasma membrane, MHC protein complex, MHC class II protein complex, serine-type peptidase activity, serine-type endopeptidase activity, Staphylococcus aureus infection, antigen processing and presentation, and graft-versus-host disease (all p < 0.001). GSEA (gene set enrichment analysis) showed that enrichment pathways such as immunoregulatory-interactions between a lymphoid and non-lymphoid cell (NES = 1.493, p. adj = 0.023, FDR = 0.017) and FCERI-mediated NF-KB activation (NES = 1.437, p. adj = 0.023, FDR = 0.017) were significantly enriched in APOC1-related phenotypes. In addition, APOC1 was significantly associated with tumor immune infiltrating cells and immune chemokines. Conclusion: APOC1 can be used as a prognostic biomarker for esophageal cancer. Furthermore, as a novel prognostic marker for patients with ESCC, it may have potential value for further investigation regarding the diagnosis and treatment of this group of patients.

The role of USP51 in attenuating chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response.

Lung cancer is the most frequent type of cancer affecting both men and women globally, and it is associated with a high mortality rate. It is clinically treated with cisplatin, a platinum-based drug that works by generating DNA lesions, which activates DNA damage response and induces cell death. However, chemoresistance by cancer cells limits the clinical usefulness of cisplatin as an anticancer drug. Here, we uncovered a role of ubiquitin-specific protease 51 (USP51) in the chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response. USP51 was more upregulated in lung cancer tissues of chemotherapy-resistant patients than those of chemotherapy-sensitive patients with adjacent, nontumor tissues. USP51 overexpression in lung cancer cells in vitro reduced γ-H2AX formation and promoted checkpoint kinase 1 (CHK1) phosphorylation, whereas USP51 knockdown showed opposite effects, indicating that USP51 played an important role in promoting DNA damage repair. Finally, USP51 knockdown weakened cisplatin resistance in A549/DDP cells and significantly suppressed tumor growth in vivo, suggesting that a USP51 inhibitor combined with cisplatin may be considered as an effective treatment strategy to eliminate drug-resistant lung cancer cells.

5-Methylcytosine (m5C) modification in peripheral blood immune cells is a novel non-invasive biomarker for colorectal cancer diagnosis.

Current non-invasive tumor biomarkers failed to accurately identify patients with colorectal cancer (CRC), delaying CRC diagnosis and thus leading to poor prognosis. Dysregulation of 5-Methylcytosine (m5C) RNA has gradually been reported in various cancers, but their role in tumor diagnosis is rarely mentioned. Our study aimed to determine the role of m5C methylation modification in blood immune cells for the diagnosis of CRC. Peripheral blood samples were obtained from a total of 83 healthy controls and 196 CRC patients. We observed that m5C RNA contents in blood immune cells of CRC patients were markedly enhanced in both training set and validation set. Moreover, levels of m5C increased with CRC progression and metastasis but reduced after treatment. Compared with common blood tumor biomarkers, m5C levels in peripheral blood immune cells had superior discrimination and reclassification performance in diagnosing CRC. Besides, bioinformatics and qRT-PCR analysis identified increased expression of m5C-modified regulators NSUN5 and YBX1 in CRC patients' blood. A series of animal models and cell co-culture models further demonstrated that CRC tumor cells could increase immune cells' m5C levels and m5C-modified regulators. Monocyte was the predominant m5C-modified immune cell type in CRC patients' blood by Gene set variation analysis (GSVA). Taken together, m5C methylation modification in peripheral blood immune cells was a promising biomarker for non-invasive diagnosis of CRC.

Transcription factor Nrf2 binds to circRNAPIBF1 to regulate SOD2 in lung adenocarcinoma progression.

Emerging evidence indicates that circular RNAs (circRNAs) play important roles in disease development, especially in cancers. Analysis of circRNA expression microarrays from the Gene Expression Omnibus database revealed that circPIBF1 was highly upregulated in lung adenocarcinoma (LUAD). The main aim of this study was to probe the function of circPIBF1 in pyroptosis of LUAD cells and the signal transduction pathways involved. CircPIBF1 was significantly overexpressed in LUAD and was related to the dismal prognosis of patients with LUAD. CircPIBF1 could bind to nuclear factor erythroid 2-related factor 2 (Nrf2), which further promoted the expression of superoxide dismutase 2 (SOD2). In addition, Nrf2 was also observed to recruit histone acetyltransferase E1A binding protein p300 (EP300) to enhance H3K27ac modification of SOD2, thus modulating the Nrf2-Keap1 signaling pathway. Moreover, we found that knockdown of circPIBF1 significantly suppressed the expression of SOD2 in cells and LUAD cell growth, while enhanced the expression of pyroptosis-related factors, which were further reversed by overexpression of SOD2 or EP300. Collectively, our findings suggest a direct involvement of circPIBF1 in pyroptosis-related LUAD carcinogenesis and implicate a role of Nrf2/EP300/SOD2 signaling in this process.

CircFBXW7 Inhibits Proliferation, Migration, and Invasion of Nonsmall Cell Lung Cancer Cells by Regulating miR-492.

Background: CircFBXW7 has been determined to be involved in various cancers; however, its role in nonsmall cell lung cancer (NSCLC) remains unclear. This study examined the function and potential mechanism of circFBXW7 in NSCLC. Methods: The structure of circFBXW7 was verified via RT-PCR and Sanger sequencing. The expression of circFBXW7 in NSCLC was determined by qRT-PCR. The effect of circFBXW7 overexpression on the proliferation, migration, and invasion of NSCLC cells was examined by CCK-8 and Transwell assays. Furthermore, a circFBXW7-miRNA network was established to explore their interaction. Predicted miRNA was determined by qRT-PCR. Moreover, the miRNA mimics were synthesized, wherein its effect on proliferation, migration, and invasion of NSCLC cells overexpressed circFBXW7 was assessed. Results: The circularity of circFBXW7 was verified. The expression of circFBXW7 was found to be downregulated in NSCLC cells compared with that in normal human lung epithelial BEAS-2B cells. Overexpression of circFBXW7 reduced cell proliferation, migration, and invasion. Furthermore, according to the circFBXW7-miRNA network prediction and qRT-PCR validation, miR-492 was identified to be the target of circFBXW7. The inhibitory effect of circFBXW7 overexpression on cell proliferation, migration, and invasion was reversed by miR-492 mimics. Conclusion: CircFBXW7 is downregulated in NSCLC. CircFBXW7 inhibits NSCLC cells proliferation, migration, and invasion by regulating miR-492.

miR-181a-5p restrains non-small cell lung cancer cell invasion and migration by regulating the GTSE1/p53/NF-κB axis.

microRNAs (miRNAs) are relevant to metastasis and invasion of non-small cell lung cancer (NSCLC). This study investigated the role of miR-181a-5p in lung cancer. Expression patterns of miR-181a-5p and GTSE1 in the human NSCLC cell line A549 and normal lung epithelial cell line BASE-2B were detected. miR-181a-5p mimic was delivered into A549 cells utilizing Lipofectamine 2000 to overexpress miR-181a-5p, followed by analysis of cell viability, proliferation, apoptosis, invasion, and migration. GTSE1 (G2 and S phase-expressed-1) was predicted as the downstream target gene of miR-181a-5p using bioinformatics analysis software. Targeting relationship between miR-181a-5p and GTSE1 was validated via dual-luciferase assay, RIP assay, and RNA pull-down. Activation of the p53/NF-κB pathway was determined. miR-181a-5p was weakly-expressed in NSCLC cells relative to normal lung epithelial cells. miR-181a-5p overexpression prevented NSCLC cell proliferation, migration, and invasion. Mechanically, miR-181a-5p targeted GTSE1. GTSE1 overexpression partly annulled repression of miR-181a-5p overexpression on NSCLC cell malignant behavior. miR-181a-5p activated the p53 pathway and inhibited the NF-κB pathway by targeting GTSE1. Overall, this study for the first time validated that miR-181a-5p impeded NSCLC cell invasion and migration through activation of the p53 pathway and inhibition of the NF-κB pathway by targeting GTSE1, which may provide a potential novel insight into NSCLC treatment.

Computed tomography-based radiomic analysis for prediction of treatment response to salvage chemoradiotherapy for locoregional lymph node recurrence after curative esophagectomy.

OBJECTIVE: To investigate the capability of computed tomography (CT) radiomic features to predict the therapeutic response and local control of the locoregional recurrence lymph node (LN) after curative esophagectomy by chemoradiotherapy. METHODS: This retrospective study included 129 LN from 77 patients (training cohort: 102 LN from 59 patients; validation cohort: 27 LN from 18 patients) with postoperative esophageal squamous cell carcinoma (ESCC). The region of the tumor was contoured in pretreatment contrast-enhanced CT images. The least absolute shrinkage and selection operator with logistic regression was used to identify radiomic predictors in the training cohort. Model performance was evaluated using the area under the receiver operating characteristic curves (AUC). The Kaplan-Meier method was used to determine the local recurrence time of cancer. RESULTS: The radiomic model suggested seven features that could be used to predict treatment response. The AUCs in training and validated cohorts were 0.777 (95% CI: 0.667-0.878) and 0.765 (95% CI: 0.556-0.975), respectively. A significant difference in the radiomic scores (Rad-scores) between response and nonresponse was observed in the two cohorts (p < 0.001, 0.034, respectively). Two features were identified for classifying whether there will be relapse in 2 years. AUC was 0.857 (95% CI: 0.780-0.935) in the training cohort. The local control time of the high Rad-score group was higher than the low group in both cohorts (p < 0.001 and 0.025, respectively). As inferred from the Cox regression analysis, the low Rad-score was a high-risk factor for local recurrence within 2 years. CONCLUSIONS: The radiomic approach can be used as a potential imaging biomarker to predict treatment response and local control of recurrence LN in ESCC patients.

Clinical Outcomes and Prognostic Factors of Salvage Treatment for Local Lymph Node Recurrence After Radical Resection of Oesophageal Carcinoma.

BACKGROUND: There are no standard therapeutic strategies for local lymph node (LN) recurrence after radical resection of oesophageal squamous cell carcinoma (ESCC), and prognostic risk factors remain controversial. We assessed clinical outcomes and prognostic factors of chemoradiotherapy (CRT) or radiotherapy (RT) for LN recurrence of ESCC after curative resection. METHODS: A total of 117 ESCC patients with LN recurrence after radical resection receiving salvage treatment at our hospital were retrospectively reviewed from 2014 to 2017. Overall survival (OS) was estimated using the Kaplan-Meier method; clinical characteristics were assessed using the Log rank test in the univariate analysis. Multivariate prognostic analysis was performed using the Cox proportional hazard model. RESULTS: With a median follow-up of 19 months, the 1-, 2- and 3-year OS rates were 75.2%, 40.2% and 27.4%, respectively. The median survival time (MST) was 19.0 months. On univariate analysis for OS, pathological TNM stage, number of LN metastasis, LN maximum (Max) diameter, salvage treatment mode and tumor response were significantly associated with OS (P = 0.0074, P = 0.015, P = 0.0011, P = 0.028, P < 0.000, respectively). On multivariate analysis, tumor response [Response vs No-response hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.53-3.90, P < 0.000] and LN Max diameter (≤28 mm vs >28 mm HR, 2.07; 95% CI, 1.33-3.32, P = 0.012) were independent prognostic factors. CONCLUSION: Salvage CRT or RT was safe and effective for treating LN recurrence after radical resection in ESCC. Patients with the small LN Max diameter (≤28 mm) and obtained response after salvage therapy appeared to achieve long-term OS.

Radiomics Analysis of Contrast-Enhanced CT for Hepatocellular Carcinoma Grading.

OBJECTIVES: To investigate the value of contrast-enhanced computer tomography (CT)-based on radiomics in discriminating high-grade and low-grade hepatocellular carcinoma (HCC) before surgery. METHODS: The retrospective study including 161 consecutive subjects with HCC which was approved by the institutional review board, and the patients were divided into a training group (n = 112) and test group (n = 49) from January 2013 to January 2018. The least absolute shrinkage and selection operator (LASSO) was used to select the most valuable features to build a support vector machine (SVM) model. The performance of the predictive model was evaluated using the area under the curve (AUC), accuracy, sensitivity, and specificity. RESULTS: The SVM model showed an acceptable ability to differentiate high-grade from low-grade HCC, with an AUC of 0.904 in the training dataset and 0.937 in the test dataset, accuracy (92.2% versus 95.7%), sensitivity(82.5% versus 88.0%), and specificity (92.7% versus 95.8%), respectively. CONCLUSION: The machine learning-based radiomics reflects a better evaluating performance in differentiating HCC between low-grade and high-grade, which may contribute to personalized treatment.

Genipin Attenuates Tau Phosphorylation and Aß Levels in Cellular Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aß) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aß generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3ß, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aß production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aß generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.

miR-666-3p Mediates the Protective Effects of Mesenchymal Stem Cell-derived Exosomes Against Oxygen-glucose Deprivation and Reoxygenation- induced Cell Injury in Brain Microvascular Endothelial Cells via Mitogen-activated Protein Kinase Pathway.

BACKGROUND: Previous studies have reported that mesenchymal stem cell (MSC)- derived exosomes can protect primary rat brain microvascular endothelial cells (BMECs) against oxygen-glucose deprivation and reoxygenation (OGD/R)-induced injury. OBJECTIVE: The aim was to identify the key factors mediating the protective effects of MSC-derived exosomes. METHODS: Primary rat BMECs were either pretreated or not pretreated with MSC-derived exosomes before exposure to OGD/R. Naïve cells were used as a control. After performing small RNA deep sequencing, quantitative reverse transcription polymerase chain reaction was performed to validate microRNA (miRNA) expression. The effects of rno-miR-666-3p on cell viability, apoptosis, and inflammation in OGD/R-exposed cells were assessed by performing the Cell Counting Kit 8 assay, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Moreover, the role of rno-miR-666-3p in regulating gene expression in OGD/R-exposed cells was studied using mRNA deep sequencing. Lastly, to evaluate whether mitogen-activated protein kinase 1 (MAPK1) was the target of rno-miR-666-3p, western blotting and the dual-luciferase assay were performed. RESULTS: MSC-derived exosomes altered the miRNA expression patterns in OGD/R-exposed BMECs. In particular, the expression levels of rno-miR-666-3p, rno-miR-92a-2-5p, and rnomiR- 219a-2-3p decreased in OGD/R-exposed cells compared with those in the control; however, MSC-derived exosomes restored the expression levels of these miRNAs under OGD/R conditions. rno-miR-666-3p overexpression enhanced cell viability and alleviated the apoptosis of OGD/R-exposed cells. Moreover, rno-miR-666-3p suppressed OGD/R-induced inflammation. mRNA deep sequencing revealed that rno-miR-666-3p is closely associated with the MAPK signaling pathway. Western blotting and the dual-luciferase assay confirmed that MAPK1 is the target of rnomiR- 666-3p. CONCLUSION: MSC-derived exosomes restore rno-miR-666-3p expression in OGD/R-exposed BMECs. Moreover, this specific miRNA exerts protective effects against OGD/R by suppressing the MAPK signaling pathway.

Overexpression of FOXA2 attenuates cigarette smoke-induced cellular senescence and lung inflammation through inhibition of the p38 and Erk1/2 MAPK pathways.

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses varying degrees of chronic obstructive bronchitis and emphysema. Our previous study showed that Forkhead box protein A2 (FOXA2) is involved in cigarette smoke (CS)-induced squamous metaplasia. However, the contribution of FOXA2 activity to CS-induced cellular senescence and lung inflammation remains largely unknown. Here, we report that FOXA2 was underexpressed in CS-exposed mouse lungs, and decreased expression of FOXA2 was related to cell senescence and inflammation. Subsequent investigation suggested that FOXA2 is an anti-senescence factor in lung that is involved in inflammatory responses. Furthermore, FOXA2 overexpression delayed CSE-induced senescence and inflammation, which correlated with regulation of the p38 and Erk1/2 MAPK signaling pathways by CSE-induced FOXA2 downregulation. Collectivelly, these findings reveal a protective role for FOXA2 as a regulator of cell senescence and inflammation during COPD.