Machine Learning Revealed a Novel Ferroptosis-Based Classification for Diagnosis in Antiretroviral Therapy-Treated HIV Patients with Defective Immune Recovery.

Despite virological suppression, the CD4+ T lymphocytes are not restored in some HIV-infected patients after antiretroviral therapy. These individuals are known as immune non-responders (INRs). INRs are at high risk of developing AIDS and non-AIDS-related events and have a shorter life expectancy. Hence, it is vital to identify INRs early and prevent their complications, but there are still no specific diagnostic indicators or models. Ferroptosis has lately been reported as a type of programmed cell death, which plays an indispensable part in diverse diseases. However, its particular regulatory mechanisms remain unclear and its function in the pathogenic process of defective immunological recovery is still unknown. Blood is mainly used for rapid diagnosis because it enables quick testing. To investigate the role of ferroptosis-related genes (FRGs) in early detection of INRs, we scrutinized Gene Expression Omnibus datasets of peripheral blood samples to estimate their effectiveness. To our knowledge, for the first time, gene expression data were utilized in this study to discover six FRGs that were explicitly expressed in peripheral blood from INRs. Later on, multiple machine-supervised learning algorithms were employed, and a superlative diagnostic model for INRs was built with the random forest algorithm, which displayed satisfactory diagnostic efficiency in the training cohort (area under the curve [AUC] = 0.99) and one external validation cohort (AUC = 0.727). Our findings suggest that FRGs are implicated in the development of defective immune recovery, presenting a potential route for early detection and potential biological targets for the most effective treatment of defective immune recovery.

A Seven-Autophagy-Related Long Non-Coding RNA Signature Can Accurately Predict the Prognosis of Patients with Renal Cell Carcinoma.

Introduction: Introduction. Renal cell carcinoma (RCC) is a common malignant tumor worldwide, and to explore, accurate prediction models are essential to the diagnosis and treatment. Methods: In the present study, the profile expression of RCC patients for long non-coding RNAs (lncRNAs) were obtained from the database of The Cancer Genome Atlas (TCGA). The Gene Set Enrichment Analysis (GSEA) showed that the gene sets related to autophagy are significantly differentially expressed among the paired normal tissues and RCC. Multivariate and univariate Cox analyses were used to construct the gene signature related to prognosis. Receiver Operating Characteristic (ROC) dependent on the time factor and the Kaplan-Meier curves are used for evaluating identified signatures. For gene signature combination, a nomogram with associated clinical constraints was designed. Results: Multivariate and Univariate Cox analyses presented seven autophagy-related lncRNAs were significantly correlated with Overall Survival (OS) for people with RCC. Risk scores of lncRNA prognostic signature, related to autophagy helped in distinguishing the patients accurately among the low-risk and high-risk RCC based on age, sex, grade of tumor, T, M, N, and AJCC stages. The RCC condition patients, as per their signature were put into the category of low and high-risk groups, having varying prognostic outcomes. Gene signature is an independent prognosticator for OS, accurately predicting 3-5 year survival time for RCC patients from either of the two groups. GSEA revealed that high-risk scores of the prognostic seven-long non-coding signature correlate with immune-regulatory and cancer, signaling pathways, whereas a low-risk score correlates with metabolism. The quantitative reverse chain reaction of transcription-polymerase verified differential expression of seven lncRNAs autophagy-related samples. Conclusion: The results depict that seven autophagy-related lncRNA prognostic signature helps in predicting the prognosis accurately among people with RCC.

Ginsenoside Rg1 alleviates ANIT-induced intrahepatic cholestasis in rats via activating farnesoid X receptor and regulating transporters and metabolic enzymes.

Ginsenoside Rg1 is an active ingredient extracted from the roots of ginsenoside, and an α-naphthylisothiocyanate (ANIT)-induced rat model of intrahepatic cholestasis was used to investigate the protective effect of Rg1 on cholestasis. 48 SD male rats were randomly divided into 6 groups: control group, model group, UDCA group (ursodeoxycholic acid), low-dose Rg1 group (10 mg/kg), medium-dose Rg1 group (20 mg/kg) and high-dose Rg1 group (40 mg/kg). The model group, the UDCA group and all the Rg1 group were then intragastrically administered with 80 mg/kg ANIT, and the control group were given equal volume of olive oil. Then the pathological changes in liver tissue were observed, the secretion of bile in the bile duct was measured, and the biochemical markers in serum were quantified, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transfer peptidase (GTP) and the content of total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA). The contents of inflammatory mediators in serum were quantified, including tumor necrosis factor (TNF-α), γ-interferon (IFN-γ) and interleukin-1ß (IL-1ß). The contents of superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in liver homogenate were quantified. Expression of farnesoid X receptor (FXR), transporters and metabolic enzymes in liver tissue was monitored. Rg1 treatment improved liver tissue pathological damage, promoted bile secretion and significantly reduced serum levels of the intrahepatic cholestasis markers ALT, AST, ALP, GTP, TBIL, DBIL and TBA. Rg1 increased the activity of SOD and GSH-Px in liver homogenate, while, reducing the serum levels of MDA and inflammatory mediators. Rg1 also regulated the expression of FXR, bile acid transporters and metabolic enzymes. Overall, Rg1 alleviated liver injury by improving secretion of bile and normalizing the activity of enzymes in the serum. The protective mechanism appeared to be related to the activation of FXR and regulation of liver transporters and metabolic enzymes.

Ginsenoside Rg1 Ameliorates Palmitic Acid-Induced Hepatic Steatosis and Inflammation in HepG2 Cells via the AMPK/NF-κB Pathway.

Nonalcoholic fatty liver disease (NAFLD) is one of the common diseases in the world, and it can progress from simple lipid accumulation to sustained inflammation. The present study was designed to investigate the effects and underlying mechanisms of ginsenoside Rg1 (G-Rg1) treatment on NAFLD in vitro. HepG2 cells were treated with palmitic acid (PA) to induce steatosis and inflammation and then successively incubated with G-Rg1. Lipids accumulation was analyzed by Oil Red O staining and intracellular triglyceride (TG) quantification. Inflammatory conditions were examined by quantifying the levels of cell supernatant alanine transaminase/aspartate aminotransferase (ALT/AST) and secretory proinflammatory cytokines, including IL-1ß, IL-6, and TNF-α in the cell supernatants. Quantitative RT-PCR and western blotting were used to measure the expressions of genes and proteins associated with lipogenic synthesis and inflammation, including AMP-activated protein kinase (AMPK) and nuclear factor-kappa B (NF-κB) pathways. HepG2 cells were pretreated with an AMPK inhibitor; then, Oil Red O staining and TG quantification were performed to study the lipid deposition. Phospho-AMPK (Thr172) (p-AMPK) and phospho-acetyl-CoA carboxylase (Ser79) (p-ACCα) were quantified by immunoblotting. Immunofluorescence was performed to demonstrate the nuclear translocation of NF-κB P65. The present study showed that PA markedly increased the intracellular lipid droplets accumulation and TG levels, but decreased AMPK phosphorylation and the expressions of its downstream lipogenic genes. However, G-Rg1 alleviated hepatic steatosis and reduced the intracellular TG content; these changes were accompanied by the activation of the AMPK pathway. In addition, blocking AMPK by using the AMPK inhibitor markedly abolished the G-Rg1-mediated protection against PA-induced lipid deposition in HepG2 cells. Furthermore, G-Rg1 reduced the ALT/AST levels and proinflammatory cytokines release, which were all enhanced by PA. These effects were correlated with the inactivation of the NF-κB pathway and translocation of P65 from the cytoplasm to the nucleus. Overall, these results suggest that G-Rg1 effectively ameliorates hepatic steatosis and inflammation, which might be associated with the AMPK/NF-κB pathway.

Ectopic expression of CC chemokine receptor 7 promotes prostate cancer cells metastasis via Notch1 signaling.

There currently exists no satisfactory treatment for patients with prostate cancer with local evolution and distant metastasis. Previous studies have confirmed the importance of CC chemokine receptor 7 (CCR7) in the invasion and metastasis of prostate cancer. And increasing evidence prove that Notch1 can play diametrically opposite roles in the development and progression of different tumors. To demonstrate the correlation between CCR7 and Notch1, PC-3 cells were transfected with pcDNA3.1-CCR7 or CCR7 si-RNA, respectively. Then Western blot analysis was used to detect the expressions of Notch1, ERK, P38, JNK, NF-κB, MMP-9, and epithelial-mesenchymal transition (EMT)-related proteins. Moreover, matrigel invasion assays were performed to assess the migratory and invasive activities of PC-3 cells. PcDNA3.1-CCR7 increased the expression of Notch1, phospho-MAPK, phospho-P65, MMP-9, N-cadherin, and Snail in PC-3 cells, but decreased the expression of E-cadherin. PcDNA3.1-CCR7 also promoted the migration and invasion of PC-3 cells. However, CCR7 si-RNA reversed the effect of pcDNA3.1-CCR7 in PC-3 cells. And MAPK and NF-κB pathway inhibitors were used to testify that activation of Notch1 induces EMT through MAPK and NF-κB pathway. All these results indicate that upregulation of Notch1 by CCR7 can accelerate the evolution of EMT and develop the invasion and metastasis in prostate cancer cells by activating MAPK and NF-κB signaling pathways in prostate cancer cells, which provides a new molecular evidence for targeted therapy in metastatic prostate cancer.

MiRNALet-7a mediates prostate cancer PC-3 cell invasion, migration by inducing epithelial-mesenchymal transition through CCR7/MAPK pathway.

Prostate cancer is one of the most common malignancies in older men. Recent evidence has demonstrated microRNA (miRNA) Let-7a expression decreased in prostate cancer, while the expression of CC chemokine receptor type 7 (CCR7) increased. In this study, we investigated whether CCR7 overexpression was associated with a decrease in the expression of miRNA Let-7a in invasion and metastasis of prostate cancer cell. Synthetic Let-7a mimics and Let-7a inhibitors were transfected into prostate cancer PC-3 cells, respectively. Then Western blot was used to detect the expression of CCR7, ERK, p38, MMP-9, and Epithelial-Mesenchymal Transition (EMT)-related proteins. Matrigel invasion assays were performed to assess the migratory and invasive activities of PC3 cells. To confirm the fact that 3'UTR of CCR7 is a direct target of Let-7a, a luciferase assay for the reporter gene expressing the Let-7a binding sites of CCR7 3'UTR was used. Synthetic Let-7a mimics decreased prostate cancer cell migration and invasion, as well as the expression of CCR7, phospho-p38, phospho-ERK1/2, MMP-9, N-cadherin, and Snail in PC-3 cells. The Let-7a inhibitors reversed the effects of Let-7a on PC-3 cells. The 3'UTR of CCR7 was confirmed as a direct target of Let-7a by using the luciferase assay. All findings demonstrated that Let-7a/CCR7 axis regulated EMT progress in prostate cancer cells and mediated the tumor cell invasion and migration process via activation of P38/ERK signal pathway. Our results suggested that the therapeutic potential of Let-7a as an antitumor and antimetastatic manager in prostate cancer and CCR7 may be regarded as a therapeutic target for the prostate cancer treatment.

56 Gb/s multi-band CAP for data center interconnects up to an 80 km SMF.

We present the first (to the best of our knowledge) experimental demonstration of a 56 Gb/s multi-band carrierless amplitude and phase modulation (CAP) signal transmission over an 80-km single-mode fiber link with zero overhead pre-FEC signal recovery and enhanced timing jitter tolerance for optical data center interconnects.