Abstract Background Lipid reprogramming in carcinoma is reported to have a role in carcinogenesis, prognosis, and therapy response. Autonomous or nonautonomous resources may contribute to lipid reprogramming. Nonautonomous lipid resources contributed by lipoproteins and their receptors have been reported in epithelial ovarian cancer (EOC), but the impact of autonomous lipid metabolites is unknown. This report reveals that a unique lipid class, ether-linked phosphatidylethanolamine (PE O–), enhanced chemoinsensitivity and progression in EOC, and potentially in other carcinomas. Method Unbiased bioinformatics analyses of data from the carcinoma databases CCLEC (Cancer Cell Line Encyclopedia Consortium) and GDSCC (Genomics of Drug Sensitivity in Cancer Consortium) and an in-house lipidomic database of human carcinoma lines were performed to identify relationships with chemoagent cytotoxicity. EOC cells (SKOV3 and OVCAR3) were treated with PE O– and/or alkylglycerone phosphate synthase (AGPS), an ether lipid-producing enzyme, inhibitor to observe cell growth, mobility, and chemosensitivity. The clinical impact of PE O– metabolic gene expression was determined by analysis of The Cancer Genome Atlas transcriptome to find an association with various clinical features of EOC. Results Glycerophospholipids were the consensus lipid class in lipid metabolism gene and chemosensitivity association analyses of the CCLEC/GDSCC database. In the lipidome database analyses of in-house human carcinoma cell lines, the glycerophospholipid, PE O–, was identified as the dominant lipid associated with cisplatin/paclitaxel sensitivity. In various hypothesis-driven cisplatin/paclitaxel sensitivity analyses of cell line lipidomes, PE O– remained the dominant lipid class. Tests of the effects of PE O– on cancer phenotypes showed that it enhanced cell growth and migratory activities and promoted insensitivity to cisplatin/paclitaxel. However, the AGPS inhibitor sensitized EOC cells to the chemocytotoxic effects of cisplatin/paclitaxel, whereas treatment with PE O– reversed this effect. Analysis of a TCGA-EOC transcriptome database showed that PE O– gene expression was positively correlated with progression in general or in those treated with platin- or taxel-based chemotherapies. Conclusion The expression of PE O– synthesis genes aggravated negative responses of EOC patients to therapy. PE O– facilitated human carcinoma cell line growth, mobility, and chemoinsensitivity.

Abstract Background Ischaemic stroke causes the abrupt reduction or cessation of blood flow to the brain results in a cascade of events that can compromise blood-brain barrier (BBB) integrity. We revealed that an increase in apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (AC3RL) is associated with endothelial cell apoptosis and inflammatory responses, indicating that AC3RL is one of the risk factors for cardiovascular events. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) triggers a cascade of events within endothelial cells that leads to endothelial dysfunction. Purpose We aimed to investigate whether AC3RL affects BBB permeability via the LOX-1, and thus increases brain damage. Methods We collected the whole blood from normal and patients with ischaemic events and separated them by centrifugation. AC3RL were collected using FPLC. We performed middle cerebral artery occlusion (MCAO) surgery to induce ischaemic stroke using B6 (C57BL/6) and LOX-1-/- mice injected with AC3RL. Triphenyl tetrazolium chloride (TTC) and Evans blue stains were accessed to confirm brain injury and BBB permeability. Results FPLC results showed that patients with ischaemic events presented higher levels of AC3RL compared to normal people. TTC stain showed the increased area of ischaemic penumbra damage in B6 mice with AC3RL injection, and LOX-1-/- mice with AC3RL injection were significantly protected. Evans blue dye leakage was observed in the brain tissues of B6 mice with AC3RL injection. LOX-1-/- mice with AC3RL injection revealed a decrease in BBB permeability. The modified neurological severity score (mNSS) method revealed a significant rise in B6 mice with AC3RL injection, which suggested a decline in motor and nervous function. LOX-1-/- mice with AC3RL injection significantly improved in motor and neurological functioning. Conclusions We demonstrate that AC3RL, through its effects on LOX-1, is associated with an increased risk of BBB damage after stroke. Therefore, pharmacological inhibition of AC3RL-LOX-1 interaction will be the main strategy to reduce severe brain damage. Figure 1: (A) AC3RL percentage (%) in individuals. Normal: healthy people, Ischemic event: patients who have experienced an ischemic event. **p < 0.001 vs. Normal group. (B, C) TTC stain of brain tissue after euthanasia to pinpoint the site of brain damage. The white portion of the mice brains indicated the site of the injury. (D, E) Evans blue dye leakage study in mice brains exhibited BBB permeability changes. (F) Assessment of mice's motor and neurological performance using the mNSS. Data are expressed as the mean ± SEM. **p < 0.001, ****p < 0.0001 vs. sham group, ##p < 0.001 vs. B6 I.V. AC3RL group.Graphical abstractFigure 1.

Numerous biological processes and diseases are influenced by lipid composition. Advances in lipidomics are elucidating their roles, but analyzing and interpreting lipidomics data at the systems level remain challenging. To address this, we present iLipidome, a method for analyzing lipidomics data in the context of the lipid biosynthetic network, thus accounting for the interdependence of measured lipids. iLipidome enhances statistical power, enables reliable clustering and lipid enrichment analysis, and links lipidomic changes to their genetic origins. We applied iLipidome to investigate mechanisms driving changes in cellular lipidomes following supplementation of docosahexaenoic acid (DHA) and successfully identified the genetic causes of alterations. We further demonstrated how iLipidome can disclose enzyme-substrate specificity and pinpoint prospective glioblastoma therapeutic targets. Finally, iLipidome enabled us to explore underlying mechanisms of cardiovascular disease and could guide the discovery of early lipid biomarkers. Thus, iLipidome can assist researchers studying the essence of lipidomic data and advance the field of lipid biology.

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that affects the immune system due to the accumulation of amyloid-β (Aβ) and tau associated molecular pathology and other pathogenic processes. To address AD pathogenesis, various approaches had been conducted from drug development to lifestyle modification to reduce the prevalence of AD. Exercise is considered a prominent lifestyle modification to combat AD. Objective: This observation prompted us to review the literature on exercise related to immune genes in the cortex of animal models of AD. We focused on animal model studies due to their prevalence in this domain. Methods: The systematic review was conducted according to PRISMA standards using Web of Science (WoS) and PubMed databases. Any kind of genes, proteins, and molecular molecules were included in this systematic review. The list of these immune-related molecules was analyzed in the STRING database for functional enrichment analysis. Results: We found that 17 research studies discussed immune-related molecules and 30 immune proteins. These studies showed that exercise had the ability to ameliorate dysfunction in AD-related pathways, which led to decreasing the expression of microglia-related pathways and Th17-related immune pathways. As a result of decreasing the expression of immune-related pathways, the expression of apoptosis-related pathways was also decreasing, and neuronal survival was increased by exercise activity. Conclusions: Based on functional enrichment analysis, exercise not only could reduce apoptotic factors and immune components but also could increase cell survival and Aβ clearance in cortex samples. PROSPERO ID: CRD42022326093.

Head and neck cancer is the leading cancer worldwide. Radiation therapy plays important role of treatment for head and neck cancer. MicroRNAs have been shown to be related to tumor progression and radiosensitivity. However, the mechanisms are still largely unknown and evidence are still limited. In the current study, we sought to identify the miRNA related the radiosensitivity of head and neck tumor cell, which leading to the disappointed prognosis of patients with head and neck cancer receiving radiation therapy. The miRNA expression profiles and clinical information of patients with head and neck cancer were obtained from The Cancer Genome Atlas. The identification of miRNA was carried out through an integrated bioinformatics analysis. The miRNA identified in previous approach was validated through in vitro and in vivo studies. MiR-4776-5p was finally identified as the role of radio-sensitizer and predicts the prognosis of patients with head and neck cancer receiving radiotherapy. 11 of 16 genes targeted by the miR-4776-5p have been discovered to regulate the mechanisms related to radiosensitivity using functional annotation.

Subjects with metabolic syndrome (MetS) commonly have atrial remodeling, which indicates a risk for atrial fibrillation. This study determined MetS-related changes in lipid components in very-low-density lipoprotein (VLDL), which has been shown to cause atrial remodeling, the effect of statins on these changes, and the correlation between atrial remodeling and VLDL lipid compositions. Blood samples were collected from 12 non-MetS and 27 sex- and age-matched MetS subjects. Fourteen patients with MetS (MetS-off statin) discontinued statin therapy 14 days before the study, while the remaining 13 remained on it (MetS-on statin). The VLDLs were isolated and processed for mass-based lipid profiling. Lipidomic analyses were performed and associated with atrial remodeling markers measured using standard echocardiography and electrocardiography. Compared with the VLDL components of the non-MetS group, glucosyl/galactosyl ceramide, lyso-phosphatidylcholine, lyso-phosphatidylethanolamine, and triglycerides were enriched in the MetS-off statin group. Statin therapy attenuated all abnormally abundant lipid classes in MetS, except for triglycerides. In addition, lyso-phosphatidylcholine, lyso-phosphatidylethanolamine, and triglycerides were significantly correlated with atrial dilatation, and the latter two were also correlated with the PR interval. Enrichment of double bonds, which indicate unsaturated fatty acids, was also significantly correlated with atrial remodeling and P-wave duration. This study suggests that the pathological lipid payload of MetS-VLDL may contribute to atrial remodeling in patients.

OBJECTIVES:Although 1H-nuclear magnetic resonance (NMR)-based lipid/metabolomics has been used to detect atherosclerosis, data regarding lipid/metabolomic signature in rheumatoid arthritis (RA)-related atherosclerosis are scarce. We aimed to identify the distinct lipid/metabolomic profiling and develop a prediction score model for RA patients with subclinical atherosclerosis (SA).METHODS:Serum levels of lipid metabolites were determined using 1H-NMR-based lipid/metabolomics in 65 RA patients and 12 healthy controls (HCs). The occurrence of SA was defined as the presence of carotid plaques revealed in ultrasound images.RESULTS:Compared with HC, RA patients had significantly higher levels of phenylalanine and glycoprotein acetyls (GlycA) and lower levels of leucine and isoleucine. RA patients with SA had significantly higher levels of phenylalanine, creatinine, and glycolysis_total and lower levels of total lipid in HDL(HDL_L) than RA patients without SA. The Lasso logistic regression analysis revealed that age, creatinine, HDL_L, and glycolysis_total were significant predictors for the presence of SA. The prediction scoring algorithm was built as ( -0.657 + 0.011*Age + 0.004*Creatinine -0.120*HDL_L + 0.056*glycolysis-related measures), with AUC 0.90, sensitivity 83.3%, and specificity 87.2%. Serum phenylalanine levels were significantly decreased, and the levels of HDL_L and HDL_Particle were significantly increased in 20 RA patients, paralleling the decrease in disease activity score for 28-joints.CONCLUSIONS:With 1H-NMR-based lipid/metabolomics, distinct profiling of lipid metabolites was identified between RA patients and HC or between RA patients with and without SA. We further developed a scoring model based on lipid/metabolomics profiling for predicting RA-associated SA.

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70-mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease.

Prostate cancer (PCa) is the second most prevalent cancer in men worldwide. The majority of PCa incidences eventually progress to castration-resistant PCa (CRPC), thereby establishing an urgent need for new effective therapeutic strategies. This study aims to examine the effects of morusin, a prenylated flavonoid isolated from Morus alba L., on PCa progression and identify the regulatory mechanism of morusin. Cell growth, cell migration and invasion, and the expression of EMT markers were examined. Cycle progression and cell apoptosis were examined using flow cytometry and a TUNEL assay, while transcriptome analysis was performed using RNA-seq with results being further validated using real-time PCR and western blot. A xenograft PCa model was used to examine tumor growth. Our experimental results indicated that morusin significantly attenuated the growth of PC-3 and 22Rv1 human PCa cells; moreover, morusin significantly suppressed TGF-[Formula: see text]-induced cell migration and invasion and inhibited EMT in PC-3 and 22Rv1 cells. Significantly, morusin treatment caused cell cycle arrest at the G2/M phase and induced cell apoptosis in PC-3 and 22Rv1 cells. Morusin also attenuated tumor growth in a xenograft murine model. The results of RNA-seq indicated that morusin regulated PCa cells through the Akt/mTOR signaling pathway, while our western blot results confirmed that morusin suppressed phosphorylation of AKT, mTOR, p70S6K, and downregulation of the expression of Raptor and Rictor in vitro and in vivo. These results suggest that morusin has antitumor activities on regulating PCa progression, including migration, invasion, and formation of metastasis, and might be a potential drug for CRPC treatment.

BACKGROUND:Research reported exercise could reduce Alzheimer's disease (AD) symptoms in human and animals. However, the molecular mechanism of exercise training via transcriptomic analysis was unclear especially in AD in the cortex area.OBJECTIVE:Investigate potential significant pathways in the cortex area that were affected by exercise during AD.METHODS:RNA-seq analysis, differential expressed genes, functional enrichment analysis, and GSOAP clustering analysis were performed in the isolated cerebral cortex from eight 3xTg AD mice (12 weeks old) randomly and equally divided into control (AD) and exercise training (AD-EX) group. Swimming exercise training in AD-EX group was conducted 30 min/day for 1 month.RESULTS:There were 412 genes significant differentially expressed in AD-EX group compared to AD group. Top 10 upregulated genes in AD-EX group against AD group mostly correlated with neuroinflammation, while top 10 downregulated genes mostly had connection with vascularization, membrane transport, learning memory, and chemokine signal. Pathway analysis revealed the upregulated interferon alpha beta signaling in AD-EX had association with cytokines delivery in microglia cells compared to AD and top 10 upregulated genes involved in interferon alpha beta were Usp18, Isg15, Mx1, Mx2, Stat1, Oas1a, and Irf9; The downregulated extracellular matrix organization in AD-EX had correlation with Aβ and neuron cells interaction and Vtn was one of the top 10 downregulated genes involved in this pathway.CONCLUSION:Exercise training influenced 3xTg mice cortex through interferon alpha beta signaling upregulation and extracellular matrix organization downregulation based on transcriptomics analysis.

Immune-related pathways can affect the immune system directly, such as the chemokine signaling pathway, or indirectly, such as the phagosome pathway. Alzheimer’s disease (AD) is reportedly associated with several immune-related pathways. However, exploring its underlying mechanism is challenging in animal studies because AD mouse strains differentially express immune-related pathway characteristics. To overcome this problem, we performed a meta-analysis to identify significant and consistent immune-related AD pathways that are expressed in different AD mouse strains. Next-generation RNA sequencing (RNA-seq) and microarray datasets for the cortex of AD mice from different strains such as APP/PSEN1, APP/PS2, 3xTg, TREM, and 5xFAD were collected from the NCBI GEO database. Each dataset’s quality control and normalization were already processed from each original study source using various methods depending on the high-throughput analysis platform (FastQC, median of ratios, RMA, between array normalization). Datasets were analyzed using DESeq2 for RNA-seq and GEO2R for microarray to identify differentially expressed (DE) genes. Significantly DE genes were meta-analyzed using Stouffer’s method, with significant genes further analyzed for functional enrichment. Ten datasets representing 20 conditions were obtained from the NCBI GEO database, comprising 116 control and 120 AD samples. The DE analysis identified 284 significant DE genes. The meta-analysis identified three significantly enriched immune-related AD pathways: phagosome, the complement and coagulation cascade, and chemokine signaling. Phagosomes-related genes correlated with complement and immune system. Meanwhile, phagosomes and chemokine signaling genes overlapped with B cells receptors pathway genes indicating potential correlation between phagosome, chemokines, and adaptive immune system as well. The transcriptomic meta-analysis showed that AD is associated with immune-related pathways in the brain’s cortex through the phagosome, complement and coagulation cascade, and chemokine signaling pathways. Interestingly, phagosome and chemokine signaling pathways had potential correlation with B cells receptors pathway.

Abstract Background Understanding the genetic alterations which occur in genes associated with various cancers can improve therapy outcomes by promoting tailored treatments for each patient. Molecular profiling is therefore a crucial tool for precision medicine and enables for a personalized approach to cancer management. Current guidelines for molecular testing of Non-Small Cell Lung Cancer (NSCLC) patients involves treatment selection of a targeted Tyrosine Kinase Inhibitor based on the minimal testing of EGFR, ALK and ROS1 genes and strongly recommending the additional testing of KRAS, BRAF, MET, RET, NTRK and ERBB2 (Her2) genes to fully evaluate the patient’s mutational status. Method The IntelliPlex Lung Cancer Panel, based on PlexBio’s multiplexing πCode® technology, is an in vitro molecular amplification assay intended for the qualitative identification of 74 DNA mutations in the KRAS, NRAS, PIK3CA, BRAF, EGFR, HER2, MEK1 and AKT1 genes and 28 gene variants of the ALK, ROS1, RET, NTRK1 and MET genes. The assay is suitable for the use with formalin-fixed paraffin-embedded (FFPE) tumor tissues from NSCLC patients. The performance of IntelliPlex Lung Cancer Panel was evaluated on FFPE specimens by comparing the results with two commercially available molecular amplification assays. Discrepant samples were resolved by a corresponding digital PCR method kit. Results The IntelliPlex Lung Cancer Panel can detect DNA mutations at very low allele frequencies (as low as 0.1%) while only requiring DNA quantities of 10ng. Most RNA rearrangements are detected with 10 or more copies present in the sample while only low RNA input quantities (50 ng) are required. The IntelliPlex Lung Cancer Panel can analyze the mutational status of 102 targets in less than 5.5 h from sample to results and allows screening of up to 48 samples in parallel. Among 50 FFPE DNA specimens tested, the overall agreement for EGFR and KRAS mutations between IntelliPlex system and the comparison method were both found to be 98%. And the overall agreement after resolved the discrepancies by digital PCR was 100%. Conclusion The multiplex amplification and detection capabilities of the IntelliPlex Lung Cancer Panel provides a comprehensive and efficient way to evaluate the individual mutational status from lung cancer patients with high sensitivity and specificity. Accurate genetic analysis provides valuable information which can support precision medicine decisions for better cancer management. This can also be used further with non-invasive whole blood sampling (i.e., “liquid biopsy”) for subsequent treatment monitoring.

Background Nonalcoholic steatohepatitis (NASH) is metabolic disease that may progress to cirrhosis and hepatocellular carcinoma. Mouse models of diet-induced NASH, which is characterized by the high levels of fats, sugars, and cholesterol in diets, are commonly used in research. However, mouse models accurately reflecting the progression of NASH in humans remain to be established. Studies have explored the potential use of serological metabolites as biomarkers of NASH severity in relation to human NASH. Methods We performed a comparative analysis of three mouse models of diet-induced NASH in terms of phenotypic and metabolomic characteristics; NASH was induced using different diets: a high-fat diet; a Western diet; and a high-fat, high-cholesterol diet. Liver cirrhosis was diagnosed using standard clinical approaches (e.g., METAVIR score, hyaluronan level, and collagen deposition level). Mouse serum samples were subjected to nuclear magnetic resonance spectroscopy–based metabolomic profiling followed by bioinformatic analyses. Metabolomic analysis of a retrospective cohort of patients with hepatocellular carcinoma was performed; the corresponding cirrhosis scores were also evaluated. Results Using clinically relevant quantitative diagnostic methods, the severity of NASH was evaluated. Regarding metabolomics, the number of lipoprotein metabolites increased with both diet and NASH progression. Notably, the levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) significantly increased with fibrosis progression. During the development of diet-induced NASH in mice, the strongest upregulation of expression was noted for VLDL receptor. Metabolomic analysis of a retrospective cohort of patients with cirrhosis indicated lipoproteins (e.g., VLDL and LDL) as predominant biomarkers of cirrhosis. Conclusions Our findings provide insight into the pathophysiology and metabolomics of experimental NASH and its relevance to human NASH. The observed upregulation of lipoprotein expression reveals a feedforward mechanism for NASH development that may be targeted for the development of noninvasive theranostics.

3-bromopyruvic acid (3-BP), a small molecule alkylating agent, has been emerged as a glycolytic inhibitor with anticancer activities. However, the effects of 3-BP on the growth and metastasis in prostate cancer have not been well investigated. Here we investigated the anti-cancer effects of 3-BP on prostate cancer in vitro and in vivo. Cell growth, apoptosis, migration, motility, and invasion were examined. The tumor growth ability was determined using a xenograft murine model. Transcriptome analysis using RNA-seq was performed to explore the mechanism of action of 3-BP. Our experimental results showed that 3-BP effectively inhibits prostate cancer cell growth, especially in castration-resistant prostate cancer (CRPC) cells. Moreover, 3-BP induces apoptosis and suppresses cell migration, motility, epithelial-mesenchymal transition (EMT), and invasion in CRPC cells. In addition, 3-BP also attenuates tumor growth in a xenograft murine model. Through transcriptome analysis using RNA-seq, 3-BP significantly regulates the cell cycle pathway and decreases the expression of downstream cycle cycle-associated genes in CRPC cells. The results of cell cycle analysis indicated that 3-BP arrests cell cycle progression at G2/M in CRPC cells. These results suggest that 3-BP has the potential in inhibiting CRPC progression and might be a promising drug for CRPC treatment.

Programmed cell death protein 1 (PD-1)/ programmed cell death protein ligand 1 (PD-L1) is the key immune checkpoint governing evasion of advanced cancer from immune surveillance. Immuno-oncology (IO) therapy targeting PD-1/PD-L1 with traditional antibodies is a promising approach to multiple cancer types but to which the response rate remains moderate in breast cancer, calling for the need of exploring alternative IO targeting approaches. A miRNA-gene network was integrated by a bioinformatics approach and corroborated with The Cancer Genome Atlas (TCGA) to screen miRNAs regulating immune checkpoint genes and associated with patient survival. Here we show the identification of a novel microRNA miR-4759 which repressed RNA expression of the PD-L1 gene. miR-4759 targeted the PD-L1 gene through two binding motifs in the 3′ untranslated region (3′-UTR) of PD-L1. Reconstitution of miR-4759 inhibited PD-L1 expression and sensitized breast cancer cells to killing by immune cells. Treatment with miR-4759 suppressed tumor growth of orthotopic xenografts and promoted tumor infiltration of CD8+ T lymphocytes in immunocompetent mice. In contrast, miR-4759 had no effect to tumor growth in immunodeficient mice. In patients with breast cancer, expression of miR-4759 was preferentially downregulated in tumors compared to normal tissues and was associated with poor overall survival. Together, our results demonstrated miR-4759 as a novel non-coding RNA which promotes anti-tumor immunity of breast cancer.

The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, we sought to identify core genes in regulating steroid hormone pathways and associating them with the disease progression of PC. The selection of steroid hormone-associated genes was identified from functional databases, including gene ontology, KEGG, and Reactome. The gene expression profiles and relevant clinical information of patients with PC were obtained from TCGA and used to examine the genes associated with steroid hormone. The machine-learning algorithm was performed for key feature selection and signature construction. With the integrative bioinformatics analysis, an eight-gene signature, including CA2, CYP2E1, HSD17B, SSTR3, SULT1E1, TUBB3, UCN, and UGT2B7 was established. Patients with higher expression of this gene signature had worse progression-free interval in both univariate and multivariate cox models adjusted for clinical variables. The expression of the gene signatures also showed the aggressiveness consistently in two external cohorts, PCS and PAM50. Our findings demonstrated a validated eight-gene signature could successfully predict PC prognosis and regulate the steroid hormone pathway.

Aurora kinase A (AURKA) carries out an essential role in proliferation and involves in cisplatin resistance in various cancer cells. Overexpression of AURKA is associated with the poor prognosis of cancer patients. Thus, AURKA has been considered as a target for cancer therapy. Developing AURKA inhibitors became an important issue in cancer therapy. A natural compound emodin mainly extracted from rhubarbs possesses anti-cancer properties. However, the effect of emodin on AURKA has never been investigated. In the present study, molecular docking analysis indicated that emodin interacts with AURKA protein active site. We also found nine emodin analogues from Key Organic database by using ChemBioFinder software. Among that, one analogue 8L-902 showed a similar anti-cancer effect as emodin. The bindings of emodin and 8L-902 on AURKA protein were confirmed by cellular thermal shift assay. Furthermore, emodin inhibited the AURKA kinase activity in vitro and enhanced the cisplatin-DNA adduct level in a resistant ovarian cancer cell line. It seems that emodin may have the potential to inhibit cancer cell growth and enhance cisplatin therapy in cancer with resistance. Collectively, our finding reveals a novel AURKA inhibitor, emodin, which may be vulnerable to ovarian cancer therapy in the future.

AIMS:Articulatin (AT), purified from the Chinese mistletoe (Viscum articulatum), belongs to the family of type II ribosome-inactivating proteins (RIPs) that contain two subunits, the A and B chains. The B chain of AT is believed to function by means of interacting with the galactose moiety of glycoproteins or glycolipids on the cell membrane and is internalized into cells through endocytosis. In the study, we aim to investigate the immunomodulatory effects of recombinant articulatin B chain (rATB) on mouse bone marrow-derived dendritic cells (BM-DCs). MAIN METHODS:Detection of surface markers expression on BM-DCs by flow cytometry. Analysis of RNA and protein expression by RNAseq and Western blotting assays. Assessment of the adaptive immune responses using an in vivo mouse model. KEY FINDING:Our study presents novel results showing the activation of mouse BM-DCs by rATB, which leads to the induction of CD80, CD86, and MHC II expression as well as primed type I CD4+ T cell differentiation and CD8+ T cell activation. RNAseq and Western blotting assays revealed rATB-induced BM-DC activation to be dependent on the MAPK and NF-κB signaling pathways. In a mouse model, rATB was observed to have adjuvant effects that induced an antigen-specific Th1 immune response. SIGNIFICANCE:Based on in vitro and in vivo assays, this study shows rATB acting as a potential adjuvant that induces BM-DC activation and antigen-specific Th1 related immune response. rATB might have potential applicability in the development of vaccines against pathogens and tumors.

Bladder cancer is one of the most common malignancies of the male genitourinary urinary system. Protodioscin is a steroidal saponin with anti-cancer effects on several types of cancers; however, the anti-cancer activities of protodioscin on bladder cancer have not yet been investigated. Therefore, we aimed to examine the anti-cancer effects of protodioscin on bladder cancer. Two types of bladder cancer cell lines, non-muscle-invasive 5637 cells and muscle-invasive T24 cells, were used to evaluate the effects of protodioscin on cell growth, migration, invasion and epithelial–mesenchymal transition(EMT) marker expressions. Transcriptome analysis was performed by RNA-seq and validated using real-time PCR and western blot; additionally, an in vivo xenograft animal model was established and the anti-tumor effects of protodioscin were tested. Our results demonstrated that protodioscin inhibited cell proliferation, migration, motility and invasion on 5637 and T24 cells. Additionally, protodioscin also induced cell apoptosis and arrested the progression of cell cycle at G2 phase in bladder cancer cells. Moreover, protodioscin inhibited EMT through increased protein expression of E-cadherin and decreased protein expression of N-cadherin and vimentin. RNA-seq analysis indicated that protodioscin regulated mitogen-activated protein kinase(MAPK) and phosphoinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR) signaling pathways as further verified by Western blot. Furthermore, protodioscin significantly inhibited tumor growth in vivo. Our results indicated that protodioscin inhibits cell growth, migration and invasion and induces apoptosis and G2 phase cell cycle arrest by activated p38 and JNK signaling pathways in bladder cancer cells, suggesting that protodioscin could be an effective agent for bladder cancer treatment.

Abstract Background Immunodeficiencies are genetic diseases known to predispose an individual to cancer owing to defective immunity towards malignant cells. However, the link between immunodeficiency and prostate cancer progression remains unclear. Therefore, the aim of this study was to evaluate the effects of common genetic variants among eight immunodeficiency pathway-related genes on disease recurrence in prostate cancer patients treated with radical prostatectomy. Methods Genetic and bioinformatic analyses on 19 haplotype-tagging single-nucleotide polymorphisms in eight immunodeficiency pathway-related genes were conducted in 458 patients with prostate cancer after receiving radical prostatectomy. Furthermore, the TNFRSF13B was knocked down in 22Rv1 and PC-3 human prostate cancer cell lines via transfecting short hairpin RNAs and cell proliferation and colony formation assays were performed. The molecular mechanisms underlying the effects of TNFRSF13B were further explored by microarray gene expression profiling. Results TNFRSF13B rs4792800 was found to be significantly associated with biochemical recurrence even after adjustment for clinical predictors and false discovery rate correction (adjusted hazard ratio 1.78, 95% confidence interval 1.16–2.71, p = 0.008), and the G allele was associated with higher TNFRSF13B expression (p = 0.038). Increased TNFRSF13B expression suggested poor prognosis in four independent prostate cancer datasets. Furthermore, silencing TNFRSF13B expression resulted in decreased colony formation of 22Rv1 and PC-3 cells through modulating the cell cycle and p53 signalling pathways. Conclusions The present study suggests the potential role of immunodeficiency pathway-related genes, primarily TNFRSF13B, in prostate cancer progression.