Asiatic acid induces ferroptosis of RA-FLS via the Nrf2/HMOX1 pathway to relieve inflammation in rheumatoid arthritis.

BACKGROUND: Ferroptosis is a distinct iron-dependent non-apoptotic type of programmed cell death that is implicated in the pathophysiology of rheumatoid arthritis (RA). Although asiatic acid (AA) is documented to have significant anti-inflammatory effects in various diseases, it is not known whether it can regulate RA via ferroptosis. METHODS: The effects of AA on rheumatoid arthritis fibroid-like synoviocytes (RA-FLS) were assessed in vitro, and a rat model of type II collagen-induced arthritis (CIA) was established to evaluate the effectiveness of AA treatment in vivo. RESULTS: AA significantly reduced both viability and colony formation in cultured RA-FLS, while increasing the levels of reactive oxygen species (ROS), ferrous iron (Fe2+), malondialdehyde (MDA), and lactate dehydrogenase (LDH), as well as the expression of COX2. Furthermore, AA induced ferroptosis in RA-FLS by promoting Fe2+ accumulation through downregulation of the expression of Keap1 and FTH1 and upregulation of Nrf2 and HMOX1. In vivo, AA treatment was found to reduce toe swelling and the arthritis score in CIA rats, as well as relieve inflammation and ankle damage and significantly upregulate the expression of Nrf2 and HMOX1 in the synovial fluid. CONCLUSION: Treatment with AA significantly reduced the viability of RA-FLS and triggered ferroptosis by promoting accumulation of Fe2+via the Nrf2-HMOX1 pathway, and was effective in relieving inflammation in CIA model rats. These findings suggest that the use of AA may be a promising strategy for the clinical treatment of RA.

PDCD4-induced oxidative stress through FGR/NF-κB axis in rectal cancer radiotherapy-induced AKI.

This study aimed to investigate the molecular mechanism of the effect of PDCD4 on radiotherapy-induced acute kidney injury (AKI) in rectal cancer through the regulation of FGR/NF-κB signaling. Differentially expressed genes were identified using Gene Expression Omnibus (GEO) datasets (GSE90627 for rectal cancer and GSE145085 for AKI) and R software. The human renal tubular epithelial cell line, HK-2, was used to establish an in vitro model of radiotherapy-induced AKI. RT-qPCR and western blotting were used to detect gene and protein expression levels, respectively. Cell proliferation and apoptosis were assessed using the CCK-8 assay and flow cytometry, respectively. The malondialdehyde and superoxide dismutase levels in the cell culture supernatants were determined. Additionally, an in vivo AKI model was established using BALB/c mice, and kidney tissue morphology, expression of the renal injury molecule KIM-1, apoptosis of renal tubular cells, and TAS and TOS in serum were evaluated. Bioinformatics analysis revealed the upregulated expression of PDCD4 in AKI. In vitro experiments demonstrated that PDCD4 induced apoptosis in renal tubular cells by promoting FGR expression, which activated the NF-κB signaling pathway and triggered an oxidative stress response. In vivo animal experiments confirmed that PDCD4 promoted oxidative stress response and radiotherapy-induced AKI through the activation of the FGR/NF-κB signaling pathway. Silencing PDCD4 attenuated radiotherapy-induced AKI. Our findings suggest that PDCD4 may induce radiotherapy-induced AKI in rectal cancer by promoting FGR expression, activating the NF-κB signaling pathway, and triggering an oxidative stress response.

Asiatic acid inhibits rheumatoid arthritis fibroblast-like synoviocyte growth through the Nrf2/HO-1/NF-κB signaling pathway.

Asiatic acid (AA) is generally recognized in the treatment of various diseases and has significant advantages in the treatment of various inflammatory diseases. The treatment of rheumatoid arthritis (RA) with AA is a completely new entry point. RA is a complex autoimmune inflammatory disease, and despite the involvement of different immune and nonimmune cells in the pathogenesis of RA, fibroblast-like synoviocytes (FLS) play a crucial role in the progression of the disease. si-Nrf2 was transfected in RA-FLS and the cells were treated with AA. MTT assay and colony formation assay were used to detect the effect of AA on the viability and formation of clones of RA-FLS, respectively. Moreover, the apoptosis of RA-FLS was observed by Hoechst 33342 staining and flow cytometry. Western blot was applied to measure the expression of the Nrf2/HO-1/NF-κB signaling pathway-related proteins. Compared with the control group, RA-FLS proliferation, and clone formation were significantly inhibited by the increase of AA concentration, and further experiments showed that AA-induced apoptosis of RA-FLS. In addition, AA activated the Nrf2/HO-1 pathway to inhibit NF-κB protein expression. However, the knockdown of Nrf2 significantly offsets the effects of AA on the proliferation, apoptosis, and Nrf2/HO-1/NF-κB signaling pathway of RA-FLS cells. AA can treat RA by inhibiting the proliferation and inducing the apoptosis of RA-FLS. The mechanism may be related to the activation of the Nrf2/HO-1/NF-κB pathway.

A Magnetic-Optical Triple-Mode Lateral Flow Immunoassay for Sensitive and Rapid Detection of Respiratory Adenovirus.

Human respiratory adenovirus (ADV) is a highly infectious respiratory virus with potential for pandemics. There are currently no specific drugs to treat ADV worldwide, so early rapid detection of ADV infection is essential. In this study, we developed an innovative magnetic-optical triple-mode lateral flow immunoassay (LFIA) using magnetic quantum dots as immunomarkers. This novel approach addresses the need for rapid and accurate ADV detection, allowing for multimodal quantitative/semiquantitative analysis of magnetic, fluorescent, and visible signals within a mere 15 min. The lower limit of detection (LOD) for magnetic, fluorescent, and visual signals was determined to be 5.6 × 103, 1.2 × 103, and 1.95 × 104 copies/mL, respectively. The detection range for ADV using this approach was 1.2 × 103-5 × 107 copies/mL. Additionally, semiquantitative analysis, which is user-friendly and does not necessitate specialized equipment, was successfully implemented. Notably, seven respiratory viruses showed no cross-reactivity with the generated LFIA test strips. The intrabatch repeatability exhibited a coefficient of variation (CV) of less than 5%, while the interbatch repeatability had a CV of less than 15%. Furthermore, recovery values ranged from 95% to 106.8% for samples analyzed concurrently with dual signals at the same spiking concentration. The assay developed in this study boasts a wide detection range and exceptional sensitivity and specificity. This technique is exceptionally well-suited for on-site rapid detection, with the potential for personal self-testing and early ADV infection diagnosis. Its versatility extends to a broad array of application scenarios.

Lysine demethylase 5C inhibits transcription of prefoldin subunit 5 to activate c-Myc signal transduction and colorectal cancer progression.

BACKGROUND: Lysine demethylase 5C (KDM5C) has been implicated in the development of several human cancers. This study aims to investigate the role of KDM5C in the progression of colorectal cancer (CRC) and explore the associated molecular mechanism. METHODS: Bioinformatics tools were employed to predict the target genes of KDM5C in CRC. The expression levels of KDM5C and prefoldin subunit 5 (PFDN5) in CRC cells were determined by RT-qPCR and western blot assays. The interaction between KDM5C, H3K4me3, and PFDN5 was validated by chromatin immunoprecipitation. Expression and prognostic values of KDM5C and PFDN5 in CRC were analyzed in a cohort of 72 patients. The function of KDM5C/PFDN5 in c-Myc signal transduction was analyzed by luciferase assay. Silencing of KDM5C and PFDN5 was induced in CRC cell lines to analyze the cell malignant phenotype in vitro and tumorigenic activity in nude mice. RESULTS: KDM5C exhibited high expression, while PFDN5 displayed low expression in CRC cells and clinical CRC samples. High KDM5C levels correlated with poor survival and unfavorable clinical presentation, whereas elevated PFDN5 correlated with improved patient outcomes. KDM5C mediated demethylation of H3K4me3 on the PFDN5 promoter, suppressing its transcription and thereby enhancing the transcriptional activity of c-Myc. KDM5C knockdown in CRC cells suppressed cell proliferation, migration and invasion, epithelial-mesenchymal transition, and tumorigenic activity while increasing autophagy and apoptosis rates. However, the malignant behavior of cells was restored by the further silencing of PFDN5. CONCLUSION: This study demonstrates that KDM5C inhibits PFDN5 transcription, thereby activating c-Myc signal transduction and promoting CRC progression.

Erythrocyte-Cancer Hybrid Membrane-Camouflaged Prussian Blue Nanoparticles with Enhanced Photothermal Therapy in Tumors.

Prussian blue (PB) nanoparticles have been widely used in photothermal therapy research due to the efficient photothermal conversion ability. In this study, PB was modified with a bionic coating using a hybrid membrane of red blood cell membranes and tumor cell membranes to prepare bionic photothermal nanoparticles (PB/RHM), which can further improve the blood circulation ability and tumor targeting of the nanoparticles to achieve efficient photothermal therapy for tumor treatment. In vitro formulation characterization showed that PB/RHM was a monodisperse spherical core-shell structured nanoparticle with a diameter of 207.2 nm and effectively retained the cell membrane proteins. The in vivo biological evaluation results showed that PB/RHM could effectively accumulate into the tumor tissue, inducing a rapid temperature increase in the tumor site to 50.9 °C within 10 min, inhibiting tumor growth efficiently with a tumor inhibition rate of 93.56% and with good therapeutic safety. In summary, this paper provided a hybrid film-modified Prussian blue nanoparticle with efficient photothermal anti-tumor capacity and safety.

SUMO1-modified DNA methyltransferase 1 induces DNA hypermethylation of VWC2 in the development of colorectal cancer.

Aberrant DNA methylation of genes is closely linked to many aspects of tumor development. This study focuses on the effect of DNA hypermethylation of von Willebrand factor C domain containing 2 (VWC2) on colorectal cancer (CRC) progression and the underpinning mechanism. According to data in the bioinformatic systems, VWC2 had the highest degree of DNA methylation in colonic adenocarcinoma, and it showed DNA hypermethylation in rectal adenocarcinoma as well. CRC and the para-tumorous tissues were collected from 86 patients. VWC2 was expressed at low levels in CRC samples and inversely correlated with tumor stage and tumor biomarker expression. DNA hypermethylation and reduced expression of VWC2 were also detected in CRC cell lines HCT-116 and HT29. VWC2 overexpression suppressed the malignant growth of cells in vitro and in vivo. Co-immunoprecipitation and western blot assays showed that small ubiquitin-like modifier 1 (SUMO1) mediated SUMOylation of DNA methyltransferase 1 (DNMT1) and strengthened its protein stability, which promoted DNA methylation and suppression of the VWC2 gene. In summary, this study demonstrates that SUMO1-mediated activation of DNMT1 induces DNA methylation and downregulation of VWC2 in CRC to augment cancer development.

Superiority of biomimetic micelle-entrapped nanoporous silica xerogel to deliver poorly water-soluble itraconazole.

Micelle-entrapped silica xerogel (M-Silica xerogel) was biomimetically synthesized to combine the advantages of micelles and silica xerogel to load poorly water-soluble drug itraconazole (ITZ). Tween 20, tween 40, and tween 80 were applied to prepare micelles as the templates for M20-Silica xerogel, M40-Silica xerogel, and M80-Silica xerogel, respectively. During the silica frame construction, the surfactant formed a micelle as the porous template, silicon hydroxyl groups interacted with the hydrophilic parts of the micelle, and polyethylenimine catalyzed silica polycondensation owing to its amino groups, resulting in the formation of the M-Silica xerogels. The results showed that the particle size of the sub-particles from the M40-Silica xerogel was larger than from the M20-Silica xerogel, and the M80-Silica xerogel was the largest among these three samples, demonstrating that the emulsifying ability had a direct impact on the particle size of the M-Silica xerogel. The M-Silica xerogel had a large pore size in the range of 10-50 nm. Small mesopores (2-5 nm) dominated the pore size of the M20-Silica xerogel, while medium mesopores (5-10 nm) occupied most the pore distribution of the M40-Silica xerogel, and large mesopores (10-50 nm) shouldered most the pore distribution for the M80-Silica xerogel. Among these three drug-loaded carriers, the M40-Silica xerogel with the largest amount of medium mesopores presented the best ITZ-release behavior, demonstrating that medium mesopores facilitated drug release, while small mesopores impeded drug release and large mesopores were not favorable to retaining amorphous drugs in the pores.

Correlation of lymph node metastasis with contrast-enhanced ultrasound features, microvessel density and microvessel area in patients with papillary thyroid carcinoma.

OBJECTIVE: This study aims to investigate the relationship of cervical lymph node metastasis (LNM) with contrast-enhanced ultrasound (CEUS) features, microvessel density (MVD) and microvessel area (MVA) in patients with papillary thyroid carcinoma (PTC), and to evaluate the diagnostic value of CEUS for PTC. METHODS: A total of 108 patients diagnosed with PTC at the First Affiliated Hospital of Jinzhou Medical University from January 2016 to December 2018 were selected and underwent preoperative CEUS of the thyroid, surgical resection and postoperative histopathological examination of their resected lesion. They were divided into a lymphatic metastasis-positive group (LNM+, n = 61) and a lymphatic metastasis-negative group (LNM-, n = 47) based on their lymph node status. The CEUS quantitative parameters, MVD and MVA, were compared between the two groups, and risk factors for LNM were analyzed by univariate and multivariate logistic regression. RESULTS: Compared with patients with in the LNM-group, the tumor diameter and the proportion of capsule contact of patients in the LNM+group were significantly greater and the patients in this group were younger. The rise time (RT), peak intensity (PI), area under the curve (AUC), MVD, and MVA were also significantly higher in the LNM+group than in the LMN-group, while there was no significant difference in time to peak (TP), mean transit time (mTT), velocity of intensity increase (IIV), and velocity of intensity decrease (IDV) between the two groups. Univariate and multivariate correlation analysis indicated that tumor size, RT, PI, AUC, MVD, and MVA were risk factors for LNM, and ROC curves further suggested that RT had the best overall predictive performance. CONCLUSION: Tumor size, RT, PI, AUC, MVD and MVA are risk factors for LNM in PTC. In other words, CEUS is an important non-invasive and preoperative tool for evaluating PTC, with MVD and MVA identified as vital postoperative diagnostic indicators.

The Number of Intraoperative Intestinal Venous Circulating Tumor Cells Is a Prognostic Factor for Colorectal Cancer Patients.

Purpose: To assess the association between intestinal venous blood (IVB) circulating tumor cells (CTCs) and clinicopathological parameters in stage I-III colorectal cancer (CRC) patients. Methods: Participants were retrospectively retrieved, who were admitted to our hospital or took annual physical exams between December 1, 2015 and December 31, 2018. A negative enrichment-immunofluorescence in situ hybridization (NE-imFISH) technique was used to isolate and identify CTCs. Receiver operating characteristic (ROC) curves and Youden index values were used to determine the critical CTC cutoff value for the diagnosis of CRC. Kaplan-Meier and log-rank methods were used to conduct survival analyses, and multivariate Cox regression analyses were employed for multivariate corrections to comprehensively evaluate the value of CTCs in the diagnosis of CRC. Relationships between IVB CTCs, clinicopathological parameters, and prognosis were then analyzed based upon patient postoperative follow-up data. Results: In total, we retrieved 282 patients including 48 healthy controls, 72 patients with benign colorectal tumors, and 162 CRC patients. CRC patients exhibited significantly higher numbers of CTCs relative to control patients or those with benign disease. CTC numbers in CRC patient peripheral blood (PB) and IVB were closely associated with tumor node metastasis (TNM) staging (P < 0.01), carbohydrate antigen-125 (CA-125) levels (P < 0.001), and KRAS (Kirsten rat sarcoma virus oncogene) mutation status (P < 0.001). The disease-free survival (DFS) of patients in the CTC-negative group was significantly longer than that of patients in the CTC-positive group (24.60 ± 13.31 months vs. 18.70 ± 10.19 months, P < 0.05), with the same being true with respect to their overall survival (OS) (30.60 ± 12.44 months vs. 35.25 ± 11.57 months, P < 0.05). A multivariate analysis revealed that the detection ≥2 CTCs/3.2 ml was independently associated with poorer DFS and OS. CTC counts were independently predictive of CRC patients TNM staging, CA-125, and KRAS mutation status in both univariate and multivariate Cox proportional hazards regression analyses. Conclusion: CTCs are valuable biomarkers that can be monitored to predict CRC patient disease progression.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

Mucin 16 Promotes Colorectal Cancer Development and Progression Through Activation of Janus Kinase 2.

BACKGROUND: Mucin 16 (MUC16), a cell surface-associated mucin, has been implicated to be upregulated in a large repertoire of malignances. However, its function in the pathogenesis of colorectal cancer (CRC) is unknown. AIMS: Here, we explored the regulatory role of MUC16 in CRC. METHODS: First, tumor and paracancerous tissues, and serum samples from 162 CRC patients, peripheral blood samples from 48 healthy volunteers and 72 benign colorectal patients were collected. The correlation between the MUC16 expression and the clinical phenotypes of the patients was analyzed. Subsequently, HCT116 and SW480 cells with deletion of MUC16 were established to detect changes in the growth and metastatic capacities of CRC cells. The genes with the highest correlation with MUC16 were predicted by bioinformatics, and their binding relationships were detected by Co-IP and double-labeled immunofluorescence, followed by functional rescue experiments. RESULTS: Overexpression of MUC16 in CRC patients was positively correlated with serum biomarkers and poor prognosis of patients. It was demonstrated by in vitro and in vivo experiments that knocking-down the expression of MUC16 could significantly inhibit the growth and metastasis of CRC cells. MUC16 activated janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) by interacting with JAK2. Further overexpression of JAK2 in cells with poor expression of MUC16 revealed a significant increase in the proliferative and metastatic capacities of CRC cells. CONCLUSIONS: MUC16 contributes to the development and progression of CRC by binding to JAK2, thereby promoting phosphorylation of JAK2 and further activating STAT3 phosphorylation.

Upregulation lnc-NEAT1 contributes to colorectal cancer progression through sponging miR-486-5p and activating NR4A1/Wnt/ß-catenin pathway.

Colorectal cancer is a major public health problem and fourth guiding cause of cancer-induced mortality worldwide. The five-year survival rate for patients with colorectal cancer remains poor, and almost half of colorectal cancer patients present recurrence and die within five years. The increasing studies showed that long non-coding RNA (lncRNA) was involved in colorectal cancer. Therefore, this study was used to explore molecular mechanisms of nuclear paraspeckle assembly transcript 1 (NEAT1) in colorectal cancer. The real-time quantitative polymerase chain reaction (RT-qPCR) was employed to estimate the expression levels of NEAT1, Nuclear receptor 4 A1 (NR4A1), and miR-486-5p in colorectal cancer tissues and cells. Kaplan-Meier curve was conducted to analyze relationship between survival time of colorectal cancer patients and level of NEAT1. The protein levels of NR4A1, ß-catenin, c-Myc, and cyclinD1 were assessed with western blot assay. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and flow cytometry assays were performed to evaluate proliferation and apoptosis of colorectal cancer cells, respectively. The migration and invasion abilities of cells were examined by transwell assay. The relationship between miR-486-5p and NEAT1 or NR4A1 was confirmed by dual-luciferase reporter assay. We found NEAT1 and NR4A1 were highly expressed in colorectal cancer tissues and cell lines compared with controls. Loss-functional experiments revealed that knockdown of NEAT1 or NR4A1 repressed proliferation and motility, while inducing apoptosis of colorectal cancer cells. The gain of NR4A1 could abolish NEAT1 silencing-induced effects in colorectal cancer cells. In addition, NEAT1 contributed to colorectal cancer progression through mediating NR4A1/Wnt/ß-catenin signaling pathway. In conclusion, NEAT1 stimulated colorectal cancer progression via acting as competing endogenous RNA to sponge miR-486-5p and regulate NR4A1/Wnt/ß-catenin signaling pathway.

All-trans retinoic acid suppressed GES-1 cell proliferation induced by exosomes from patients with precancerous lesions by arresting the cell cycle in S-phase.

We aimed to detect the expression of specific LncRNAs in exosomes isolated from the serum of patients with precancerous lesions and to study the effect of these serum exosomes on the activity of GES-1 cells in patients with precancerous lesions, as well as the activity of all-trans retinoic acid on GES-1 cells with or without the exosomes. Exosomes were extracted from the serum of patients with precancerous lesions and normal controls. Based on our previous sequencing results, quantitative real time-PCR was used to detect differentially expressed LncRNAs. Exosomes from the serum of patients with precancerous lesions were cocultured with GES-1 cells, and 5 µM all-trans retinoic acid was added as an intervention. Changes in cell viability and expression of LncHOXA10 were observed. Compared with the blank group, the proliferation activity of GES-1 cells cocultured with exosomes derived from the serum of patients with precancerous lesions was increased (P < 0.01), the proportion of cells in S phase was increased (P < 0.05). After adding 5 µM all-trans retinoic acid, the viability of cells decreased significantly (P < 0.01), the proportion of cells in S phase decreased significantly (P < 0.05). The expression of LncHOXA10 was decreased (P < 0.05). All-trans retinoic acid can conduct its chemopreventive effects by inhibiting the expression of LncHOXA10, thereby reducing the activity of LncHOXA10 in GES-1 cells cocultured with serum exosomes from patients with precancerous lesions.

All-Trans Retinoic Acid Rescues the Tumor Suppressive Role of RAR-ß by Inhibiting LncHOXA10 Expression in Gastric Tumorigenesis.

Numerous long noncoding RNAs (LncRNAs) were having recently been shown to be involved in cancer development, including gastric cancer (GC). However, the precise mechanism and treatments to target these molecules have rarely been studied. Thus, we aimed to investigate the function of LncHOXA10 in gastric tumorigenesis and targeted therapy. First, we measured the differences in LncHOXA10 and retinoic acid receptor ß (RAR-ß) levels in gastric cancer tissues and cell lines compared with those in noncancerous tissues and cell lines. We observed that LncHOXA10 was significantly upregulated in gastric cancer tissues and cell lines, whereas RAR-ß showed the opposite trend. Subsequently, loss and gain of LncHOXA10 cell lines were constructed to determine whether LncHOXA10 plays a role in gastric tumorigenesis. The results showed that LncHOXA10 promoted the proliferation, migration, and invasion of cells, whereas apoptosis was markedly inhibited. Subsequently, mechanistic investigations revealed that LncHOXA10 can repress RAR-ß expression and that all-trans retinoic acid (ATRA) can rescue the expression of RAR-ß. Finally, we showed that ATRA can reverse the pro-cancerous function of LncHOXA10. We showed that LncHOXA10 may be a prognostic and therapeutic factor of gastric cancer by negatively regulating RAR-ß. Furthermore, ATRA can inhibit the role of LncHOXA10 in gastric tumorigenesis.

Comprehensive Analysis of Alternative Splicing Signature in Gastric Cancer Prognosis Based on The Cancer Genome Atlas (TCGA) and SpliceSeq Databases.

BACKGROUND Increasing evidence suggests that the alternative splicing (AS) signature plays a role in the carcinogenesis and prognosis of various cancers. However, the prognostic role of AS in gastric cancer is not clear and needs to be clarified. MATERIAL AND METHODS To identify the differentially expressed AS (DEAS) events, we performed a differential expression analysis between normal and tumor tissue. The DEAS event was further applied to construct a prognostic signature by performing univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis. The Kaplan-Meier curve analysis and receiver operating characteristic curve (ROC) analysis were used to evaluate the prognostic value of the AS signature. In addition, the network of the splicing events with splicing factors was constructed using the Cytoscape software. RESULTS A total of 30 005 alternative splicing (AS) events with 372 patients were retrieved from the SpliceSeq database and TCGA database. By performing differential expression analysis, a total of 419 alternative splicing events were screened out, including 56 upregulated and 363 downregulated. We further constructed an AS-related prognostic signature by conducting a series bioinformatics analyses. Moreover, we identified that the AS signature could serve as an independent predictor for the prognosis of GC. We also found that AS signature had a more robust and precise efficacy for prognostic prediction in GC patients. Interestingly, the areas under 3- and 5-year survival curves are similar, both of which are greater than 1-year survival curve, suggesting that the long-term predictive accuracy of our prognostic model built upon AS signature is superior. CONCLUSIONS We performed a comprehensive analysis of overall prognostic-associated AS events concerning GC and constructed a prognostic model to predict the long-term prognostic survival outcomes in GC patients. We also developed a network of splicing events with splicing factors to reveal new potential molecular diagnostic biomarkers and therapeutic targets for GC patients.

Diet and liver cancer risk: a narrative review of epidemiological evidence.

Primary liver cancer is the third leading cause of cancer-related death worldwide. Most patients are diagnosed at late stages with poor prognosis; thus, identification of modifiable risk factors for primary prevention of liver cancer is urgently needed. The well-established risk factors of liver cancer include chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), heavy alcohol consumption, metabolic diseases such as obesity and diabetes, and aflatoxin exposure. However, a large proportion of cancer cases worldwide cannot be explained by current known risk factors. Dietary factors have been suspected as important, but dietary aetiology of liver cancer remains poorly understood. In this review, we summarised and evaluated the observational studies of diet including single nutrients, food and food groups, as well as dietary patterns with the risk of developing liver cancer. Although there are large knowledge gaps between diet and liver cancer risk, current epidemiological evidence supports an important role of diet in liver cancer development. For example, exposure to aflatoxin, heavy alcohol drinking and possibly dairy product (not including yogurt) intake increase, while intake of coffee, fish and tea, light-to-moderate alcohol drinking and several healthy dietary patterns (e.g. Alternative Healthy Eating Index) may decrease liver cancer risk. Future studies with large sample size and accurate diet measurement are warranted and need to consider issues such as the possible aetiological heterogeneity between liver cancer subtypes, the influence of chronic HBV or HCV infection, the high-risk populations (e.g. cirrhosis) and a potential interplay with host gut microbiota or genetic variations.

User abnormal behavior recommendation via multilayer network.

With the growing popularity of online services such as online banking and online shopping, one of the essential research topics is how to build a privacy-preserving user abnormal behavior recommendation system. However, a machine-learning based system may present a dilemma. On one aspect, such system requires large volume of features to pre-train the model, but on another aspect, it is challenging to design usable features without looking to plaintext private data. In this paper, we propose an unorthodox approach involving graph analysis to resolve this dilemma and build a novel private-preserving recommendation system under a multilayer network framework. In experiments, we use a large, state-of-the-art dataset (containing more than 40,000 nodes and 43 million encrypted features) to evaluate the recommendation ability of our system on abnormal user behavior, yielding an overall precision rate of around 0.9, a recall rate of 1.0, and an F1-score of around 0.94. Also, we have also reported a linear time complexity for our system. Last, we deploy our system on the "Wenjuanxing" crowd-sourced system and "Amazon Mechanical Turk" for other users to evaluate in all aspects. The result shows that almost all feedbacks have achieved up to 85% satisfaction.

[Up-expression of ICOS and PD-1 on peripheral CD3+CD8+ effector memory T cells and Tfh cells are associated with the severity of rheumatoid arthritis].

Objective To investigate the expression of programmed cell death 1 (PD-1) and inducible costimulatory molecules (ICOS) on peripheral T lymphocytes of patients with rheumatoid arthritis (RA) and to determine its relationship with disease severity. Methods The study included 30 RA patients and 26 healthy people. Flow cytometry was used to detect the ratio of CD3+CD8+ effector memory T cells (Tem) and follicular helper T (Tfh) cells in peripheral blood, and then to detect the proportion of PD-1 and ICOS-positive cells in lymphocyte subsets. Correlation between them and 28 joint disease activity scores (DAS28) was assessed by Spearman correlation analysis. Results The absolute number of Tem and Tfh cells in the RA group was higher than that in the healthy group. The expression of ICOS and PD-1 in the RA group was higher than that in the healthy group. There was a positive correlation between the expression of ICOS and PD-1 on peripheral CD3+CD8+ Tem and Tfh cells and DAS28 in RA group. Conclusion PD-1 and ICOS on peripheral CD3+CD8+ Tem and Tfh cells may be involved in the development of RA and may be an indicator of RA activity.