Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses.

Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered. Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53fl/flLSL-KrasG12D, Ccr7-/-, Cd93-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed. Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93. Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.

Land cover dataset of the China Central-Asia West-Asia Economic Corridor from 1993 to 2018.

Land Cover (LC) maps offer vital knowledge for various studies, ranging from sustainable development to climate change. The China Central-Asia West-Asia Economic Corridor region, as a core component of the Belt and Road initiative program, has been experiencing some of the most severe LC change tragedies, such as the Aral Sea crisis and Lake Urmia shrinkage, in recent decades. Therefore, there is a high demand for producing a fine-resolution, spatially-explicit, and long-term LC dataset for this region. However, except China, such dataset for the rest of the region (Kyrgyzstan, Turkmenistan, Kazakhstan, Uzbekistan, Tajikistan, Turkey, and Iran) is currently lacking. Here, we constructed a historical set of six 30-m resolution LC maps between 1993 and 2018 at 5-year time intervals for the seven countries where nearly 200,000 Landsat scenes were classified into nine LC types within Google Earth Engine cloud computing platform. The generated LC maps displayed high accuracies. This publicly available dataset has the potential to be broadly applied in environmental policy and management.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Off-stoichiometry and molybdenum substitution effects on elastic moduli of B1-type titanium carbide.

B1-type MX ceramics are composed of transition metals (M) and C, N, and/or O (X) occupying the M and X sites, respectively, and having M-X nearest neighbor (NN) bonds and M-M and X-X next nearest neighbor (NNN) bonds. Substitution of the elements and the formation of structural vacancies in B1-type ceramics change the numbers and strengths of the bonds, leading to novel properties. The change in elastic modulus of off-stoichiometric TiC in equilibrium with a Ti-Mo solid solution phase was experimentally investigated based on the rule of mixtures from the Voigt model. The experimentally obtained values agreed well with the results of density functional theory calculations. The bulk modulus (K) of TiC increased from 205.6 to 239.2 GPa as the fraction of Ti sites occupied by Mo increased from 0.11 to 0.33, whereas the Young's modulus (E) and the shear modulus (G) remained nearly constant. On the other hand, all three elastic moduli decreased with increasing vacancy fraction at the C sites. These results suggest that the M-X bond strength should be the dominant factor in these moduli and the effect of M-M bond on K is greater than that of G and E.

Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model.

Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

UPLC-QE-Orbitrap-Based Cell Metabolomics and Network Pharmacology to Reveal the Mechanism of N-Benzylhexadecanamide Isolated from Maca (Lepidium meyenii Walp.) against Testicular Dysfunction.

Testicular dysfunction (TDF) is characterized by testosterone deficiency and is caused by oxidative stress injury in Leydig cells. A natural fatty amide named N-benzylhexadecanamide (NBH), derived from cruciferous maca, has been shown to promote testosterone production. Our study aims to reveal the anti-TDF effect of NBH and explore its potential mechanism in vitro. This study examined the effects of H2O2 on cell viability and testosterone levels in mouse Leydig cells (TM3) under oxidative stress. In addition, cell metabolomics analysis based on UPLC-Q-Exactive-MS/MS showed that NBH was mainly involved in arginine biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, the TCA cycle and other metabolic pathways by affecting 23 differential metabolites, including arginine and phenylalanine. Furthermore, we also performed network pharmacological analysis to observe the key protein targets in NBH treatment. The results showed that its role was to up-regulate ALOX5, down-regulate CYP1A2, and play a role in promoting testicular activity by participating in the steroid hormone biosynthesis pathway. In summary, our study not only provides new insights into the biochemical mechanisms of natural compounds in the treatment of TDF, but also provides a research strategy that integrates cell metabolomics and network pharmacology in order to promote the screening of new drugs for the treatment of TDF.

Debt default, financial risk transmission and governance from the perspective of supply chain network.

The stock risk spillovers of 31 associated enterprises of Evergrande supply chain in China were measured with DCC-GARCH and CoVaR model, and high, moderate and low risk overflow networks in four periods were constructed, finally the overall metrics and dynamic evolution of risk spillover network were explored. The results showed that: With COVID-19 under control in China, the risk spillover of Evergrande supply chain associated enterprises continues to diverge, with the quantity and scope of high risk declining and moderate and low risk rising; The infection scope of high risk spillover has narrowed, from indirect to direct infection; Evergrande subsidiaries play obvious bridge roles in moderate and low risk networks, have strong control over the risk spread; Commercial banks suffer and trigger more risk spillovers, a number of risk spillover groups with commercial banks as cores formed in high and moderate risk networks.

Primary cilia-associated protein IFT172 in ciliopathies.

Cilium is a highly conserved antenna-like structure protruding from the surface of the cell membrane, which is widely distributed on most mammalian cells. Two types of cilia have been described so far which include motile cilia and immotile cilia and the latter are also known as primary cilia. Dysfunctional primary cilia are commonly associated with a variety of congenital diseases called ciliopathies with multifaceted presentations such as retinopathy, congenital kidney disease, intellectual disability, cancer, polycystic kidney, obesity, Bardet Biedl syndrome (BBS), etc. Intraflagellar transport (IFT) is a bi-directional transportation process that helps maintain a balanced flow of proteins or signaling molecules essential for the communication between cilia and cytoplasm. Disrupted IFT contributes to the abnormal structure or function of cilia and frequently promotes the occurrence of ciliopathies. Intraflagellar transport 172 (IFT172) is a newly identified member of IFT proteins closely involved in some rare ciliopathies such as Mainzer-Saldino syndrome (MZSDS) and BBS, though the underpinning causal mechanisms remain largely elusive. In this review, we summarize the key findings on the genetic and protein characteristic of IFT172, as well as its function in intraflagellar transport, to provide comprehensive insights to understand IFT172-related ciliopathies.

Comprehensive analysis to identify the influences of SARS-CoV-2 infections to inflammatory bowel disease.

Background: Coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) are both caused by a disordered immune response and have direct and profound impacts on health care services. In this study, we implemented transcriptomic and single-cell analysis to detect common molecular and cellular intersections between COVID-19 and IBD that help understand the linkage of COVID-19 to the IBD patients. Methods: Four RNA-sequencing datasets (GSE147507, GSE126124, GSE9686 and GSE36807) from Gene Expression Omnibus (GEO) database are extracted to detect mutual differentially expressed genes (DEGs) for IBD patients with the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to find shared pathways, candidate drugs, hub genes and regulatory networks. Two single-cell RNA sequencing (scRNA-eq) datasets (GSE150728, PRJCA003980) are used to analyze the immune characteristics of hub genes and the proportion of immune cell types, so as to find common immune responses between COVID-19 and IBD. Results: A total of 121 common DEGs were identified among four RNA-seq datasets, and were all involved in the functional enrichment analysis related to inflammation and immune response. Transcription factors-DEGs interactions, miRNAs-DEGs coregulatory networks, and protein-drug interactions were identified based on these datasets. Protein-protein interactions (PPIs) was built and 59 hub genes were identified. Moreover, scRNA-seq of peripheral blood monocyte cells (PBMCs) from COVID-19 patients revealed a significant increase in the proportion of CD14+ monocytes, in which 38 of 59 hub genes were highly enriched. These genes, encoding inflammatory cytokines, were also highly expressed in inflammatory macrophages (IMacrophage) of intestinal tissues of IBD patients. Conclusions: We conclude that COVID-19 may promote the progression of IBD through cytokine storms. The candidate drugs and DEGs-regulated networks may suggest effective therapeutic methods for both COVID-19 and IBD.

Clinical study of the combined use of dexmedetomidine and remifentanil in patients with coronary heart disease undergoing 3D laparoscopic surgery with EEG bispectral index monitoring.

OBJECTIVE: This study sought to investigate the safety and clinical outcomes associated with the combined administration of dexmedetomidine (Dex) and remifentanil (Rem) in patients with coronary heart disease undergoing three-dimensional (3D) laparoscopic surgery, with concurrent monitoring of the electroencephalography (EEG) bispectral index. METHODS: This study is of a retrospective nature and involved a total of 60 patients with coronary heart disease who underwent 3D laparoscopic surgery at our hospital between June 2020 and September 2021. In a double-blind manner, these patients were randomly assigned to two groups: the control group (Group I), which consisted of 30 patients, and the treatment group (Group II) receiving a combination of Dex and Rem, also comprising 30 patients. The study's primary objective was to compare and assess the treatment outcomes in these two patient groups. RESULTS: Patients in Group II who developed postoperative coronary heart disease experienced a significant reduction in blood pressure, heart rate, and electrocardiogram values (P<0.05). Additionally, Group II exhibited lower bispectral index (BIS) and visual analog scale (VAS) values (P<0.05). CONCLUSION: In patients with coronary heart disease undergoing 3D laparoscopic surgery, the intraoperative use of Dex combined with Rem anesthesia offers several advantages. It helps stabilize hemodynamics, reducing the risk of myocardial ischemia, and significantly alleviates postoperative pain, all without increasing the likelihood of adverse postoperative reactions. Furthermore, this approach effectively dampens the intraoperative and postoperative stress response, facilitating enhanced recovery after surgery (ERAS). Overall, the clinical impact is positive, safe, and reliable.

[A new approach for optimizing empirical prescriptions of famous physicians based on network target: taking Qingluo Decoction as an example].

Based on the network target approach and technology, this study proposed for the first time a novel optimization method for Chinese medicine formulae. Moreover, with Qingluo Decoction as an example, a method for the research and development of Chinese medicine, which combines scientific methodology and experience of famous doctors, was developed. Specifically, based on the composition of Qingluo Decoction, this study used the using network target for intelligent and quantitative analysis on drug actions(UNIQ) to predict the medicinals that targeted the key pathways of rheumatoid arthritis(RA) such as angiogenesis. Then, combining the experience of the first national Chinese medical master LI Ji-ren and Aihui famous Chinese medicine doctor LI Yan and Chinese medicine theory, this study developed a novel angiogenesis-targeted prescription modified Qingluo Decoction(MQLD). Afterward, the clinical efficacy and mechanism of MQLD were verified. The results showed that 27 medicinals with significant regulatory effect on angiogenesis-related key signaling pathways were identified by UNIQ, among which 6 were selected by the Chinese medicine physicians to develop the MQLD. Clinical trials demonstrated that the clinical efficacy of MQLD, in terms of either American College of Rheumatology 20% improvement and 50% improvement criteria(ACR20, ACR50) or TCM syndrome evaluation, was better than that of Qingluo Decoction. Experimental study revealed that MQLD can inhibit RA angiogenesis by acting on the vascular endothelial growth factor(VEGF) pathway, nuclear factor κB(NF-κB) pathway, inflammatory cytokine release, and immune cell regulation. Taken together, this study developed a new formula MQLD with improved clinical efficacy, precise applicable clinical settings, and authorized patent through the network target technology, thus providing a new way for the precise development of Chinese medicine and preservation of the experience of famous physicians.

Screening of the Active Compounds against Neural Oxidative Damage from Ginseng Phloem Using UPLC-Q-Exactive-MS/MS Coupled with the Content-Effect Weighted Method.

The neuroprotective properties of ginsenosides have been found to reverse the neurological damage caused by oxidation in many neurodegenerative diseases. However, the distribution of ginsenosides in different tissues of the main root, which was regarded as the primary medicinal portion in clinical practice was different, the specific parts and specific components against neural oxidative damage were not clear. The present study aims to screen and determine the potential compounds in different parts of the main root in ginseng. Comparison of the protective effects in the main root, phloem and xylem of ginseng on hydrogen peroxide-induced cell death of SH-SY5Y neurons was investigated. UPLC-Q-Exactive-MS/MS was used to quickly and comprehensively characterize the chemical compositions of the active parts. Network pharmacology combined with a molecular docking approach was employed to virtually screen for disease-related targets and potential active compounds. By comparing the changes before and after Content-Effect weighting, the compounds with stronger anti-nerve oxidative damage activity were screened out more accurately. Finally, the activity of the selected monomer components was verified. The results suggested that the phloem of ginseng was the most effective part. There were 19 effective compounds and 14 core targets, and enriched signaling pathway and biological functions were predicted. After Content-Effect weighting, compounds Ginsenosides F1, Ginsenosides Rf, Ginsenosides Rg1 and Ginsenosides Rd were screened out as potential active compounds against neural oxidative damage. The activity verification study indicated that all four predicted ginsenosides were effective in protecting SH-SY5Y cells from oxidative injury. The four compounds can be further investigated as potential lead compounds for neurodegenerative diseases. This also provides a combined virtual and practical method for the simple and rapid screening of active ingredients in natural products.

Manual Acupuncture or Combination of Rehabilitation Therapy to Treat Poststroke Dysphagia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Backgroundand Objective. Poststroke dysphagia is one of the most common stroke complications with high morbidity and long course, while acupuncture treatment is easily accepted by patients due to its reliability, feasibility, simple operation, low price, and quick effect. Our objective was to evaluate the efficacy of manual acupuncture in poststroke dysphagia patients. Methods. Databases including Medline, Web of Science, PubMed, Cochrane Library databases, EMBASE, CNKI (China National Knowledge Infrastructure), WanFang (WanFang Database), and VIP (Chongqing VIP) were searched from inception until Aug 19, 2022. Data were analyzed using Revman 5.3, Stata 14.0, and TSA 0.9.5.10 Beta software. Evidence quality evaluation was performed by using GRADE profiler 3.6. Results. A total of 33 randomized control trials (RCTs) enrolled 2680 patients. Meta-analysis results revealed that compared to rehabilitation, acupuncture decreased water swallow test (WST) and standard swallowing assessment (SSA) scores. Meanwhile, in contrast to rehabilitation alone, integration of acupuncture with rehabilitation effectively decreased WST and SSA scores; improved swallowing scores of videofluoroscopic swallowing study (VFSS), swallowing scores of Fujishima Ichiro, Barthel index (BI), and swallowing quality of life questionnaire (SWAL-QOL); reduced the aspiration rates as well as aspiration pneumonia; and shortened the duration of empty swallowing and the duration of 5 mL water swallowing. Pooled analysis did not reveal any significant differences in dysphagia outcome severity scores (DOSS) (p=0.15 > 0.05p) between the acupuncture group combined with rehabilitation group and the rehabilitation group alone. After the risk-of-bias assessment, these studies were not of low quality, except in terms of allocation concealment and blindness. Evidence quality evaluation showed that allocation concealment and blindness led to a downgrade and primary outcomes' evaluation of acupuncture combined with rehabilitation were ranked as moderate-quality evidence while acupuncture alone was ranked as low-quality. Conclusion. This meta-analysis provided positive pieces of evidences that acupuncture and acupuncture combined with rehabilitation were better than using rehabilitation alone in the treatment of poststroke dysphagia.

Association between vitamin D serum levels and insulin resistance assessed by HOMA-IR among non-diabetic adults in the United States: Results from NHANES 2007-2014.

Insulin resistance, a pathological response to insulin hormone in insulin-dependent cells, is characterized by the presence of high glucose and insulin concentrations. The homeostasis model of insulin resistance (HOMA-IR) is one of the most used indexes to estimate insulin resistance by assessing the fasting glucose and insulin levels. An association was observed between vitamin D levels and insulin resistance, which varied in different ethnic groups, and there is some evidence that vitamin D supplementation could contribute to the improvement of insulin resistance. This study assessed the association between 25-hydroxyvitamin D (25[OH]D) concentration and HOMA-IR in American adults aged 20 years and older, without diabetes and other chronic diseases that can influence insulin resistance. The data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014 were used by exploiting the free and publicly-accessible web datasets. Linear regression models were performed to evaluate the association between serum 25(OH)D concentration and HOMA-IR, and a negative association was observed, which remained significant following the adjustment for age, gender, race/ethnicity, education, body mass index (BMI), physical activity, the season of examination, current smoking, hypertension, the use of drugs which can influence insulin resistance, serum bicarbonates, triglycerides, and calcium and phosphorus levels. Only in non-Hispanic Blacks was this inverse association between vitamin D and HOMA-IR not observed in the fully adjusted model. Further studies are needed to explain the mechanisms of the observed ethnic/racial differences in the association of vitamin D levels with HOMA-IR.

High levels of triglycerides, apolipoprotein B, and the number of colorectal polyps are risk factors for colorectal polyp recurrence after endoscopic resection: a retrospective study.

Background: The recurrence of polyps after endoscopic treatment is a difficult problem and there may be an association between blood lipid levels and colorectal polyps, but this is controversial and the aim of this study is to explore the risk factors for colorectal polyp recurrence. Methods: A total of 357 patients who underwent intestinal polypectomy from January 1, 2019 to June 1, 2020 in Sichuan Provincial People's Hospital were included in this retrospective study to analyze the potential association between blood indices and recurrence risk. Polyp recurrence was defined as the detection of 1 or more polyps at any time after polypectomy, regardless of site. Follow-up was performed through the electronic medical record system. Patients' age, gender, tobacco and alcohol liking, duration of follow-up, body mass index (BMI), polyp size, number, type of pathology, and lipid profiles (triglycerides, cholesterol, apolipoprotein B, and apolipoprotein A) were collected. Results: Triglycerides (1.54±0.95 vs. 1.25±1.01, P=0.036) and apolipoprotein B (0.87±0.26 vs. 0.79±0.16 mL, P=0.001) were significantly different in both the recurrence and non-recurrence groups. Binary logistic regression identified 3 independent risk factors for recurrence: triglycerides [odds ratio (OR): 1.763, 95% confidence interval (CI): 1.003 to 3.098, P=0.049], apolipoprotein B (OR: 5.438, 95% CI: 1.411 to 20.961, P=0.014), and the number of polyps (OR: 2.540, 95% CI: 1.649 to 3.911, P<0.001). Conclusions: High levels of triglycerides, apolipoprotein B, and the number of colorectal polyps are risk factors for colorectal polyp recurrence after endoscopic resection. Therefore, for patients at high risk of polyp recurrence, we recommend aggressive control of triglyceride and apolipoprotein B levels.

A novel hypoxia-driven gene signature that can predict the prognosis and drug resistance of gliomas.

Hypoxia spontaneously forms in the interior of glioma tissues and regulates the expression of various genes. However, the status of hypoxia-driven genes in glioma tissues is not completely known. In the current study, RNA-seq data of 695 glioma tissues in The Cancer Genome Atlas (TCGA) were set as a discovery cohort and were used to identify hypoxia-driven genes and construct a novel gene signature. The prognostic values of that signature were verified in data from the TCGA and the Chinese Glioma Genome Atlas (CGGA). The expression and diagnostic values of hypoxia-driven genes were analyzed using immunohistochemistry and receiver operator characteristic curves. Finally, the effects of hypoxia-driven genes on temozolomide (TMZ) resistance were analyzed by western blot, CCK-8 and colony formation assay. A total of 169 hypoxia-driven genes were identified, which were associated with a poor outcome in glioma patients. Among them, 22 genes had a degree score ≥10 and 6 genes (WT1, HOXA2, HOXC6, MMP9, SHOX2 and MYOD1) were selected to construct a signature to classify glioma patients into low- or high-risk groups. That signature had a remarkable prognostic value for glioma patients in TCGA and CGGA. The expression of HOXC6, MMP9, SHOX2 and MYOD1 was associated with hypoxia degree in glioma tissues and in recurrent cases, had a remarkable diagnostic value and a significant relationship with disease free survival in glioma patients. Moreover, SHOX2 was highly expressed in glioma tissues with O-6-methylguanine-DNA methyltransferase (MGMT)-unmethylation and temozolomide (TMZ) resistant glioma cell lines, and associated with MGMT expression. Knockdown the expression of SHOX2 significantly reduced the TMZ-resistance induced by hypoxia in glioma cells. Ultimately, we identified six novel hypoxia-driven genes for reliable prognostic prediction in gliomas and found that SHOX2 might be a potential target to overcome the TMZ resistance induced by hypoxia.

Gp350-anchored extracellular vesicles: promising vehicles for delivering therapeutic drugs of B cell malignancies.

Although chimeric antigen receptor-modified (CAR) T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia, its effect on Burkitt lymphoma (BL) and chronic B lymphocytic leukemia (B-CLL) is unsatisfactory. Moreover, fatal side effects greatly impede CAR T cell application. Extracellular vesicles (EVs) are excellent carriers of therapeutic agents. Nevertheless, EVs mainly accumulate in the liver when administered without modification. As an envelope glycoprotein of Epstein-Barr viruses, gp350 can efficiently bind CD21 on B cells. Here, gp350 was directly anchored onto red blood cell EVs (RBC-EVs) via its transmembrane region combined with low-voltage electroporation. The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs (RBC-EVs/gp350Etp) exhibited increased targeting to CD21+ BL and B-CLL relative to RBC-EVs. After the loading of doxorubicin or fludarabine, RBC-EVs/gp350Etp had powerful cytotoxicity and therapeutic efficacy on CD21+ BL or B-CLL, respectively. Moreover, RBC-EVs/gp350Etp loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal B cells. Therefore, our findings indicate that drug-loaded RBC-EVs/gp350Etp may be adopted in the treatment of CD21+ B cell malignancies.

Liraglutide Attenuates Restenosis After Vascular Injury in Rabbits With Diabetes Via the TGF-ß/Smad3 Signaling Pathway.

Background: Lower limb ischemia due to arterial stenosis is a major complication in patients with diabetes mellitus (DM). Liraglutide is a long-acting analogue of a glucagon-like peptide 1 (GLP-1) receptor agonist used for lowering blood glucose in patients with DM, and is believed to possess cardiovascular protective effects. The aim of this study was to investigate whether liraglutide has a protective effect on blood vessels and alleviates vascular intimal hyperplasia in streptozotocin (STZ)-induced rabbits with DM and its molecular mechanism. Methods: Rabbits with DM were induced by STZ, and a lower limb ischemia model was established. The animals were divided into a control group, DM-injury group and liraglutide treatment group. Pathological staining was used to observe the intimal growth, analyze the oxidation levels of malondialdehyde (MDA), superoxide dismutase (SOD) and plasma glutathione peroxidase (GSH-Px), and analyze the changes in expression of marker proteins and signaling pathway proteins by Western blotting. A hyperglycemia (HG)-injured vascular smooth muscle cells (VSMCs) model was established to analyze reactive oxygen species (ROS) levels, Cell-Counting Kit-8 (CCK-8) was used to analyze cell proliferation, scratch assay and Transwell Migration Assay to analyze cell migration, flow cytometry to analyze apoptosis and Western blotting was used to analyze changes in the expression of marker and signaling pathway proteins. Results: The results of pathological staining showed that intimal hyperplasia was severe after diabetes-induced lower limb ischemia in rabbits at 4 weeks, and liraglutide treatment reduced symptoms. Liraglutide treatment significantly decreased MDA content, increased SOD, GSH-Px content, and augmented total antioxidant capacity levels in tissues. The results of Western blotting analysis showed that E-cadherin, mitochondrial membrane potential 9 (MMP-9), proliferating cell nuclear antigen (PCNA), and type I collagen protein expression levels were significantly decreased after liraglutide treatment compared with the DM injury group. The results indicated that liraglutide inhibited epithelial-mesenchymal transition (EMT) progression, vascular cell proliferation and migration and collagen production. Liraglutide inhibits transforming growth factor beta 1 (TGF-ß1)/Smad3 signaling pathway protein expression. In vitro assays have shown that liraglutide reduces cellular ROS levels, inhibits cell proliferation and migration and promotes apoptosis. Liraglutide down-regulated the expression of E-cadherin, MMP-9, PCNA, type I collagen protein as well as the TGF-ß1/Smad3 signaling pathway, but this effect could be reversed by tumor necrosis factor alpha (TNF-α). Conclusion: Liraglutide can significantly improve tissue antioxidant capacity, reduce vascular cell proliferation and migration via the TGF-ß1/Smad3 signaling pathway, inhibit the EMT and collagen production processes, and alleviate hyperglycemia(HG)-induced lower limb ischemia and intimal hyperplasia.

Prevalence of myopia and influencing factors among high school students in Nantong, China: A cross-sectional study.

INTRODUCTION: Myopia is an increasingly serious health problem in China. The aim of this study was to investigate the prevalence of myopia and the factors associated with it among students in Nantong, China, to show the current status of myopia prevention. METHODS: This school-based, cross-sectional study examined students from all high schools in an urban area of Nantong, China. At least two classes were randomly selected from each grade of each school. A self-reported questionnaire was used to collect the required information.Univariate analyses were performed to identify associations between myopia and various parameters.Non-cycloplegic autorefraction and visual acuity were assessed for each student. Factors that were statistically significant in univariate analyses were selected for multivariate analyses. Myopia was defined as a spherical equivalent refraction of ≤ -0.5 diopters. RESULTS: The completion percentage of students out of the whole high school was 6.5%.The overall prevalence of myopia was 94%. The response percentage of the number of validated questionnaires was 90.2%, of which 50.2% (n = 1,466) were from male participants, and 49.8% (n = 1,452) were from female participants. The mean (SD) of age was 15.22±1.75 years, ranging from 12-18 years. Factors such as female sex, older age, parental myopia, sitting in the back of the classroom, increased homework time, and minimal outdoor activity were significantly associated with a higher risk of myopia (P < 0.05). In the myopic population, most students (67.9%) did not take measures to prevent further progression of myopia. CONCLUSION: The prevalence of myopia among high school students was 94%. Female sex, older age, parental myopia, sitting in the back of the classroom, increased homework time, and minimal outdoor activity were significantly associated with a higher risk of myopia. Most students with myopia (67.9%) did not take measures to prevent further progression of myopia.