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IGF1R plays an important role in regulating cellular metabolism and cell growth, and has been identified as an anti-cancer and diabetes drug target. Although research have been reported many crystal and cryo-EM structures of IGF1R, the mechanism of ligand binding remains controversial, mainly because the structure differences among its cryo-EM, crystal and homologous protein insulin receptor structures. Here, we further determined one new high-resolution symmetric cryo-EM structure of ligand-bound IGF1R and be the first to prove that the receptor could bind to two IGFI molecules by single particle cryo-electron microscopy. And the structure is very different from its homologous protein insulin receptor: the two ligands just exist at the binding site 2 with saturating ligand conditions. Then, our findings resolved the major dispute about the comformational changes of IGF1R, and proposed a new theory how IGF1R binds to its ligands. Meanwhile, these findings imply more attention may be needed to study the relationship between the special conformation and their corresponding physiological functions in future.

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase ubiquitously expressed mainly in the cytoplasm of several tissues. SHP2 modulates diverse cell signaling events that control metabolism, cell growth, differentiation, cell migration, transcription and oncogenic transformation. It interacts with diverse molecules in the cell, and regulates key signaling events including RAS/ERK, PI3K/AKT, JAK/STAT and PD-1 pathways downstream of several receptor tyrosine kinases (RTKs) upon stimulation by growth factors and cytokines. SHP2 acts as both a phosphatase and a scaffold, and plays prominently oncogenic functions but can be tumor suppressor in a context-dependent manner. It typically acts as a positive regulator of RTKs signaling with some inhibitory functions reported as well. SHP2 expression and activity is regulated by such factors as allosteric autoinhibition, microRNAs, ubiquitination and SUMOylation. Dysregulation of SHP2 expression or activity causes many developmental diseases, and hematological and solid tumors. Moreover, upregulated SHP2 expression or activity also decreases sensitivity of cancer cells to anticancer drugs. SHP2 is now considered as a compelling anticancer drug target and several classes of SHP2 inhibitors with different mode of action are developed with some already in clinical trial phases. Moreover, novel SHP2 substrates and functions are rapidly growing both in cell and cancer. In view of this, we comprehensively and thoroughly reviewed literatures about SHP2 regulatory mechanisms, substrates and binding partners, biological functions, roles in human cancers, and different classes of small molecule inhibitors target this oncoprotein in cancer.

Lung cancer is one of the most common malignant tumors with growing morbidity and mortality worldwide. Several treatments are used to manage lung cancer, including surgery, radiotherapy and chemotherapy, as well as molecular-targeted therapy. However, the current measures are still far from satisfactory. Therefore, the current research should focus on exploring the molecular mechanism and then finding an effective treatment. Interestingly, we and others have embarked on a line of investigations focused on the mechanism of lung cancer. Specifically, lncRNA small nucleolar RNA host gene has been shown to be associated with biological characteristics and therapeutic resistance of lung cancer. In addition, small nucleolar RNA host genes may be used as diagnostic biomarker in the future. Herein, we will provide a brief review demonstrating the importance of small nucleolar RNA host genes in lung cancer, especially non-small cell lung cancer. Although lncRNA has shown a crucial role in tumor-related research, a large number of studies are needed to validate its clinical application in the future.

We examined the relationship between trimester of SARS-CoV-2 infection, illness severity, and risk for preterm birth.We analyzed data for 6336 pregnant persons with SARS-CoV-2 infection in 2020 in the United States. Risk ratios for preterm birth were calculated for illness severity, trimester of infection, and illness severity stratified by trimester of infection adjusted for age, selected underlying medical conditions, and pregnancy complications.Pregnant persons with critical COVID-19 or asymptomatic infection, compared to mild COVID-19, in the second or third trimester were at increased risk of preterm birth. Pregnant persons with moderate-to-severe COVID-19 did not show increased risk of preterm birth in any trimester.Critical COVID-19 in the second or third trimester was associated with increased risk of preterm birth. This finding can be used to guide prevention strategies, including vaccination, and inform clinical practices for pregnant persons.

Retinopathy of prematurity (ROP), which is characterized by retinal neovascularization (RNV), is a major cause of neonatal blindness. The primary treatment for ROP is anti-vascular endothelial growth factor (VEGF) therapy, which is costly and can rapidly lead to desensitization. Celastrol, a bioactive compound extracted fromiTripterygium wilfordii/iHook F. ("Thunder of God Vine"), has been shown to exert anticancer and anti-inflammatory effects. However, whether celastrol has antiangiogenic activity and can suppress inflammation to inhibit ROP progression is unclear. This was investigated in the present study in vitro as well as in vivo using a mouse model of oxygen-induced retinopathy (OIR). Our results showed that celastrol treatment reduced neovascular and avascular areas in the retina and inhibited microglia activation and inflammation in OIR mice. Celastrol also inhibited proliferation, migration, and tube formation in cultured human retinal microvascular endothelial cells, and reversed the activation of the microRNA (miR)-17-5p/hypoxia-inducible factor (HIF)-1α/VEGF pathway in the retina of OIR mice. These results indicate that celastrol alleviates pathologic RNV in the retina by protecting neuroglia and suppressing inflammation via inhibition of miR-17-5p/HIF-1α/VEGF signaling, and thus has therapeutic potential for the prevention and treatment of ROP.bAbbreviations:/bBSA, bovine serum albumin; COX2, cyclooxygenase 2; ECM, endothelial cell medium; FBS, fetal bovine serum; HDAC, histone deacetylase; HIF-1, hypoxia-inducible factor 1; HRMEC, human retinal microvascular endothelial cell; Hsp70, heat shock protein; IB4, isolectin B4; ICAM-1, intercellular adhesion molecule 1; IL-1β/6, interleukin 1 beta/6; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; miRNA, microRNA; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; OIR, oxygen-induced retinopathy; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time PCR; RNV, retinal neovascularization; ROP, retinopathy of prematurity; RTCA, real-time cell analyzer; RVO, retinal vaso-obliteration; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.

Increasing clinical trials demonstrated that the discontinuation of aspirin while maintaining a P2Y

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Objective Recently, fibulin-1 (FBLN1) has been shown to be downregulated in various cancers via promoter hypermethylation. Our study aimed to determine the expression and methylation status of FBLN1 in tongue squamous cell carcinoma (TSCC) tissues and cells. Methods Methylation-specific PCR was implemented to detect the methylation status of the FBLN1 gene in TSCC tissues and Western blot analysis was used to detect the expression of FBLN1 protein. The human TSCC cell lines, CAL27 and SCC9, were cultured in vitro and treated with 5-aza-deoxycytidine (5-Aza-dC). CCK-8, colony formation, and Transwell assays were performed to test TSCC cell proliferation, migration, and invasion following 5-Aza-dC treatment or overexpression of FBLN1, which was further verified in in vivo experiments. Results FBLN1 was hypermethylated and the protein expression was reduced in TSCC tissues. After human TSCC cell lines (CAL27 and SCC9) were treated with 5-Aza-dC or overexpressed FBLN1, FBLN1 expression was upregulated and the TSCC cell proliferation, migration, and invasion abilities were suppressed. In vivo experiments further showed that demethylation or overexpression of FBLN1 slowed tumor growth in nude mice. Conclusion This study demonstrated that 5-Aza-dC treatment or overexpression of FBLN1 inhibited the growth of human TSCC.

The B-mode ultrasound (BUS) based computer-aided diagnosis (CAD) has shown its effectiveness for developmental dysplasia of the hip (DDH) in infants. In this work, a two-stage meta-learning based deep exclusivity regularized machine (TML-DERM) is proposed for the BUS-based CAD of DDH. TML-DERM integrates deep neural network (DNN) and exclusivity regularized machine into a unified framework to simultaneously improve the feature representation and classification performance. Moreover, the first-stage meta-learning is mainly conducted on the DNN module to alleviate the overfitting issue caused by the significantly increased parameters in DNN, and a random sampling strategy is adopted to self-generate the meta-tasks; while the second-stage meta-learning mainly learns the combination of multiple weak classifiers by a weight vector to improve the classification performance, and also optimizes the unified framework again. The experimental results on a DDH ultrasound dataset show the proposed TML-DERM algorithm achieves the superior classification performance with the mean accuracy of 85.89%, sensitivity of 86.54%, and specificity of 85.23%.

Backgrounds:. Azithromycin mass drug administration (MDA) is a key part of the strategy for controlling trachoma. This systematic review aimed to comprehensively summarize the present studies of azithromycin MDA on trachoma; provide an overview of the impact of azithromycin MDA on trachoma in different districts; and explore the possible methods to enhance the effectiveness of azithromycin MDA in hyperendemic districts. Methods:. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov were searched up to February 2021 with no language restriction. Studies reporting the effect of azithromycin MDA on trachoma were included. Mathematical modeling studies, animal studies, case reports, and reviews were excluded. The trachomatous inflammation-follicular (TF) 30.0%), especially with baseline TF >50.0%, annual MDA was unable to achieve the TF 10.0% is not appropriate for all eligible districts.

Disturbances of gastrointestinal microbiome may result in the development of attention-deficit/hyperactivity disorder (ADHD). Antibiotic therapy is commonly known to influence the gastrointestinal microbiome. However, results from studies on the association between antibiotic exposure and ADHD have been inconsistent. Several databases (PubMed, PsychInfo, EMBASE) were searched on January 1, 2021, to identify relevant studies. A random effects model was used to calculate the pooled risk estimate. Statistical heterogeneity was tested using the chi-square test and the I2 statistic. There were four risk estimates on antibiotic intake during pregnancy and eight risk estimates on antibiotic intake after birth. The pooled odds ratio for ADHD comparing antibiotic exposure with non-exposure during pregnancy was 1.14 (95% confidence interval [CI], 1.10–1.18). The pooled odds ratio with postnatal antibiotic exposure was 1.12 (95% CI, 0.99–1.26). Substantial heterogeneity existed among these analyses. The timing of antibiotic exposure, type of antibiotic, and number of antibiotic intakes might influence the association between antibiotic exposure and ADHD. Our findings suggest that maternal antibiotic intake during pregnancy may be associated with an increased risk of ADHD in the offspring. However, there was insufficient evidence for the association between antibiotic intake after birth and ADHD risk. Further studies should be performed before a definitive conclusion can be established.

Objective Our study seeks to assess the value of transvaginal two-dimensional ultrasound combined with color Doppler in evaluating ovarian function and reproductive function after uterine artery embolization (UAE). Methods Totally 64 cases with cesarean scar pregnancy (CSP) were collected. Their information was recorded, including baseline information, intraoperative and postoperative information, preoperative and postoperative uterine receptivity, and preoperative and postoperative levels of sex hormones in serum. Finally, the patients were followed up to observe whether they were pregnant after treatment. Results In comparison with 24 hours after UAE, decreases were found in endometrial blood flow pulsatility index (PI), endometrial thickness, ovarian artery peak end-systolic velocity (Vs), ovarian artery resistance index (RI), and the ratio of Vs to peak end-diastolic velocity (S/D) 1 and 3 months after embolization, while Vd increased markedly 3 months after embolization. In addition, in terms of sex hormones, a significant increase was revealed in the level of follicle-stimulating hormone, while the reduction in the levels of luteinizing hormone (LH), estrogen (E2), prolactin (PRL), and progesterone (P) in the first month and the third month of menstrual resumption compared with those before treatment. From the follow-up data, there were 50 cases of pregnancy, including 45 cases of intrauterine pregnancy, 2 cases of tubal pregnancy, and 3 cases of recurrent CSP. Conclusion UAE is a safe and effective method to prevent massive hemorrhage of CSP. Transvaginal two-dimensional ultrasound combined with color Doppler can more accurately evaluate its therapeutic effect and provide a basis for effective treatment.

Hepatocellular carcinoma (HCC) is an extraordinarily heterogeneous tumor, which holds high recurrence and metastasis rates. Liver cancer stem cells (LCSCs) have been considered to be important influencing factors of these pathological properties, but the underlying mechanisms are poorly understood in HCC. Considerable evidences have shown that autophagy has an important role in cancer stemness. However, it is still unknown whether a long noncoding RNA (lncRNA) TINCR is involved in autophagy and self-renewal maintenance of HCC. In this study, TINCR was found to be highly expressed in HCC tissues and LCSCs. In vitro and in vivo assays for the first time showed that TINCR was required for LCSC self-renewal and tumorigenesis. Moreover, gene ontology analysis revealed the involvement of autophagy in the maintenance of TINCR-regulated stemness. Mechanically, TINCR was associated with polypyrimidine tract binding protein 1 (PTBP1) protein, which further promoted the transcription activity of autophagy related gene ATG5. In conclusion, we demonstrated that TINCR regulated LCSC self-renewal by autophagy activation through PTBP1/ATG5 regulatory pathway, offering a potential new target for HCC therapy.

Background: Lacunar stroke accounts for a quarter of all strokes, but little is known about the underlying pathological mechanisms. Analysis of serum metabolites may allow better understanding of the underlying biological processes. Mendelian randomization (MR) can provide information on the causality of associations. Aims: To identify causal relationships between serum metabolites and lacunar stroke. Methods: We applied a two-sample MR analysis to evaluate relationships between 486 serum metabolites and lacunar stroke. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of the exposure on the outcome, while sensitivity analyses were performed using MR-Egger, weighted median, and MR-PRESSO to eliminate the pleiotropy. We also performed a metabolic pathway analysis to identify potential metabolic pathways. Results: We identified 15 known (8 risk and 7 protective) and 14 unknown serum metabolites associated with lacunar stroke. Among the known risk metabolites, two were lipids (1-linoleoylglycerophosphoethanolamine and dihomo-linolenate (20:3n3 or n6)), five amino acids (kynurenine, isobutyrylcarnitine, aspartate, trans-4-hydroxyproline, and 3-methyl-2-oxovalerate), and one peptide (ADSGEGDFXAEGGGVR). The known protective metabolites included four lipids (4-androsten-3beta,17beta-diol disulfate 1, 1-palmitoleoylglycerophosphocholine, adrenate (22:4n6), and glycodeoxycholate), one amino acid (methionine), and two exogenous metabolites (homostachydrine and 2-methoxyacetaminophen sulfate). Metabolic pathway analysis identified several pathways that might be involved in the disease. Conclusion: We identified eight risk and seven protective human serum metabolites associated with lacunar stroke. Isobutyrylcarnitine was positively associated with an increased risk of lacunar stroke. In addition, 3-methyl-2-oxovalerate and aspartate may be involved in the disease pathogenesis through metabolic pathways.

Multiwalled carbon nanotubes (MWCNTs) are currently widely used and are expected to be used as drug carriers and contrast agents in clinical practice. Previous studies mainly focused on their lung toxicity; therefore, their effects on the vascular endothelium are unclear. In this study, a human angiogenesis array was used to determine the effect of MWCNTs on the expression profile of angiogenic factors in endothelial cells and to clarify the role of vascular endothelial growth factor (VEGF) in MWCNT-induced endothelial cell injury at the cellular and animal levels. The results indicated that MWCNTs (20-30 nm and 30-50 nm) could enter endothelial cells and disrupt human umbilical vein endothelial cell (HUVECs) activity in a concentration-dependent manner. MWCNTs disrupted the tube formation ability and cell migration function of HUVECs. The results from a Matrigel Plug experiment in mice showed that angiogenesis in the MWCNT experimental group was significantly reduced. The results of a protein chip analysis indicated that VEGF expression in the MWCNT treatment group was decreased, a finding that was validated by ELISA results. The protein expression levels of AKT and eNOS in the MWCNT treatment group were significantly decreased; the administration of recombinant VEGF significantly alleviated the migration ability and tube formation ability of endothelial cells injured by MWCNTs, upregulated the protein expression of AKT and eNOS, and increased the number of neovascularization in mice in the MWCNT treatment group. This study demonstrated that MWCNTs affect angiogenesis via the VEGF-Akt-eNOS axis which can be rescued by VEGF endothelial treatment.

From a developmental system perspective, the present study constructed a moderated mediation model to examine whether youth core self-evaluation (individual factor) served as a mediator and peer support (peer system) served as a moderator in the effect of parental fixed mindset (family system) on youth mental health symptoms. In total, 658 pairs of emerging adults and their parents participated in this study. Youth completed measurements on core self-evaluation, peer support, and mental health symptoms, while their parents filled in the questionnaire on fixed mindset. Mediation analysis indicated that parental fixed mindset was related to increased youth mental health symptoms, and youth core self-evaluation partially mediated this relationship. Moderated mediation analysis suggested that peer support mitigated the mediating process with the direct pathway from parental fixed mindset to youth mental health symptoms and the indirect pathway from parental fixed mindset to youth core self-evaluation being weaker at a high level of peer support. This study highlights how and when a family system, peer system, and individual factors combine to influence youth mental health. The findings suggest it is the interaction of these factors that has to be addressed in efforts to reduce the prevalence of youth mental health symptoms.

Astragalus (Hedysarum Multijugum Maxim., Huangqi) is a Chinese herbal medicine, and according to the theory of traditional Chinese medicine (TCM), Chinese medicinal preparations containing astragalus can be used clinically to treat radiation-induced lung injury (RILI). To systematically review the efficacy and safety of Chinese medicinal preparations containing astragalus in the prevention and treatment of RILI by means of meta-analysis.A systematic literature on randomized controlled trials (RCTs) of prescriptions containing astragalus in the treatment of RILI by Pubmed, Embase, Web of Science, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, WANFANG Database. The retrieval time is from the establishment of the database to January 18, 2022. Meta-analysis, heterogeneity test and sensitivity analysis were performed on eligible RCTs using Revman 5.4 software and STATA 17.0 software, and a "funnel plot" was used to analyze potential publication bias.A total of 25 RCTs were included, including 1762 patients, and the most widely used drugs were heat-clearing and detoxifying, yin-nourishing and qi-nourishing. The prescriptions containing astragalus can significantly reduce the total incidence of RILI (P .01), improve the total effective rate and cure rate of RILI (P .01), improve the quality of life of patients, alleviate breathing difficulties and reduce the expression of inflammatory factors (P .01), and no adverse reactions related to TCM treatment were reported.The traditional Chinese medicinal preparation containing astragalus can effectively alleviate the clinical symptoms of RILI, reduce the toxic side effects, and is safe to use in clinic.

This study aimed to exhibit the crash distribution and compare the contributory factors (crash characteristics, driver characteristics, vehicle characteristics and road characteristics) responsible for road crashes between non-commercial and commercial vehicles. To achieve the objective, a step-wise binary logistic regression (LR) model was employed with the forward LR method to explore the contributing factors to road crashes between the non-commercial and commercial vehicles. The road crash data (2013-2017) on motorways (M1 and M2) was collected from the National Highway and Motorway Police (NHMP) in Pakistan. During the study period, a total of 1110 road crashes were recorded. The proportion of fatal and non-fatal crashes were 29% and 71% for non-commercial vehicles and 31% and 69% for commercial vehicles, respectively. The results from LR model revealed that drowsy driving, poor road conditions, overspeeding and tire bursting were found to be significant predictors of road crashes. Road crashes caused by drowsy driving and poor vehicle condition were prevalent in commercial vehicles. On the contrary, overspeeding and tire bursting were more prevalent in non-commercial vehicles. The remaining factors could not achieve significant values in the model. On the basis of these empirical findings, suggestions to improve safety were pointed out.

Percutaneous coronary intervention (PCI) has become increasingly mature and has gradually become the main treatment for coronary heart disease (CHD). However, evaluation of myocardial reperfusion after PCI remains a major clinical challenge. This study aimed to explore the VVI technique in evaluating the effect, prognosis, and follow-up of CHD patients after percutaneous coronary intervention. We performed a quantitative analysis of left ventricular myocardial contractile strain and dyssynchrony before and after stent implantation in patients by VVI.Thirty-five patients diagnosed with CHD who underwent percutaneous coronary stenting (PCI) in the Department of Cardiovascular Medicine, Affiliated Hospital of Jiangnan University from March 2019 to October 2020 were selected as the case group. Continuous dynamic two-dimensional images of the patient's left ventricle were analyzed using VVI at 1 day before PCI (group A), 7 days after PCI (group B), and 30 days after PCI (group C). The patients' left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricle ejection fraction (LVEF), peak longitudinal strain, and peak radial strain of myocardial contraction were measured. The VVI images of 35 healthy subjects who underwent physical examination in the outpatient department of our hospital from March 2019 to October 2020 were selected as controls.There were no significant differences in the LVEF, LVEDD, and LVESD between the case and control groups (P0.05). The peak systolic longitudinal and radial strain values at 1 month after treatment were higher than those before treatment. The differences among myocardial segments were statistically significant, except for the apical septum, base anterior, apical anterior, and base inferior segments (P0.05). The peak systolic longitudinal and radial strain values at 1 week after treatment were not significantly different from those at 1 month after treatment, except for the base anterior septum, mid anterior, posterior, and inferior myocardial segments (P0.05).VVI technology can comprehensively and objectively evaluate the overall and local myocardial function of the left ventricle, thereby providing a novel method for the clinical treatment of CHD as well as the evaluation of curative effect and prognosis.

Background: In China, family caregivers play a major role in caring for people living with Alzheimer’s disease (PLWAD), but little is known about the burden this creates. Objective: This study aimed to investigate the burden among family caregivers of PLWAD and the factors influenced it. Methods: Family caregivers of PLWAD were recruited from a hospital in China from January 2018 to July 2018. All data were collected online using the Chinese version of the Zarit Burden Interview (ZBI), and the participants’ sociodemographic and caregiving details were obtained. T-tests and Kruskal-Wallis H (K) tests were used to compare ZBI scores between groups. Factors related to the caregiver psychological burden were analyzed using multiple linear regression analysis. Results: A total of 300 participants were assessed, of which 213 (71.00%) were female. More than half of the caregivers were the patient’s daughter (51.0%, n = 153). The average ZBI score of the caregivers was 43.05 (13.42). The level of burden was influenced by age, the relationship of the caregiver to the patient, the severity of AD, the caregiver’s retirement status, the income level of the caregiver, and the caring time. Regression analysis showed that retired caregivers were more likely to have higher levels of burden and that burden increased with AD severity. Conclusion: Most family caregivers of PLWAD have a considerable caregiver psychological burden. The findings increase the understanding of factors that influence family caregiver burden, and pave the way for potential interventions, such as social support and caregiver empowerment, to reduce their burden.

Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.

The prevalence of problem gambling in the correctional system is about 10 times higher than in the general population, but programming for gambling problems in the correctional system is scarce. Examined barriers to treatment for problem gamblers in the correctional system, sex or gender differences, and options for program design. We conducted interviews with 16 experts who had worked with problem gamblers in the correctional system and analyzed the data in terms of themes. For barriers, the experts discussed a lack of awareness about problem gambling, as well as stigmatization and lockdowns. Experts described the content of current programs as equally applicable to both men and women, but that emotional components were more important for women. Finally, the experts had mixed views on whether programming should be integrated with other programs such as substance abuse. Programming implications for this population are discussed.

Cricopharyngeal botulinum toxin (BTX) injection is one of the treatments for neurogenic cricopharyngeal dysfunction (CPD). We conducted this prospective study to investigate the effect and safety of BTX injection for neurogenic CPD with a novel guidance. Twenty-one patients with neurogenic CPD whose symptoms did not reduce after conventional swallowing therapy were included in this study. The impact of BTX injection on the swallowing function of the patients was evaluated. After the injection, the Functional Oral Intake Scale (FOIS) score increased in 17 of 21 patients (80.9%), which ranged from 1 to 3 (P

Background Although the efficacy of hepatitis B vaccines among hemodialysis patients has been documented, the long-term persistence of immunogenicity in this population remains largely unknown. We explored the long-term persistence of immunogenicity induced by different hepatitis B vaccine regimens in hemodialysis patients. Methods In initial study, we conducted a randomized, multicenter, double-blind, parallel-controlled trial among hemodialysis patients in 13 hospitals in Shanxi Province, China. A total of 352 hemodialysis patients were allocated to receive 3-dose 20 μg (IM20 group) and 3-dose 60 μg (IM60 group) recombinant hepatitis B vaccine at months 0, 1, and 6. Vaccine-induced immune responses were measured at month 7. In this study, the responders (anti-HBs ≥ 10 mIU/mL) were followed up at months 18, 24, 30, 36 and 42, respectively. We used the generalized log-rank test and generalized estimating equations (GEE) to analyze the long-term durability of responses and the kinetics of anti-HBs levels, respectively. Results A total of 284 patients were involved in the extended follow-up period. The duration of vaccine-induced response with 75% of patients maintained protective antibody were 12 months and 18 months in the IM20 group and IM60 group, respectively (P = 0.291). The long-term persistent immunogenicity induced by 3-dose 60 μg was more satisfactory than that by 3-dose 20 μg hepatitis B vaccine in patients with hemodialysis duration ≥ five years (P = 0.023). The peak anti-HBs levels in 100–1000 mIU/mL or ≥ 1000 mIU/mL were more likely to maintain long-term protective antibody compared to anti-HBs levels in 10–100 mIU/mL (P ＜ 0.05). The kinetic profile was similar between the two groups (P = 0.334). Conclusion High-dose 60 μg hepatitis B vaccine could lead a satisfactory long-term durability of immunogenicity among patients with hemodialysis duration of five years or more. Peak anti-HBs level after vaccination was associated with the long-term persistence of immunogenicity.

Summary We here aimed to investigate the impact of gender on the clinical characteristics and laboratory results of patients with coronavirus disease 2019 (COVID-19) and provide clues to the pathological mechanisms underlying COVID-19. A retrospective study was performed. Clinical characteristics, severity of lung infection, laboratory results, and prognoses of patients of different gender were analyzed. A total of 242 patients were finally included. The median age was 58 years (IQR: 40–68), including 54 (22.3%) hospital staffs. Ninety-four (38.8%) were male and 148 (61.1%) were female. The proportion of patients with diabetes was significantly higher in the male group than in the female group (P=0.034). Male patients had a significantly larger proportion of severe lung infection, higher leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio, C-reactive protein, and procalcitonin than female. Furthermore, male patients had worse liver, cardiac, and coagulation function than their female counterparts. Male patients with COVID-19 showed more severe inflammation reaction and coagulation dysfunction than female patients. In conclusion, gender is associated with host response to SARS-CoV-2 infection.

Background Flap endonuclease 1 (FEN1) is a structure-specific nuclease that plays a role in a variety of DNA metabolism processes. FEN1 is important for maintaining genomic stability and regulating cell growth and development. It is associated with the occurrence and development of several diseases, especially cancers. There is a lack of systematic bibliometric analyses focusing on research trends and knowledge structures related to FEN1. Purpose To analyze hotspots, the current state and research frontiers performed for FEN1 over the past 15 years. Methods Publications were retrieved from the Web of Science Core Collection (WoSCC) database, analyzing publication dates ranging from 2005 to 2019. VOSviewer1.6.15 and Citespace5.7 R1 were used to perform a bibliometric analysis in terms of countries, institutions, authors, journals and research areas related to FEN1. A total of 421 publications were included in this analysis. Results Our findings indicated that FEN1 has received more attention and interest from researchers in the past 15 years. Institutes in the United States, specifically the Beckman Research Institute of City of Hope published the most research related to FEN1. Shen BH, Zheng L and Bambara Ra were the most active researchers investigating this endonuclease and most of this research was published in the Journal of Biological Chemistry. The main scientific areas of FEN1 were related to biochemistry, molecular biology, cell biology, genetics and oncology. Research hotspots included biological activities, DNA metabolism mechanisms, protein-protein interactions and gene mutations. Research frontiers included oxidative stress, phosphorylation and tumor progression and treatment. Conclusion This bibliometric study may aid researchers in the understanding of the knowledge base and research frontiers associated with FEN1. In addition, emerging hotspots for research can be used as the subjects of future studies.

The present study is to explore the anticancer effect of loonamycin (LM) in vitro and in vivo, and investigate the underlying mechanism with combined multi-omics. LM exhibited anticancer activity in human triple negative breast cancer cells by promoting cell apoptosis. LM administration inhibited the growth of MDA-MB-468 tumors in a murine xenograft model of breast cancer. Mechanistic studies suggested that LM could inhibit the topoisomerase I in a dose-dependent manner in vitro experiments. Combined with the transcriptomics and proteomic analysis, LM has a significant effect on O-glycan, p53-related signal pathway and EGFR/PI3K/AKT/mTOR signal pathway in enrichment of the KEGG pathway. The GSEA data also suggests that the TNBC cells treated with LM may be regulated by p53, O-glycan and EGFR/PI3K/AKT/mTOR signaling pathway. Taken together, our findings predicted that LM may target p53 and EGFR/PI3K/AKT/mTOR signaling pathway, inhibiting topoisomerase to exhibit its anticancer effect.

ObjectiveTo investigate the prevalence of frailty and pre-frailty and its associated factors in Chinese older adults with diabetes through a nationwide cross-sectional study.Research design and methodsThe data were obtained from the Sample Survey of the Aged Population in Urban and Rural China (SSAPUR), conducted in 2015, which was a cross-sectional study involving a nationally representative sample of older adults aged 60 years or more from 31 provinces, autonomous regions, and municipalities in mainland China. Subjects with diabetes were included in this study. Frailty index (FI), based on 33 potential deficits, was used to categorize individuals as robust, pre-frail, or frail.ResultsA total of 18,010 older adults with diabetes were included in this study. The weighted prevalence of frailty and pre-frailty in older adults with diabetes in China was 22.7% (95% CI 22.1–23.3%) and 58.5% (95% CI 57.8–59.2%), respectively. The prevalence of frailty and pre-frailty among older adults with diabetes from different provinces/municipalities/autonomous regions was significantly different. Multinomial logistic regression analysis showed living alone, poor economic status, ADL disability, and comorbidities were strongly correlated with frailty and pre-frailty in older adults with diabetes.ConclusionFrailty and pre-frailty are common in older adults with diabetes in China, and exhibit sociodemographic and geographic differences. In the clinical setting of older adults with diabetes, there is a need to increase awareness of frailty and to advance the early diagnosis and intervention of frailty.

Overall survival of non-small cell lung cancer (NSCLC) patients remains disappointingly low. The estrogen receptor (ER) was considered a promising therapeutic target for NSCLC. Numerous studies have linked expression of ERβ to lung cancer outcome. However, results are conflicting regarding the association of ERβ with surviving lung cancer. The aim of this meta-analysis was to evaluate the prognostic aspect of ERβ expression on survival among NSCLC patients. We performed a final analysis of prognostic value of overexpression ERβ on 3500 patients from 18 evaluable studies (from January 1, 2000 to May 1, 2021). The reference category is specified as low ERβ expression levels. Summarized hazard ratios were calculated. Our study showed that the pooled hazard ratios of ERβ overexpression for overall survival in NSCLC was 0.81 (95% confidence interval (CI): 0.64–1.02, P = 0.07) by univariate analysis and 1.06 (95% CI: 0.83–1.36, P = 0.63) by multivariate analysis. Pooled hazard ratio by univariate analysis in Asian studies was 0.73 (95%CI: 0.59–0.89, P = 0.002). Pooled hazard ratio by univariate analysis was 0.75 (95% CI: 0.61–0.93, P = 0.009) from seven studies reported for nuclear ERβ. No significant results were found in subgroups by multivariate analysis. No significant results were found in studies outside Asia or in studies reported for cytoplasmic ERβ. Our results suggested that expression of ERβ might not be a direct prognostic factor for NSCLC patients. More detailed prospective studies are needed to identify direct prognostic factors in these patients.

The rate of second primary malignancies (SPM) is gradually increasing. Yet, the risk of death from primary cancer vs. SPM is still not well understood. In this study, we investigated the survival of patients with colorectal cancer (as SPM) who had cancer in the past (prior cancer) and the risk factors of SPM death in this population.Based on the Surveillance, Epidemiology, and End Results (SEER) database, we identified 1866 colon cancer patients with prior cancer in our main cohort and 43,959 colon cancer patients, including 37,440 patients with colon cancer as only malignancy and 6519 patients with colon cancer as subsequent colon cancer (SCC), in a second cohort and 3429 colon cancer patients, including 2371 patients with prior colon cancer (PCC) and 1058 patients with colon cancer as SPM, in a third cohort. After propensity score matching, 6519 pairs of subjects were identified in second cohort.Patients with prior prostate and breast cancer had a higher risk of developing colon cancer compared to those with gastrointestinal cancer. Also, colon cancer patients with different prior cancer had different survival rates. Furthermore, except for prior lung cancer (52.78 vs. 25.93%), most subjects died due to colon cancer complications. The ratio of colon cancer deaths to prior cancer deaths in patients with a low stage and high stage was 1.51 and 6.64, respectively. In addition, colon cancer-specific survival (CSS) and OS rates were significantly lower in subjects with colon cancer as the SPM than in those with PCC. Also, compared with PCC, SPM was associated with OS and CSS with HR 1.59 (95 CI 1.43-1.78) and HR 2.00 (95% CI 1.70-2.36). Furthermore, compared with only colon cancer, SCC was associated with OS and CSS with HR 1.23 (95 CI 1.17-1.29) and HR 1.13 (95% CI 1.06-1.21).Prior cancer was found to have an adverse impact on OS in patients with colon cancer (secondary cancer), most of whom died due to colon cancer as secondary cancer itself rather than prior cancer. Early detection and treatment strategies should be investigated in this population.

Alzheimer's disease (AD), known as a common incurable and elderly neurodegenerative disease, has been widely explored for accurate detection of its biomarker (Aβ oligomers) for early diagnosis. Although great efforts have been made, it is still of great importance to develop fluorescence probes for Aβ oligomers with good selectivity and low background. Herein, starting from BODIPY493/503 (a commercial dye for neutral lipid droplets), which exhibited a small Stokes shift and no response toward Aβ peptides, two fluorescence probes

The prevalence of iron overload in Tibetans in Tibet is higher than that in Han. DNA methylation (DNAm) is closely related to iron metabolism and iron level. Nevertheless, the epigenetic status of Tibetans with iron overload is unknown, and we therefore aimed to explore whether the phenomenon observed in the Tibetan population is regulated by epigenetics. The results showed that 2.26% of cytosine was methylated in the whole genome, and that the rate of CG cytosine methylation was higher in individuals in the iron overload (TH) group than in those in the iron normal (TL) group. We analyzed differentially methylated genes (DMGs) in whole-genome bisulfite sequencing data from the TH and TL groups of high-altitude Tibetans. Protein-protein interaction and pathway analyses of candidate DMGs related to iron uptake and transport showed that epigenetic changes in 10 candidate genes (ACO1, CYBRD1, FLVCR1, HFE, HMOX2, IREB2, NEDD8, SLC11A2, SLC40A1 and TFRC) are likely to relate to iron overload. This work reveals, for the first time, changes of DNAm in Tibetan people with iron overload, which suggest that DNAm is a mechanism underlying differences in iron content between individuals in the high-altitude Tibetan population. Our findings should contribute to the study of iron metabolism and the overall health status of Tibetans.

Background Repressor element 1-silencing transcription (REST)/neuron-restrictive silencer factor is considered a new therapeutic target for neurodegenerative disorders such as Alzheimer’s disease (AD). However, the relationship between AD and REST remains unclear. This study aimed to 1) examine plasma REST levels and REST gene levels in AD patients and 2) further explore the pathological relationships between REST protein levels and cognitive decline in clinical conditions, including medial temporal lobe atrophy. Methods Participants (n = 252, mean age 68.95 ± 8.78 years) were recruited in Beijing, China, and then divided into a normal cognition (NC) group (n = 89), an amnestic mild cognitive impairment (aMCI) group (n = 79), and an AD dementia group (n = 84) according to diagnostic criteria. All participants underwent neuropsychological assessments, laboratory tests, and neuroimaging scans (magnetic resonance imaging) at baseline. Plasma REST protein levels and the distribution of REST single nucleotide polymorphisms (SNPs) were compared among the three groups. Correlations between cognitive function, neuro-imaging results, and REST levels were determined by a multivariate linear regression analysis. Results The plasma REST levels in both the NC group (430.30 ± 303.43)pg/ml and aMCI group (414.27 ± 263.39)pg/ml were significantly higher than that in the AD dementia group (NC vs AD dementia group, p = 0.034; aMCI vs AD dementia group, p = 0.033). There was no significant difference between the NC and aMCI groups (p = 0.948). No significant difference was found among the three groups regarding the genotype distribution (rs2227902 and rs3976529 SNPs) of the REST gene. The REST level was correlated with the left medial temporal lobe atrophy index (r = 0.306, p = 0.023). After 6 months of follow-up, the REST level in the NC group was positively correlated with the change in the Mini-Mental State Examination score (r = 0.289, p = 0.02). Conclusion The plasma REST protein level is decreased in AD dementia patients, which is associated with memory impairment and left temporal lobe atrophy and may have potential value for clinical diagnosis of AD dementia.

Supplemental Digital Content is available in the text., OBJECTIVES: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care. DESIGN: Retrospective, international, Sapphire study. SETTING: Academic Medical Center. PATIENTS: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We stratified patients enrolled in the Sapphire study into three groups—those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2–3 acute kidney injury within the first 3 days compared with 14% without stage 2–3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53–11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2–3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8–34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury. CONCLUSIONS: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.

This study aimed to investigate the mechanism of how miR-362-3p/orosomucoid 1 (ORM1) involved in hypoxia/reoxygenation (H/R)-induced cardiomyocytes injury. Based on data obtained from Gene Expression Omnibus (GEO) database, we revealed that ORM1 was highly expressed and positively correlated with the expression of inflammatory factors (MAPK1, MAPK3, IL1B and CASP9). miR-362-3p was identified as an upstream regulatory miRNA of ORM1 and negatively modulated the mRNA and protein expression levels of ORM1 in H/R-injured cardiomyocytes. Moreover, we found that miR-362-3p was downregulated in cardiomyocytes injured by H/R. The promoting influence of miR-362-3p mimic on the proliferation and the inhibitory effect of miR-362-3p mimic on the apoptosis of H/R-stimulated cardiomyocytes were eliminated by overexpression of ORM1. Furthermore, miR-362-3p affected the expression of MAPK1, MAPK3, IL1B and CASP9 in H/R-injured cardiomyocytes through targeting ORM1. Our outcomes illustrated that miR-362-3p exhibited a protective influence on H/R-induced cardiomyocytes through targeting ORM1.

Voluntary self-exclusion programs allow gamblers to voluntarily be denied access to gambling venues for an agreed upon period. Many people who self-exclude decide to return to gambling venues after the exclusion period has ended, however people who reinstate may be at risk for the recurrence of gambling problems. This study was designed to determine the efficacy of a tutorial created with the intent of reducing the risk of harm to those who reinstate. People who wished to be reinstated were asked to complete a survey on gambling related issues and then watch the tutorial video. An online video-based tutorial designed to reduce gambling related harm and to provide information about treatment services was developed. The control group (N = 131) consisted of people who reinstated in the year prior to the implementation of the online tutorial. The experimental intervention group (N = 104) were those who reinstated after the implementation of the online tutorial. There was a significant decrease in gambling and problem gambling comparing pre-exclusion to during exclusion in both the experimental and control group. Furthermore, this drop in gambling problem was sustained for 6-months and 12-months after reinstatement. However, no main effect or interaction was found that supported the efficacy of the tutorial. Self-exclusion by itself was associated with a sustained reduction in problem gambling. There was no significant evidence that the educational tutorial had any additional impact on the reinstatement process. Supplementary Information The online version contains supplementary material available at (10.1007/s10899-021-09998-x).

Background Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It was approved by the U.S. Food and Drug Administration (FDA) for clinical use in 2003. However, gefitinib has only come to China in recent years. Previous studies have not compared the efficacy and safety of domestic and imported gefitinib. Therefore, we conducted this study. Methods This study included 227 patients with advanced non-small cell lung cancer (NSCLC) who received gefitinib treatment in four medical institutions: The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Fudan University Shanghai Cancer Center, Shandong Provincial Institute of Cancer Prevention and Jiangsu Cancer Hospital, from January 2017 to July 2018. The patients were divided into a Yiruike group (55 patients treated with domestic gefitinib, Yiruike) and an Iressa group (172 patients treated with imported gefitinib, Iressa). Because gefitinib resistance usually occurs within 8-10 months of gefitinib administration, the patients were followed up for one year to observe their conditions and compare the occurrence of adverse reactions between the two groups. Results The two groups had no significant difference in baseline data. The median progression-free survival (PFS) of Yiruike group and that of Iressa group were 10.270±2.036 and 12.970±1.634 months, respectively. The mean PFS of Yiruike group and that of Iressa group were 12.598±1.083 and 15.958±0.987 months, respectively. The one-year disease control rate (DCR) of Yiruike group and that of Iressa group were 61.8% and 59.3%, respectively. The differences were all insignificant (P>0.05). The incidence of adverse reactions in these two groups were not significantly different. Conclusions Yiruike was slightly superior to Iressa in terms of DCR. However, comparisons of bioequivalence and DCR were not sufficient for evaluating a drug. Other comparisons require long-term follow-up studies with a large sample size.

Background There is limited available evidence of a relationship between uric acid (UA) level and stroke in hypertensive populations worldwide. We aimed to estimate the relationship between UA level and stroke in Chinese hypertensive populations. Methods A total of 4 710 essentially hypertensive Chinese patients, including 307 with stroke, were recruited consecutively by cluster sampling from 60 communities in Shenzhen from April 2010 to September 2011. Demographic characteristics, UA level and stroke diagnosis were collected from every participant. Logistic regression analysis was used to estimate the association between UA level and stroke. Results The study population comprised 2 361 females and 2 349 males, with a mean age of 58 ± 11.75 years. There were significant associations between UA level and stroke and ischaemic stroke (IS) risk for females in the crude model (M0), model 1 (M1) and model 2 (M2), with increasing odds ratios (OR) as the quartiles (Q) increased. The odds of stroke risk was highest in Q4 in M2 (UA > 396 µmol/l, OR: 3.05, 95% CI: 1.74-5.36 and OR: 3.19, 95% CI: 1.74-5.85), but not for males in M0, M1 and M2. A significant dose-response relationship existed between UA level and stroke, and between UA level and IS for females but not for males. Hyperuricaemia (HU) was also significantly associated with stroke and IS for females but not for males. Taking negative uric acid, homocysteine, triglycerides, total cholesterol and low-density lipoprotein cholesterol (UA-Hcy-TG-TC-LDL-C-) as the reference, the combinations of UA+Hcy+TG-TC-LDL-, UA+Hcy+TG+TC+LDL-C- and UA+Hcy+TG+TC+LDL-C+ were significantly associated with the risk of stroke for females (OR = 2.48, 7.85 and 3.04). Conclusions High UA level could significantly increase stroke risk in female hypertensive patients. Female hypertensive patients may benefit from managing UA at normal levels for stroke prevention.

We explored the long-term immunogenicity induced by 60 μg and 20 μg hepatitis B vaccines among patients receiving methadone maintenance treatment (MMT). In initial study, a randomized controlled trial was conducted, in which patients receiving MMT were administered 20 µg (IM20 group) or 60 µg (IM60 group) hepatitis B vaccines at months 0, 1, and 6. In this study, the responders at month 7 were followed-up at months 18, 30, and 42 to estimate long-term immunogenicity. The response rate decreased from 78.0% (39/50) to 31.1% (14/45) in the IM20 group, and from 86.0% (43/50) to 50.0% (20/40) in the IM60 group from month 7 to 42. Vaccine-induced responses in 75% of patients were observed for 14.2 months in the IM20 group and for 20.0 months in the IM60 group, and differences between these two groups were non-significant (P > 0.05). The three-dose 20 µg and 60 µg hepatitis B vaccines showed similar rapid hepatitis B surface antibody decreases. Abbreviations: HBV, hepatitis B virus; MMT, methadone maintenance treatment; HCC, hepatocellular carcinoma; HBsAg, hepatitis B surface antigen; anti-HBs, hepatitis B surface antibody; HR, hazard ratio; CI, confidence interval; IQR, interquartile range; GEE, generalized estimated equation.

Low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio may carry additional information and has been suggested as a better predictor for atherosclerosis progression and cardiovascular disease (CVD) than LDL-C and HDL-C alone. Therefore, we aim to explore the association between LDL-C/HDL-C ratio and high carotid intima-media thickness (CIMT) risk in a large Cohort in Beijing, China. This cohort study included 13,612 adults without high CIMT at first entry and who attended the baseline examination and at least one follow-up annual examination between 2009 and 2016. We used multivariable Cox regression to estimate hazard ratios (HR) with their 95% confidence intervals (CI) for the association between LDL-C/HDL-C ratio and risk of high CIMT. During 37,912 person-years of follow-up, 1996 (1268 men and 728 women) developed high CIMT. Compared with the first quartile of LDL-C/HDL-C ratio, the risk of high CIMT was significantly increased for the fourth quartile of LDL-C/HDL-C ratio (HR = 1.51, 95% CI: 1.29-1.78). We observed a significant association between LDL-C/HDL-C ratio and high CIMT risk comparing LDL-C/HDL-C ratio >2.78 with LDL-C/HDL-C ratio ≤2.78 and significant dose-response relationship between LDL-C/HDL-C ratio and risk of high CIMT. The restricted cubic spline showed a significant nonlinear association between LDL-C/HDL-C ratio and the risk of high CIMT (pnon-linearity = 0.009). We identify a significant association between LDL-C/HDL-C ratio and the risk of high CIMT in the Chinese Cohort study. Future studies are needed to evaluate the effectiveness of reducing LDL-C/HDL-C ratio treatment on the development of high CIMT.

Background During the early stages of the pandemic, some coronavirus disease (COVID‐19)patients were misdiagnosed as having influenza, which aroused the concern that some deaths attributed to influenza were actually COVID‐19‐related. Howerver, little is known about whether coinfection with influenza contributes to severity of COVID‐19 pneumonia, and the optimal therapeutic strategy for these patients. Methods We retrospectively studied 128 hospitalized patients with COVID‐19 pneumonia. All patients were positive severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)positive by nucleic acid detection. 64 cases were co‐infected with influenza A/B and the other 64 were influenza negative, matched by age, sex, and days from onset of symptoms. Results Among the 64 co‐infected patients, 54 (84.4%) were co‐infected with influenza A, and 10 (15.6%) with influenza B. The median duration of viral shedding time from admission was longer for patients with influenza coinfection (17.0 days) than for those without influenza coinfection (12.0 days) (P

Fat emulsion is an important component of parenteral nutrition in premature infants. However, intravenous fat emulsions (IVFE) was reported to be associated with some serious complications, such as bronchopulmonary dysplasia (BPD). Compared to conventional soybean oil-based IVFE, new-generation IVFE may protect against BPD but the results are conflicting. Relevant literatures search was conducted and the summary effect estimates of odds ratio (OR) and 95% confidence interval (CI) were calculated with fixed-effects models. Of 22 studies involving 3781 infants were selected in this study and BPD was reported as part of the included studies. The pooled estimate for 13 studies, comparing administration of new-generation IVFE with conventional IVFE, indicated that new-generation IVFE was not associated with a reduced risk of BPD in preterm infants, compared with conventional IVFE (OR 0.96; 95% CI 0.80–1.14); the pooled estimate for 18 studies, comparing administration of fish oil-containing IVFE with non-fish oil IVFE, indicated that fish oil-containing IVFE has no protective effect against the occurrence of BPD in preterm infants (OR 0.88; 95% CI 0.71–1.08). There is no evidence to support that the new-generation IVFEs could prevent the incidence of BPD or fish oil-containing IVFEs could show a beneficial effect to BPD in premature infants.

ObjectiveWe used resting-state functional connectivity (rsFC) to evaluate the integrity of the neural circuits associated with primary and secondary rewards in bipolar disorder (BD) with different mood phases.MethodsSixty patients with BD [21 patients with depressive episode of BD (BDD) and 41 patients with maniac episode of BD (BDM)] and 42 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. rsFC was assessed using region of interest-wise analyses.ResultsAttenuation of rsFC at the orbitofrontal cortex (OFC) and the left ventral striatum (LVS) was observed in the secondary reward circuit of patients with BD compared to that of HCs. Among BDD, BDM and HCs, the rsFC between OFC and LVS in BDM was intermediate, while the rsFC between OFC and right ventral striatum/right amygdala in BDM was the highest; the corresponding rsFC values in BDD were the lowest. Furthermore, a positive correlation was found between rsFC and Young Mania Rating Scale scores in BDM.ConclusionsThis study suggests that there may be an abnormal rsFC between OFC and LVS in the second reward of patients with BD and the discrepant patterns of rsFC may exist between different mood states in patients with BD.

Background In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited. Objective We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19. Methods Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients. Results We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19. Conclusions Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.

Aim: To investigate the efficacy of adjuvant chemotherapy plus tumor-infiltrating lymphocytes (TILs) therapy in osteosarcoma patients with a poor response to neoadjuvant chemotherapy. Materials & methods: 40 patients received adjuvant chemotherapy (Group 1) and 40 patients received adjuvant chemotherapy plus TILs therapy (Group 2). Disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan–Meier analysis. Results: The median DFS (mDFS; 65.3 months) and median OS (mOS; 95.8 months) in Group 2 were significantly prolonged compared with those in Group 1 (55.5 months for mDFS and 80.4 months for mOS). Univariate and multivariate analyses indicated that a greater number of TILs transfused was an independent prognostic factor for both mDFS and mOS. Conclusion: Adjuvant chemotherapy plus TILs therapy may prolong survival of patients with a poor response to neoadjuvant chemotherapy.

The present study aimed to investigate the effects of miR-504 in cervical cancer. Normal and cervical cancer tissue specimens derived from TCGA and GTEx databases were employed to analyze the miR-504 and PAICS (one of potential target gene of miR-504) expression. Kaplan–Meier strategy was applied to analyze the prognostic powers of miR-504 and PAICS. The proliferation, clonogenic ability, invasion, and migration of cervical cancer cells (C-33A and HeLa) were detected using Cell Counting Kit 8, colony formation, and transwell assays. Pearson correlation analysis was used to assess the correlation between miR-504 and PAICS, which was confirmed using luciferase reporter assay. The mRNA and protein levels were detected by qRT-PCR and western blot, respectively. TCGA data revealed that miR-504 expression might be decreased in cervical cancer, which was correlated with unfavorable prognosis. Further experiments exhibited that abnormal miR-504 expression negatively affected malignant cellular behaviors in cervical cancer, including proliferation, colony formation, invasion, and migration. PAICS was identified as a putative target of miR-504, and negatively related with miR-504 expression. PAICS expression was increased in cervical cancer and its high-regulation-induced worse outcomes of patients with cervical cancer. Rescue experiments indicated that PAICS restricted the impacts of miR-504 in cervical cancer cells. Analysis of western blot suggested that overexpression of PAICS overturned the miR-504-induced EMT inactivation. Our observations elucidated that miR-504, acting as a suppressor for the progression of cervical cancer, inhibits cell proliferation, invasion and migration, and mediates EMT via negatively regulating PAICS.

The ubiquitin-proteasome system (UPS) is a complex process that regulates protein stability and activity by the sequential actions of E1, E2 and E3 enzymes to influence diverse aspects of eukaryotic cells. However, due to the diversity of proteins in cells, substrate selection is a highly critical part of the process. As a key player in UPS, E3 ubiquitin ligases recruit substrates for ubiquitination specifically. Among them, RING E3 ubiquitin ligases which are the most abundant E3 ubiquitin ligases contribute to diverse cellular processes. The multisubunit cullin-RING ligases (CRLs) are the largest family of RING E3 ubiquitin ligases with tremendous plasticity in substrate specificity and regulate a vast array of cellular functions. The F-box protein Skp2 is a component of CRL1 (the prototype of CRLs) which is expressed in many tissues and participates in multiple cellular functions such as cell proliferation, metabolism, and tumorigenesis by contributing to the ubiquitination and subsequent degradation of several specific tumor suppressors. Most importantly, Skp2 plays a pivotal role in a plethora of cancer-associated signaling pathways. It enhances cell growth, accelerates cell cycle progression, promotes migration and invasion, and inhibits cell apoptosis among others. Hence, targeting Skp2 may represent a novel and attractive strategy for the treatment of different human cancers overexpressing this oncogene. In this review article, we summarized the known roles of Skp2 both in health and disease states in relation to the UPS.

Bailong Hu,1,* Haiyan Zhou,2,* Xiaohua Zou,1 Jing Shi,1 Xingyu Li,1 Li Tan1 1Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang,People’s Republic of China; 2Department of Clinical Research Centre, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bailong Hu Email 375896605@qq.comObjective: To compare the efficacy of dexmedetomidine and midazolam in the prevention of postoperative nausea and vomiting (PONV) caused by hemabate in postpartum hemorrhage during cesarean delivery.Methods: One hundred and five parturients with American Society of Anesthesiology (ASA) physical status I and II, aged 20– 40 years, undergoing elective cesarean delivery under epidural anesthesia were randomly allocated into dexmedetomidine group (group D, n=35), midazolam group (group M, n=35) and control group (group C, n=35). Patients received an intrauterine injection of 250 μg hemabate and continuous intravenous infusion of 5 units oxytocin immediately following the delivery of the infant. At the same time, patients in group D received 1μg/kg intravenous dexmedetomidine, group M received 0.02 mg/kg intravenous midazolam and group C received 20 mL intravenous saline. Parameters such as the PONV, other adverse reactions (chest distress, flush, etc.) caused by hemabate, patient satisfaction, the sedation (OAA/S) scores, and the hemodynamic parameters were recorded in both groups.Results: The PONV incidence in group D and group M was significantly lower compared with group C (6%, 17%, and 71% for group D, group M, and group C, respectively, P< 0.05). The sedation (OAA/S) scores in group D and group M was significantly higher compared with group C (1.62± 0.28, 1.75± 0.31, and 1.00± 0.00 for group D, group M, and group C, respectively, P< 0.05). The patient satisfaction in group D and group M was significantly higher compared with group C (94%, 69%, and 46% for group D, group M, and group C, respectively, P< 0.05). Furthermore, there were more patients satisfied with group D than group M (94% vs.69%, P< 0.05).Conclusion: Intravenous dexmedetomidine (1 μg/kg) and midazolam (0.02 mg/kg) were equally effective in preventing PONV introduced by hemabate and dexmedetomidine is superior to midazolam in patient satisfaction.Keywords: dexmedetomidine, midazolam, PONV, hemabate, cesarean delivery

Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p

Background Atherosclerosis (AS) is the basis of cardiovascular diseases, characterized by chronic inflammatory and lipid metabolism disorders. Although the anti-inflammatory effect of Klotho in AS has been clearly shown, its lipid-lowering effect is unclear. In this study, we examined the effects of recombinant Klotho (Re-KL) protein on lipid accumulation in foam cells. Methods THP-1 cells were exposed to 100 nM phorbol myristate acetate for 24 h and then to oxidized low-density lipoprotein (ox-LDL; 80 mg/mL) to induce foam cell formation. Subsequently, the foam cells were incubated with Re-KL and/or DKK1, an inhibitor of the Wnt/β-catenin pathway. Results Oil red O staining and cholesterol intake assay revealed that the foam cell model was constructed successfully. Pre-treatment of the foam cells with Re-KL decreased total cholesterol level, up-regulated the expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1), and down-regulated the expression of acyl coenzyme a-cholesterol acyltransferase 1 (ACAT1) and members of the scavenger family (SR-A1 and CD36). In addition, the expression of Wnt/β-catenin pathway-related proteins in foam cells was significantly decreased by the stimulus of Re-KL. Interestingly, the effect of Re-KL was similar to that of DKK1 on foam cells. Conclusions The Re-KL-induced up-regulation of reverse cholesterol transport capacity promotes cholesterol efflux and reduces lipid accumulation by suppressing the Wnt/β-catenin pathway in foam cells.