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Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.

This study aimed to evaluate the efficacy and safety of long-term postpartum tenofovir disoproxil fumarate (TDF) therapy in hepatitis B virus (HBV)-infected mothers with high viral load.In this retrospective cohort study, HBV-infected mothers with HBV DNA2 × 10 5 IU/mL who initiated TDF prophylaxis treatment during pregnancy were divided into TDF continuation and discontinuation groups according to whether they stopped TDF treatment within 3 months after birth or not. Virological and biochemical markers were collected before TDF treatment, antepartum and postpartum.In 131 women followed for a median of 18 months postpartum, alanine aminotransferase (ALT) abnormality rate was significantly lower in TDF continuation group vs. discontinuation group (39.4% vs. 56.9%, P = 0.045), and continuous TDF therapy in postpartum was independently associated with lower risk of ALT flares [OR = 0.308, 95% confidence interval (CI), 0.128-0.742; P = 0.009]. Long-term postpartum TDF treatment can promote the decline of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels, but the HBeAg seroconversion rate in two groups was not significant (15.5% vs. 11.7%, P = 0.541). There were no statistical differences in bone metabolism markers between two groups ( P 0.05). Compared with the TDF discontinuation group, TDF continuation group had a significantly lower estimated glomerular filtration rate level and higher creatinine level in postpartum but within normal ranges ( P 0.05).For pregnant women who received prophylactic TDF treatment, long-term TDF therapy continued in postpartum can reduce the risk of ALT flares and promote the rapid decline of HBeAg and HBsAg levels.

Fear of progression (FoP) is a common psychosocial problem among adult cancer patients, but data on parents of children undergoing cancer treatment are scarce. This study aimed to determine the prevalence of FoP in parents of children undergoing cancer treatment and explore the associated factors.Overall, 285 parents of children undergoing cancer treatment were recruited from three general hospitals in China. FoP in the parents was assessed using the Chinese version of the Fear of Progression Questionnaire-parent version (FoP-Q-SF/PR). Other questionnaires included the Self-Compassion Scale, Pittsburgh Sleep Quality Index, Posttraumatic Stress Disorder Checklist-Civilian Version, and items on socio-demographic and medical characteristics. Pearson correlation and multiple linear regression analysis were used to identify factors associated with FoP.A total of 75.1% of the participants showed dysfunctional levels of FoP. The mean FoP-Q-SF/PR score was 39.98 (standard deviation = 9.18). Parental FoP was significantly associated with a shorter time since diagnosis, lower levels of self-compassion, poor sleep quality, and severe posttraumatic stress symptoms (Adjusted R Squared = 0.369, F = 12.838, p 0.01).FoP is a frequently reported problem among parents of children undergoing cancer treatment. In this cohort, parents of children with a shorter time since cancer diagnosis were at higher risk of suffering from FoP. Interventions to enhance self-compassion, improve sleep quality, and mitigate posttraumatic stress symptoms may help with the psychological adjustment and well-being of parents whose children are undergoing cancer treatment.

Context The optimal timing to performing thyroid surgery following a diagnosis of papillary thyroid cancer (PTC) has yet to be fully defined. Objective We aimed to examine if a delayed surgery may worsen the clinical outcome of PTC patients with intermediate- to high-risk of recurrence. Methods All consecutive PTC patients with intermediate- to high-risk of recurrence who underwent total thyroidectomy and radioactive iodine (RAI) ablation at 3 tertiary hospitals in southwest China were retrospectively included. Excellent response at 1-year follow-up after initial therapy was defined as no clinical, imaging, or biochemical evidence of PTC. Association of the timing of surgery and excellent response rates. Results The study included 871 patients. The median time interval between PTC diagnosis and surgery was 2 months (range, 1-87 months). Patients were divided according to the timing of surgery, < 6 months (group A, 624/871 [71.6%]), ≥ 6 to 11 months (group B, 123/871 [14.1%]), or ≥ 12 months (group C, 124/871 [14.2%]). One year after initial therapy, 64.7%, 71.5%, and 66.1% of patients in groups A, B, and C, respectively, achieved excellent response (P = 0.27). The lack of impact of surgery timing was observed across intermediate- to high-risk classifications and all T stage categories. These findings did not change when we separately analyzed the groups according to RAI dose (intermediate-dose group: ≤ 3.7 GBq [n = 654], and high-activity group: 5.5 GBq [n = 217]) further subdivided according to the timing of surgery. Conclusion Timing of surgery does not seem to affect short-term disease outcomes in intermediate- to high-risk PTC patients. Further research is necessary to assess the impact of delayed surgery on long-term prognosis.

Background Different techniques have been reported to prevent perineal lacerations, but the effects of the use of lubricant have been unclear and is still subject of debate. Objective To assess the effect of lubricants on reducing perineal trauma during vaginal delivery. Search strategy PubMed, Embase, the Cochrane Library, CINAHL, China National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBM), WanFang databases, ClinicalTrials.gov in 25 June 2021. Selection criteria Randomized controlled trials published in English or Chinese that compared the vaginal application of lubricant with standard care in women with cephalic presentation at vaginal delivery were included . Data collection and analysis Two independent reviewers selected eligible trials and extracted data on perineal trauma, duration of the second-stage labor, postpartum hemorrhage and Apgar score for meta-analysis. Main results Nineteen trials enrolling 5445 pregnant women were included. Compared with standard care, women using lubricants had a lower incidence of perineal trauma (RR 0.84, 95%CI 0.76 to 0.93), second-degree perineal laceration (RR 0.72, 95%CI 0.64 to 0.82) and episiotomy (RR 0.77, 95%CI 0.62 to 0.96), had a shorter duration of the second-stage labor (MD -13.72 minutes, 95%CI -22.68 to -4.77). Subgroup analysis indicated that women with obstetric gel had a shorter duration of the second-stage (MD -16.9 minutes, 95%CI -27.03 to -6.78 vs MD -8.38 minutes, 95%CI -11.11 to -5.65; P interaction=0.02) when compared with liquid wax. Conclusions Compared with standard care, lubricants could reduce the incidence of perineal trauma, especially second-degree perineal laceration, and shorten the duration of the second-stage labor.

Laryngopharyngeal reflux (LPR) may be associated with the severity of obstructive sleep apnea (OSA). However, it is unknown whether LPR may be associated with arousal.To clarify the effect of LPR on arousal in OSA.This study included 120 OSA patients. The correlations between LPR scores and arousal index (ArI) were analyzed. Finally, to further clarify the effect of LPR on ArI, we analyzed the correlations between respiratory event-related arousal index (BERAI), leg-movement-related arousal index (LMRAI), snore-related arousal index (SRAI), spontaneous arousal index (SAI), and RSI score.Partial correlation analysis showed that the RSI score was positively correlated with ArI (The effect of LPR symptoms on arousal in OSA exists. The more severe the LPR was, the more frequent the arousal in OSA patients was. Thereinto, respiratory event-related arousal and spontaneous arousal were the most obvious.

Yuan Cheng,1,2,&ast; Fushun Kou,1,2,&ast; Xiaosi Zhang,1,2 Yi Dai,3 Lei Shi,2 Chune Xie,2 Xiaohong Li,2 Junxiang Li2 1Second Clinical Medical College, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Pharmacotherapy and Oriental Medicine, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan&ast;These authors contributed equally to this workCorrespondence: Junxiang Li; Xiaohong Li, Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, No. 6, 1st Section Fangxingyuan, Fangzhuang, Fengtai District, Beijing, 100078, People’s Republic of China, Email junxiangli1226@126.com; lxhktxz@163.comPurpose: Proton pump inhibitors, as the first-line drugs for treating gastroesophageal reflux disease (GERD), are unable to completely relieve patients’ symptoms and patients are prone to recurrence after prolonged drug withdrawal. Thus, it is crucial to find herbal medicines as a complementary and alternative treatment. Hewei Jiangni granule (HWJNG) is a classical Chinese medicinal formula with clinical therapeutic effects on GERD, but its pharmacological mechanism of action remains unclear. This study aimed to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy.Methods: A network pharmacology approach was applied to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy. The active ingredients of HWJNG, as well as therapeutic targets of GERD were acquired from specialized databases. The “herb-ingredient-gene-target” network for HWJNG in GERD treatment was built. The protein–protein interaction (PPI) network was constructed to screen the core coincident targets. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The core targets and signaling pathways associated with the anti-neurogenic inflammatory effect were partially verified via experiments in vivo at molecular level.Results: In total, 179 chemical ingredients in HWJNG and 298 intersection targets between GERD and HWJNG were selected from databases. A large proportion of core targets and top signaling pathways were involved in neurogenic inflammation. HWJNG significantly alleviated pathological injuries of esophagus and reversed dilated intracellular spaces. Additionally, HWJNG markedly inhibited the excessive release of inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor receptor (TNF-a), as well as regulated stimulation sensors including transient receptor potential vanilloid type 1 (TRPV1) and its related neuroinflammatory mediators in GERD mice.Conclusion: HWJNG is a promising therapeutic strategy for GERD treatment via regulation of multiple targets and pathways, its effects in alleviating neurogenic inflammation are especially acknowledged.Keywords: Hewei Jiangni granule, gastroesophageal reflux disease, network pharmacology, neurogenic inflammation

Host immune system genes play key roles in the progression of chronic hepatitis C virus (HCV) infection. Transporters associated with antigen processing (TAP) play an important role in the loading of viral peptides onto MHC class I molecules. This study aimed to investigate the association between TAP gene polymorphisms and chronic HCV in a Chinese Han population. A total of 232 chronic hepatitis C (CHC) patients and 362 healthy individuals were recruited from the Han population in Yunnan province in southwest China, and a TaqMan SNP genotyping assay was used to detect six single nucleotide polymorphisms (SNPs) of TAP1 and three SNPs of TAP2 genes. The association of the TAP gene with CHC was analysed at the allele, genotype, and haplotype levels. There were no significant differences in the allele and genotype frequencies of these SNPs in the TAP gene between CHC patients and controls after Bonferroni correction. A novel TAP1 allele (TAP1*unknown_1: rs41555220-rs41549617-rs1057141-rs1135216-rs1057149-rs41551515: G-G-A-G-G-G) was only present in the CHC group, and this allele significantly increased susceptibility to CHC (p = .005, odds ratio [OR] = 11.105. 95% confidence interval [CI]: 1.362-90.558). Homozygous TAP1*03:01/TAP1*03:01 was observed only in the CHC group that exhibited an obvious risk for CHC (p = .002, OR = 9.637, 95% CI: 1.153-80.574). And the haplotype TAP1*unknown_1-TAP2*01:01 was only present in the CHC group and indicated a significant risk for CHC (p = .002, OR = 9.498, 95% CI: 1.140-79.149). We observed significant interactions among HLA-A, -B,C, TAP1, and TAP2 alleles, and combination analysis revealed that the combination of TAP1*01:01-TAP2*01:01-HLA-B*35:01 was only present in the control group (2.2%) and resulted in significantly increased resistance to CHC (p = .002, OR = 0.096, 95% CI: 0.012-0.759). Whereas, the combination of TAP1*01:01-TAP2*01:01-HLA-C*07:02 and TAP1*03:01-TAP2*01:01-HLA-C*01:02 increased the susceptibility to CHC significantly (p = .001, OR = 2.016, 95% CI: 1.309-3.106 and p = .002, OR = 8.070, 95% CI: 1.018-63.997, respectively). Our results indicated that TAP and HLA-I may exert a combined effect on CHC susceptibility in the Chinese Han population.

Inflammation is widely recognized as an essential inducer of epithelial-mesenchymal transition (EMT). Meanwhile, competitive endogenous RNA (ceRNA) has been involved in a variety of disease processes. Therefore, the aim of the current study is to explore the regulation of ceRNA in the PI3K/AKT pathway and EMT mechanism in inflammatory response caused by low molecular weight-polycyclic aromatic hydrocarbons (LMW-PAHs). The A549 cells were treated with an equal mixture of phenanthrene (Phe) and fluorene (Flu), and total RNA was extracted for transcriptome sequencing. The target regulation of ceRNA hsa_circ_0039929/hsa-miR-15b-3p_R-1/FGF2 was further determined for mechanism study. The mixture of Phe and Flu significantly upregulated the expressions of hsa_circ_0039929 and FGF2, down-regulated hsa-miR-15b-3p_R-1, activated the PI3K/AKT pathway and promoted EMT. Mechanically, the overexpression of hsa-miR-15b-3p_R-1 inhibited the expressions of hsa_circ_0039929 and FGF2, reversed the activation of PI3K/AKT signaling pathway by LMW-PAHs, and blocked the occurrence of EMT progression. Furthermore, knockdown of hsa_circ_0039929 could promote the levels of hsa-miR-15b-3p_R-1, while inhibit the expression of FGF2. The effects of hsa_circ_0039929 knockdowns on PI3K/AKT pathways and EMT progress resembled the hsa-miR-15b-3p_R-1 overexpression. All above suggested that ceRNA hsa_circ_0039929/hsa-miR-15b-3p_R-1/FGF2 played an important role in the inflammation and EMT caused by LMW-PAHs.

Little is known about the epidemiology and impact of atrial fibrillation (AF) on cardiovascular diseases (CVD) mortality among hypertensive elderly population in northeast China. The community-based study included 4497 hypertensive elderly residents aged ≥65 years who lived in northeast China from September 2017 to March 2019. Information on CVD deaths was obtained from baseline until July 31, 2021. Cox proportional hazard regression models were performed in the evaluation of CVD mortality. We identified 101 persons with AF. The prevalence of AF was 2.2% among elderly hypertensive population, which increased significantly with age. The prevalence of AF was higher in men than in women. The awareness rate was 51.5%, higher in urban areas than in rural areas (68.8% vs 43.5%, P = .018). Only 4.0% patients received oral anticoagulant (OAC) therapy among AF patients. Moreover, diabetes (26.7%) and dyslipidemia (37.6%) were highly prevalent in AF patients. Furthermore, 212 persons died due to CVD (14.7/1000 person-years) during a median follow-up of 3.2 years. AF patients had a 3.42 (95% CI: 2.07-5.63) times higher risk of CVD mortality than the patients without AF in the fully adjusted model. Therefore, the burden of AF among hypertensive elderly population in northeast China was considerable. Long-term screening and management strategies for AF and related risk factors are required among hypertensive elderly in northeast China.

The DNA damage response (DDR) pathway generally protects against genome instability, and defects in DDR have been exploited therapeutically in cancer treatment. We have reported that histone demethylase PHF8 demethylates TOPBP1 K118 mono-methylation (K118me1) to drive the activation of ATR kinase, one of the master regulators of replication stress. However, whether dysregulation of this physiological signalling is involved in tumorigenesis remains unknown. Here, we showed PHF8-promoted TOPBP1 demethylation is clinically associated with breast tumorigenesis and patient survival. Mammary gland tumors from Phf8 knockout mice grow slowly and exhibit higher level of K118me1, lower ATR activity, and increased chromosomal instability. Importantly, we found that disruption of PHF8-TOPBP1 axis suppresses breast tumorigenesis and creates a breast tumor-specific vulnerability to PARP inhibitor (PARPi) and platinum drug. CRISPR/Cas9 mutation modelling of the deleted or truncated mutation of PHF8 in clinical tumor samples demonstrated breast tumor cells expressing the mimetic variants are more vulnerable to PARPi. Together, our study supports the pursuit of PHF8-TOPBP1 signalling pathway as promising avenues for targeted therapies of PHF8-TOPBP1 proficient tumors, and provides proof-of-concept evidence for loss-of-function of PHF8 as a therapeutic indicator of PARPis.

COVID-19, caused by SARS-CoV-2, has been spreading worldwide for more than two years and has led to immense challenges to human health. Despite the great efforts that have been made, our understanding of SARS-CoV-2 is still limited. The viral helicase, NSP13 is an important enzyme involved in SARS-CoV-2 replication and transcription. Here we highlight the important role of the stalk domain in the enzymatic activity of NSP13. Without the stalk domain, NSP13 loses its dsRNA unwinding ability due to the lack of ATPase activity. The stalk domain of NSP13 also provides a rigid connection between the ZBD and helicase domain. We found that the tight connection between the stalk and helicase is necessary for NSP13-mediated dsRNA unwinding. When a short flexible linker was inserted between the stalk and helicase domains, the helicase activity of NSP13 was impaired, although its ATPase activity remained intact. Further study demonstrated that linker insertion between the stalk and helicase domains attenuated the RNA binding ability and affected the thermal stability of NSP13. In summary, our results suggest the crucial role of the stalk domain in NSP13 enzymatic activity and provide mechanistic insight into dsRNA unwinding by SARS-CoV-2 NSP13.

Developmental and Epileptic Encephalopathy (DEE) is a group of disorders affecting children at early stages of infancy, which is characterized by frequent seizures, epileptiform activity on EEG, and developmental delayor regression. Developmental and epileptic encephalopathy-30 (DEE30) is a severe neurologic disorder characterized by onset of refractory seizures soon after birth or in the first months of life. Which was recently found to be caused by heterozygous mutations in the salt-inducible kinase SIK1. In this study, we investigated a patient with early onset epilepsy. DNA sequencing of the whole coding region revealed a de novel heterozygous nucleotide substitution (c.880G A) causing a missense mutation (p.A294T). This mutation was classified as variant of unknown significance (VUS) by American College of Medical Genetics and Genomics (ACMG). To further investigate the pathogenicity and pathogenesis of this mutation, we established a human neuroblastoma cell line (SH-SY5Y) stably-expressing wild type SIK1 and A294T mutant, and compared the transcriptome and metabolomics profiles. We presented a pediatric patient suffering from infantile onset epilepsy. Early EEG showed a boundary dysfunction of activity and MRI scan of the brain was normal. The patient responded well to single anti-epileptic drug treatment. Whole-exome sequencing found a missense mutation of SIK1 gene (c.880G A chr21: 43,420,326 p. A294T). Dysregulated transcriptome and metabolome in cell models expressing WT and MUT SIK1 confirmed the pathogenicity of the mutation. Specifically, we found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. We found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. Our finding further expanded the disease spectrum and provided novel mechanistic insights of DEE30.

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587

Abstract: In recent years, bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, has been one of the most widely studied targets. BRD4 is a transcriptional regulation factor, which regulates cell transcription, marks mammalian biological mitosis, regulates cell cycle, and plays an important role in the biological process of cancer occurrence and development. It has been demonstrated that the imbalance or dysfunction of BRD4 expression leads to various types of cancers, including testicular gene nuclear protein melanoma, acute myeloid leukemia, colon cancer, breast cancer, liver cancer, and midline cancer. Therefore, inhibition of BRD4 has become a valuable approach in the treatment of these cancers. To date, there are numerous BRD4 inhibitors in preclinical development, some of which have entered human clinical trials. In this review, current progress in the development of privileged scaffolds designed as BRD4 inhibitors will be discussed by focusing on structure-activity relationship, selectivity, and mechanisms of action.

Socio-economic metabolism refers to the human-driven migration and transformation of material and energy within and at the boundary of the socio-economic system. The research of socio-economic metabolism has become the core in industrial ecology. We introduced the connotation and basic steps of socio-economic metabolism research with typical cases, and summarized the main findings of socio-economic metabolism research. The research provide a method and model to track the sources, sinks, and flow path of materials in the socio-economic system, reveal how materials and their socio-economic metabolic processes supported modern production and lifestyle. Related studies have clarified the mechanism by which human activities driving the ecological and environmental problems related to material metabolism. It provides the model and database for evaluating the resource efficiency, the trend of resource supply and demand, and the potential of urban mining. We put forward the future directions of socio-economic metabolism research: to increase research objects and enhance the research precision of each object; to expand and deepen the temporal and spatial boundaries of the research system; to introduce and integrate new data sources and research methods; to connect the material flows of socio-economic metabolism with its related ecological and environmental impacts; and to establish a data platform that could be shared, expanded and accumulated.社会经济代谢是指由于人类活动导致的物质和能量在社会经济系统内部和边界上的迁移和转换。社会经济代谢研究已经成为产业生态学的核心领域。本文结合典型案例介绍了社会经济代谢研究的内涵和基本步骤,总结了社会经济代谢研究的主要发现:提供了追踪物质在社会经济系统的来源、去向和流动路径的方法与模型;揭示了物质材料及其社会经济代谢过程对现代化生产和生活方式的支撑作用;阐明了人类活动驱动与物质代谢相关的生态环境问题的机制;提供了评估资源利用效率、资源供需趋势和城市矿产开发潜力的模型与基础数据。最后指出了社会经济代谢研究的发展方向:增加研究对象并深化对每种对象的研究精度;拓展或细化研究系统的时空边界;引入并融合新的数据来源和研究方法;将社会经济代谢中的物质流对接到与其相关的生态环境影响;建立可共享、可拓展、可累积的数据平台。.

The social-economic-natural system is a complex system for human survival and development, and the data-driven system research provides a new value-added orientation to enhance the cognition of the ecosystem. Under the new data context, the social-economic-natural complex system shows new features. The research object is gradually changing from a single element to a multi-factor coupling direction, which makes the data system more diversified, data sources more extensive, data expression more visualized. The research scale shows the characteristics of gradually expanding, and the research object would be more detailed. In the process of data identification, expression and visualization, it is therefore necessary to strengthen the coupling of time, space, structure, quantity and order, as well as to focus on the integration with decision making and local services. The future research of complex ecosystems in the new era should be carried out in terms of key scientific issues and supporting technologies, the role of scale and multi-factor coupling, as well as scientific and technological support for local and global governance. Under the continuous innovation of data, strengthening the cognition of multi-source data, long-term monitoring and time series still needs to be studied in depth. Carrying out data-driven analysis of complex ecosystems not only provides technical support for ecosystem services and sustainable development and enhances the long-term data sharing mechanism, but also provides more value support for realizing decision making and information dissemination.社会-经济-自然系统是人类赖以生存和发展的复合系统,而数据驱动下的系统研究为加强生态系统的认知提供了新的增值导向。在新的数据语境下,社会-经济-自然复合系统呈现出一些新的特征,研究对象逐渐从单一要素向多要素耦合的方向转变,使支撑量化研究的数据体系更多样化、数据来源更广泛化、数据表达更具可视化,并呈现出研究尺度逐渐扩大化、研究对象更精细化的特征。在对数据的识别、表达和可视化的过程中,既要加强对时间、空间、结构、数量和秩序的耦合,也要注重与决策制定和地方服务的结合。新时期复合生态系统的未来研究方向应该从关键科学问题及支撑技术、尺度作用和多要素耦合以及地方和全球治理的科技支撑等方面展开,在数据的不断革新下,加强对多源数据、长期监测和时间序列的认知仍是需要深入研究的课题。开展复合生态系统的数据驱动分析,不仅能为生态系统的服务及可持续发展提供技术支撑,增强数据的长效共享机制,同时可为实现决策制定和信息传播等方面提供更多的价值支持。.

PurposeTo determine the association between poor visual acuity, the use of digital devices and physical activity (PA) during the COVID-19 pandemic.MethodsA total of 327,646 Chinese children and adolescents were included in the analysis using a cluster random sampling method; this is a case-control study, of those 144,708 children and adolescents with poor visual acuity were included in the case group, while 182,938 who did not have poor visual acuity were included in the control group. A logistic regression model was used to assess the contribution of PA and the use of digital devices to poor visual acuity.ResultsA total of 144,708 children and adolescents experienced poor visual acuity during the COVID-19 pandemic; 54.8% were male, and 55.2% live in rural areas. Compared to controls, children and adolescents with poor visual acuity exhibited more time for the use of digital devices (4.51 ± 2.44 vs. 3.79 ± 2.34 for cases and controls, respectively; P < 0.001) and PA (3.07 ± 0.92 vs. 2.85 ± 1.00 for cases and controls, respectively; P < 0.001). During the COVID-19 pandemic, risk factors related to poor visual acuity among children and adolescents included the use of digital devices (OR 1.135; 95% CI 1.132–1.139), and PA (OR 1.269; 95%CI 1.259–1.278). The results of interaction analysis show that for children and adolescents aged 12 to 17, the positive association between the use of digital devices and poor visual acuity decreased. The interaction effect between PA and digital devices is 0.987.ConclusionsChildren and adolescents were at risk of poor visual acuity during the COVID-19 pandemic. Extended use of the digital devices increased the risk of poor visual acuity, especially for children aged 6–11 years. But the risk of poor visual acuity among children and adolescents decreases as the time spent on PA increases.

To analyze the genotype and clinical phenotype of a 3-month-old female infant featuring unresponsiveness.The infant was subjected to genetic testing, and her clinical features were compared with syndromes associated with variants of the candidate gene.The patient has featured long fingers, long and overlapped toes, musk-like face, blepharophimosis, ptosis, and lacrimal duct anomaly. She was found to harbor a heterozygous de novo variant NM_012330.3: c.3040CT (p.Gln1014*) in exon 16 of the KAT6B gene. Her clinical phenotype and genotype have both conformed to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS).The child was diagnosed with SBBYSS syndrome due to the c.3040CT (p.Gln1014*) variant of the the KAT6B gene. Discovery of the unique features has expanded the phenotypic spectrum of this syndrome.

Vitamin D deficiency is common in chronic liver diseases, it may increase the severity of the diseases. However, studies on the potential role of vitamin D in hepatitis B virus (HBV) related end stage liver disease are still limited. This study was performed to assess the prevalence of vitamin D deficiency in patients with different stages of chronic HBV infection and explore whether vitamin D deficiency can be established as an index of severity and prognosticator of disease progression. Serum 25(OH)D

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion–positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion–positive cholangiocarcinoma. Significance: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion–positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171

Polycystic ovarian syndrome (PCOS) is one of the major causes encouraging the elevation of androgens, obesity along with menstrual complications. Here we study the effect of Apigenin in rat model of polycystic ovarian syndrome.Female Sprague Dawley (SD) rats were treated with Dehydroepiandrosterone (DHEA) (6 mg/100g) opting the post-pubertal approach for developing rat model of polycystic ovarian syndrome, Metformin was used as standard. The treatments were given for 21 days along with coloproctological analysis. After the treatment regimen, the biochemical analysis was carried in plasma samples, whereas the ovaries were submitted for histopathological analysis.The treatment of DHEA resulted in disturbed lipid profile and anti-oxidant status along with increased weight, ovarian diameter and cysts in rats confirming the development of PCOS. However, treatment of Apigenin showed ameliorative effect by improving the lipid profile and anti-oxidant status, the treatment also normalised the body weight, reduced ovarian diameter, cysts and restored the healthy follicles compared to control rats. The treatment of Apigenin also suppressed the levels of oestradiol and testosterone compared to control group, also, levels of progesterone were increased in Apigenin treated group of rats. The treatment of Apigenin suppressed the levels of inflammatory cytokines TNF-α and IL-6. It was observed that the effect of Apigenin were to some extent parallel to standard drug Metformin.The findings confirmed that Apigenin ameliorates the disturbed hormonal levels, lipid profile and antioxidant status in PCOS rats.

A complete toxicity profile, toxicity profile, and safety ranking of immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC) will be provided in this network meta-analysis.We searched 14 randomized clinical trials (RCTs) including 9572 NSCLC patients by PubMed, EMBASE, Cochrane, and ClinicalTrials.gov. Randomized pairwise and network meta-analyses were used to compare the incidence of severe immune-related adverse events (irAEs) across different ICIs-based treatments using risk ratios (RRs) and 95% confidence intervals (CI).For severe dermatologic irAEs, the corresponding ranking of incidences of the nine groups from high to low was: nivolumab + ipilimumab + platinum (79.1%), pembrolizumab (75.2%), nivolumab + ipilimumab (72.9%), camrelizumab + platinum (64.9%), atezolizumab + platinum (47.4%), nivolumab (44.2%), durvalumab (40.5%), pembrolizumab + platinum (15.5%), platinum-based chemotherapy (10.3%). For severe colitis, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab + platinum (72.4%), nivolumab (63.1%), atezolizumab + platinum (56.9%), durvalumab (56.6%), pembrolizumab (54.9%), pembrolizumab + platinum (38.6%), platinum-based chemotherapy (7.4%). For severe endocrine irAEs, the corresponding ranking of incidences of the nine groups from high to low was: durvalumab (74.3%), atezolizumab + platinum (54.5%), nivolumab + ipilimumab (54.0%), camrelizumab + platinum (51.7%), nivolumab + ipilimumab + platinum (51.6%), pembrolizumab + platinum (49.8%), pembrolizumab (49.2%), nivolumab (46.3%), platinum-based chemotherapy (18.6%). For severe pneumonitis, the corresponding ranking of incidences of the nine groups from high to low was: nivolumab (84.3%), pembrolizumab (84.1%), durvalumab (66.1%), camrelizumab + platinum (61.4%), atezolizumab + platinum (50%), pembrolizumab + platinum (43.4%), platinum-based chemotherapy (16.2%), atezolizumab (6.2%). For severe hepatitis, the corresponding ranking of incidences of the eight groups from high to low was: pembrolizumab (68.8%), nivolumab + ipilimumab + platinum (65%), pembrolizumab + platinum (64.6%), durvalumab (57.9%), nivolumab (47.1%), atezolizumab + platinum (43.4%), camrelizumab + platinum (42%), platinum-based chemotherapy (11.2%).In addition to platinum-based chemotherapy, pembrolizumab + platinum for severe dermatologic irAEs and colitis, nivolumab for severe endocrine irAEs, atezolizumab for severe pneumonitis, camrelizumab + platinum for severe hepatitis may be associated with lower rates of irAEs than other immune-based regimens.

It has been acknowledged that microRNAs (miRNAs/miRs) assume a critical role in hypoxia/reoxygenation (H/R) – induced hepatocyte injury. Therefore, cell experiments were performed in this study to investigate the mechanism of miR-297 in H/R-induced hepatocyte injury with the involvement of sirtuin 3 (SIRT3) and NOD-like receptor pyrin domain containing 3 (NLRP3). Initially, transformed human liver epithelial-2 (THLE-2) cells were utilized for H/R challenge. After miR-297 antagomir and NLRP3 adenovirus vector delivery, THLE-2 cell proliferation and apoptosis were measured by MTT, EdU, and TUNEL assays, respectively. Enzyme-linked immunosorbent assay was conducted to evaluate the levels of apoptosis-related indicators (Bax and Bcl-2) and inflammation-related indicators (interleukin 6 (IL-6) and IL-10), Western blot analysis to detect NLRP3, and cleaved caspase-1 expression. The binding relation between miR-297 and SIRT3 was examined using dual-luciferase assay. The results showed that miR-297 antagomir repressed the apoptosis and inflammation induced by H/R treatment in THLE-2 cells. Mechanistically, miR-297 antagomir diminished the extent of IκBα and nuclear factor-kappa B (NF-κB) phosphorylation and NLRP3 activation in H/R-induced THLE-2 cells by targeting SIRT3. Furthermore, NLRP3 overexpression normalized the promoting effects of miR-297 antagomir on proliferation and its inhibitory effects on apoptosis and inflammation in H/R-induced THLE-2 cells. In summary, our results elucidated that miR-297 antagomir repressed H/R-induced THLE-2 cell injury via SIRT3 promotion and NLRP3 inactivation.

Zenker's peroral endoscopic myotomy (Z-POEM) has revolutionized the therapeutic strategy for Zenker's diverticulum (ZD) with promising results. We conducted this meta-analysis to estimate the safety and efficacy of Z-POEM for ZD and compare the feasibility and effectiveness of Z-POEM with that of flexible endoscopic septotomy (FES).A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and Cochrane Library databases to query for studies that assessed the safety and efficacy of Z-POEM for ZD. All articles published from inception to July 31, 2021 were included. The primary outcomes were the overall technical success rate, clinical success rate, incidence of adverse events, and clinical recurrence rate.Eleven studies involving 357 patients undergone Z-POEM were included. Overall, the quality of included studies was above average, with five studies rated as high quality and six ranked as moderate quality. The overall pooled technical success rate for Z-POEM was 96.3% (95% confidence interval [CI] 93.6-97.9%; IZ-POEM could be an effective and safe therapeutic modality for ZD, and even has a slightly higher clinical success rate than FES. However, comparative studies with long-term follow-up will be needed to further confirm our finding.

Platinum-based metal complexes, especially cisplatin (cis-diamminedichloroplatinum II, CDDP), possess strong anticancer properties and a broad anticancer spectrum.

Background Previous research has found a link between sleep quality and psychological distress. However, the underlying mechanisms of this connection have still not been well explored. The aim of this study was to examine the roles of activities of daily living (ADL), physical activity, and perceived social support in the link between sleep quality and psychological distress among older adults. Methods Three thousand two hundred fifty valid individuals (aged 60 years or above) participated in face-to-face questionnaire-based surveys. Older individuals were assessed using the Pittsburgh Sleep Quality Index, Barthel Index, International Physical Activity Questionnaire, Perceived Social Support Scale, and Depression Anxiety Stress Scale-21. The PROCESS macro developed by Hayes was used to conduct moderated mediation analysis. Results In older adults, sleep quality had a substantial direct influence on psychological distress. ADL mediated the association between sleep quality and psychological distress. Physical activity significantly reduced ADL’s mediating influence on the relationship between sleep quality and psychological distress. Furthermore, perceived social support moderated the direct relationship between sleep quality and psychological distress, as well as the second half of the mediating effect of the ADL. Moreover, physical activity and perceived social support were preventive factors that might successfully mitigate the detrimental effects of poor sleep quality on ADL and psychological distress. Conclusions The findings contribute to existing understanding by clarifying the fundamental mechanisms that link sleep quality and psychological distress. These results may provide a valuable reference to the Chinese government for improving mental health in older individuals.

Background Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory response. Persistent allergic rhinitis (PAR) is a subtype of AR, but the treatment of PAR is still a problem. Acupuncture is used as an alternative therapy for AR in clinical practice. The aim of this study is to evaluate the effectiveness of acupuncture therapy combined with fluticasone propionate nasal spray in comparison to fluticasone propionate nasal spray alone in the relief of symptoms for PAR. Methods This study is a multicenter, single-blind, randomized controlled trial. A total of 260 eligible patients will be randomly assigned into the treatment group or the control group. The treatment group will receive the nasal fluticasone propionate combined with acupuncture, and the control group will receive fluticasone propionate nasal spray alone for 6 weeks. The primary outcome is the change in the Reflective Total Nasal Symptom Score (rTNSS) from baseline to the end of treatment, and the Total Non Nasal Symptom Score (TNNSS), reflective total ocular symptom score (rTOSS), Rhinitis Quality of Life Questionnaire (RQLQ), use of antiallergic drugs, and the Rhinitis Control Assessment Test (RCAT) are used as secondary outcomes. The participants will be followed up for another 24 weeks after treatment. Discussion This clinical trial will be able to provide high level evidence on the acupuncture therapy combined with fluticasone propionate nasal spray in the treatment of PAR. Trial registration ISRCTN Registry, ID: ISRCTN44040506. Registered on 22 July 2020.

Background Bacterial infections are common complications in patients with cirrhosis or liver failure and are correlated with high mortality. Clinical practice guideline (CPG) is a reference used to help clinicians make decisions. This systematic appraisal aimed to evaluate the methodological quality and summarize the recommendations of reported CPGs in these patients. Methods We systematically searched CPGs published from 2008 to 2019. The methodological quality of the included CPGs was assessed using the AGREE II instrument. We extracted and compared recommendations for prophylactic and empirical treatment strategies. Results Fourteen CPGs with a median overall score of 56.3% were included. The highest domain score was Clarity of Presentation (domain 4, 85.4%), and the lowest was for Stakeholder Involvement (domain 2, 31.3%). Three CPGs had an overall score above 80%, and 6 CPGs had a score above 90% in domain 4. Prophylaxis should be strictly limited to patients with varicose bleeding, low ascites protein levels and a history of spontaneous bacterial peritonitis. Fluoroquinolones (norfloxacin and ciprofloxacin), third-generation cephalosporins (G3) (ceftriaxone and cefotaxime) and trimethoprim–sulfamethoxazole (SXT) are recommended for preventing infections in patients with cirrhosis or liver failure. G3, β-lactam/β-lactamase inhibitor combinations (BLBLIs) and carbapenems are recommended as the first choice in empirical treatment according to local epidemiology of bacterial resistance. Conclusions The methodological quality of CPGs focused on patients with cirrhosis or liver failure evaluated by the AGREE II instrument is generally poor. Three CPGs that were considered applicable without modification and 6 CPGs that scored above 90% in domain 4 should also be paid more attention to by healthcare practitioners. Regarding recommendations, norfloxacin, ciprofloxacin, ceftriaxone, cefotaxime, and SXT are recommended for prophylactic treatment appropriately. G3, BLBLIs, and carbapenems are recommended for use in empirical treatment strategies.

Aims: Lipoprotein (a) deposition in coronary vascular plaques and cerebral vessels is a recognized risk factor for cardiovascular disease, and research supports its role as a “repair factor” in vascular walls weakened by vitamin C deficiency. Background: Humans depend on dietary vitamin C as an important antioxidant and as a cofactor in collagen synthesis, yet are prone to vitamin C deficiency. The brain is the one with the highest vitamin C content, owing to its high oxygen consumption and oxidative stress. It has been shown that brain aging is accompanied by accumulated oxidative damage, which can lead to memory decline and neurological diseases. Objective: Our transgenic mouse, Gulo (-/-); Lp(a)+, presents a unique model for the study of key aspects of human metabolism with respect to a lack of internal vitamin C synthesis and the production of human lipoprotein(a). Methods: This mouse model was used in our study to investigate the effects of prolonged intake of low and high levels of vitamin C, at different ages, on oxidative damage, cholesterol levels and lipoprotein( a) deposition in the brain. Result: The results show that a long-term high vitamin C intake is important in maintaining brain cholesterol homeostasis and preventing oxidative damage in Gulo(-/-);Lp(a)+ mice as they age. Moreover, we observed that the formation of brain lipoprotein(a) deposits was negatively correlated with brain level of vitamin C, thereby confirming its role as a stability factor for an impaired extracellular matrix. Conclusion: Our study emphasizes the critical role of vitamin C in protecting brain health as we age. Other: Our findings show that optimal vitamin C intake from early life to old age is important for brain health as it prevents oxidative stress damage and maintains cholesterol homeostasis in the brain. More importantly, the negative correlation between brain ascorbic levels and the formation of Lp(a) deposit on the choroid plexus further emphasizes the critical role of vitamin C in protecting brain health throughout the normal aging process.

Background & aims Immunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation. Methods We enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival. Results Adverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects. Conclusions The adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC. Clinical trials registration This study was registered at ClinicalTrials.gov (NCT03899415).

This study aimed to compare the sedation and analgesic effects of butorphanol alone and butorphanol in combination with dexmedetomidine on dressing changes in adult burn patients.From June 2016 to May 2019, 44 adult burn patients from our department were enrolled in this prospective, double-blinded study. Their total burn surface area (TBSA) varied from 10% to 30%; and the depth of burn injury ranged from second degree to third degree. The patients were randomized into two groups. In the control group, butorphanol combined with saline was injected into the body via venous route during dressing change. In the observation group, butorphanol in combination with dexmedetomidine was injected. The variation in mean blood pressure, heart rate, respiratory rate, and peripheral oxygen saturation were recorded at various time-points of the procedure. Visual Analogue Scale (VAS) of pain and Ramsay Sedation Scores (RSS) were also recorded at different time points. Consumption of butorphanol and adverse events in these two groups were compared.The mean blood pressure and heart rate were significantly decreased in the observation group before butorphanol injection (P0.05) and before the dressing change (P0.05). The respiratory rates and peripheral oxygen saturation of these two groups showed no significant differences at all time points (P0.05). Patients in the observation group had lower VAS scores during dressing change (P0.05). The RSS Scores in the observation group were higher than those in the control group during (P0.05) and after the dressing change (P0.05). The consumption of butorphanol was more in the control group (P0.05), and the adverse events recorded in the control group were higher (P0.05).Butorphanol combined with dexmedetomidine can reduce analgesic use of butorphanol during dressing change. This combination resulted in a higher sedation score and fewer adverse effects.

Diabetes retinopathy (DR) is associated with retinal microvascular system injury induced by high glucose (HG). This study aims to explore the role and mechanism of long non-coding RNA THRIL in regulating cell proliferation and migration of human retina microvascular endothelial cells (hRMECs) under HG condition. The gene and protein expression were detetced by RT-PCR and western blot, respectively. Cell proliferation and migration of hRMECs were examined using MTT assay and Transwell assay, respectively. The interaction between miR-125b-5p and THRIL or autophagy-related gene 4D (ATG4D) was analyzed using luciferase activity assay. THRIL expression was induced by HG in hRMECs. THRIL overexpression enhanced the proliferation and migration of hRMECs induced by HG, whereas THRIL silencing yielded the opposite results. Furthermore, THRIL overexpression induced autophagy activation, and inhibition of autophagy by 3-methyladenine abrogated the promotory effects of THRIL overexpression on cell proliferation and migration of hRMECs. Mechanismly, THRIL inhibited miR-125b-5p to upregulate the expression of ATG4D (an important autophagy-related gene), thereby promoting autophagy. Moreover, miR-125b-5p overexpression or ATG4D silencing alone abolished the promoting effects of THRIL overexpression on HG-induced autophagy, proliferation and migration of hRMECs. THRIL promotes HG-induced cell proliferation and migration of hRMECs through activation of autophagy via the miR-125b-5p/ATG4D axis. THRIL may serve as a potential therapeutic target for DR.

The aim of this study was to determine whether carbohydrate antigen 72–4 (CA72–4) is elevated in diabetic kidney disease (DKD), and examine the association between urinary albumin-to-creatinine ratio (UACR) and CA72–4 in patients with type 2 diabetes mellitus (T2DM). Non-dialysis patients with T2DM (n=296) and 90 healthy controls were recruited in this study. CA72–4 level was measured by electrochemiluminescence immunoassay. DKD was defined as UACR≥ 30 mg/g in the absence of a urinary infection or other renal diseases. We found that patients with DKD had significantly higher serum CA72–4 levels compared to those with normoalbuminuria and healthy controls. Positive rates of CA72–4 increased gradually and markedly from normoalbuminuria to microalbuminuria and to macroalbuminuria in diabetic patients (7.5, 11.2, and 17.4%, respectively; P for trend< 0.05). CA72–4 also showed a positive correlation with UACR (r=0.288, P< 0.01). Logistic regression analysis revealed the association of increased UACR with an increased odds ratio of elevation of CA72–4 levels (P for trend< 0.05) after multivariable adjustment. In conclusion, serum levels of CA72–4 increase abnormally with the increase in urinary albumin excretion, which affects the specificity of diagnosis of malignancies. An appropriate interpretation of CA72–4 is essential to prevent unnecessary and even hazardous diagnostic procedures in patients with T2DM.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.

Bone marrow mesenchymal stromal cells (BMMSCs) are widely sourced and easily amplified in vitro; thus, they have a great potential in the treatment of hemopathies. Recent findings suggested that BMMSCs express the aryl hydrocarbon receptor (AHR). However, few studies have reported on the regulation of proliferative behaviors and metabolism by AHR in BMMSCs. In the present study, we found that activating AHR reduced the proliferation of BMMSCs and enhanced their mitochondrial function, whereas inhibiting AHR exerted the opposite effects. This study may provide the basis for further unveiling the molecular mechanisms and therapeutic potential of AHR in BMMSCs.

Bromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer.

This study examined the longitudinal changes of movement behaviors and their relationships with posttraumatic stress disorder (PTSD) among university students during the coronavirus disease 2019 in China. A total of 569 university students completed online surveys twice (Time 1: between December 2020 and January 2021; Time 2: between November and December 2021). Physical activity, sedentary behavior, sleep duration and quality, as well as PTSD were self-reported. According to Canadian 24-h movement guidelines, the longitudinal shifts in each movement behavior from Time 1 to Time 2 were divided into four categories (consistently meeting the guidelines, from meeting to not meeting the guidelines, from not meeting to meeting the guidelines, and consistently not meeting the guidelines). Generalized linear mixed models were conducted using 410 valid responses (20.2 ± 1.0 years old at Time 2, 41.2% males). From Time 1 to Time 2, 22.2%, 2.0%, and 45.6% of the students consistently met the physical activity, sedentary behavior, and sleep guidelines, respectively. Compared to those who consistently met the sedentary behavior guideline, students who consistently failed to meet or changed from meeting to not meeting the guidelines had higher levels of PTSD. Students who had poor sleep quality at both time points or changed from good to bad sleep quality had higher levels of PTSD than those who maintained good sleep quality over time. Compared to those who consistently failed to meet the guideline, students who consistently met the PA guideline had higher levels of PTSD. These findings highlight the needs to improve and maintain healthy behaviors for mental health.

Home enteral nutrition was reported to be a treatment reducing malnutrition rates and improving the rational allocation of medical resources. We aim to investigate the epidemiological characteristics and improved the management of home enteral nutrition.3953 patients with home enteral nutrition were enrolled in West China Hospital, located in Sichuan province, between January 1, 2021, and December 31, 2021.7238 visit records (3429 females and 3809 males) were included. The median age was 59.0, with the age from 1 to 115. The top two diseases were oncologic disorders (40.3%) and digestive disorders (15.9%). Oral nutritional supplements (86.2%) was the major treatment of home enteral nutrition. The median daily energy intake and daily protein intake were 575.1 kcal and 31.2 g. 25.8%, 39.3%, 34.9% patients choose online clinic (1867), offline clinic (2843) and hospital to home (2528) respectively. Interestingly, 63.6% patients were revisited, and the rate of online clinic, offline clinic and hospital to home was increasingly lower (91.9%, 71.5%, 33.8%) among them, revealing online clinic improving the revisit rate. Most patients lived in Chengdu (60.5%), and 67.4% patients from Chengdu were revisited. The median monthly cost of hospital to home patients (¥ 1863.8) was higher than the total median monthly cost (¥ 1714.5), illustrating the cost may reduce the revisit rate.Distance, cost and convenience may be the key factors to determine the method of visit and revisit in patients of home enteral nutrition. Online clinic may enhance the patients' follow-up.

BackgroundTo study the corresponding strategies to control inflammatory bowel disease (IBD), a comprehensive assessment of the disease burden is required. Herein, we present long-term trends in the burden of IBD in China over the last three decades, as well as its epidemiological features.MethodsWe characterized the burden of IBD in China using the GBD 2019 methods and results, based on prevalence, incidence, mortality, years lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) estimated using the DisMod-MR 2-1. We also used joinpoint and age-period-cohort (apc) analysis methods to interpret IBD epidemiological characteristics and compare them to global prevalence trends.ResultsThe age-standardized incidence and mortality rates in both sexes changed from 1.47 (95% CI: 1.24, 1.74) to 3.01 (95% CI: 2.59, 3.50) and from 0.86 (95% CI: 0.59, 1.16) to 0.30 (95% CI: 0.24, 0.35) per 100,000 people in China from 1990 to 2019. The age-standardized DALY rate in China decreased from 24.47 (95% CI: 17.88, 30.19) per 100,000 people in 1990 to 13.10 (95% CI: 10.29, 16.31) per 100,000 people in 2019. The average annual percentage change (AAPC) in age-standardized incidence, prevalence, and mortality rates for IBD in China were 2.51 (95% CI: 2.44, 2.57), 2.53 (95% CI: 2.41, 2.66), and −3.62 (95% CI: −3.85, −3.39). The effects of age, period, and cohort on incidence and mortality rates differed.ConclusionsThe increasing age-standardized prevalence rates are contributed to by the reduction in age-standardized mortality rates and DALYs, compounded by the rise in the age-standardized incidence rates between 1990 and 2019 in China. The burden of IBD in China will be a major public health challenge, given the country's large population base and aging population.

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

To the authors' knowledge, there is no current consensus regarding the optimal interprocedural interval for patients who have undergone bilateral total knee arthroplasty (BTKA). The purpose of this study is to evaluate complication rates and functional outcome in patients who have undergone BTKA (simultaneous or sequential at different time intervals), and to determine an optimal time frame for the second knee. Data from 315 patients who were able to tolerate simultaneous BTKA according to the anaesthesiologist’s preoperative assessment between 2016 and 2020 were analysed retrospectively. According to the operative time interval, they were divided into simultaneous, ≤ 1-month sequential, 1- to 3-month sequential, and ≥ 3-month sequential BTKA groups. The primary outcomes were revision and readmission rates during the follow-up period, and the secondary outcomes were hospital length of stay (LOS), transfusion and postoperative complications. There was no difference in the implant survival or readmission rate between the groups (p > 0.05). Multivariable linear regression showed that interprocedural interval and body mass index (BMI) affected LOS; the LOS of simultaneous BTKA was the shortest (p

Psychostimulant drugs, such as cocaine, inhibit dopamine reuptake via blockading the dopamine transporter (DAT), which is the primary mechanism underpinning their abuse. Atypical DAT inhibitors are dissimilar to cocaine and can block cocaine- or methamphetamine-induced behaviors, supporting their development as part of a treatment regimen for psychostimulant use disorders. When developing these atypical DAT inhibitors as medications, it is necessary to avoid off-target binding that can produce unwanted side effects or toxicities. In particular, the blockade of a potassium channel, human ether-a-go-go (hERG), can lead to potentially lethal ventricular tachycardia. In this study, we established a counter screening platform for DAT and against hERG binding by combining machine learning-based quantitative structure-activity relationship (QSAR) modeling, experimental validation, and molecular modeling and simulations. Our results show that the available data are adequate to establish robust QSAR models, as validated by chemical synthesis and pharmacological evaluation of a validation set of DAT inhibitors. Furthermore, the QSAR models based on subsets of the data according to experimental approaches used have predictive power as well, which opens the door to target specific functional states of a protein. Complementarily, our molecular modeling and simulations identified the structural elements responsible for a pair of DAT inhibitors having opposite binding affinity trends at DAT and hERG, which can be leveraged for rational optimization of lead atypical DAT inhibitors with desired pharmacological properties.

ONC201 is a first-in-class imipridone compound that is in clinical trials for the treatment of high-grade gliomas and other advanced cancers. Recent studies identified that ONC201 antagonizes D2-like dopamine receptors at therapeutically relevant concentrations. In the current study, characterization of ONC201 using radioligand binding and multiple functional assays revealed that it was a full antagonist of the D2 and D3 receptors (D2R and D3R) with low micromolar potencies, similar to its potency for anti-proliferative effects. Curve-shift experiments using D2R-mediated b-arrestin recruitment and cAMP assays revealed that ONC201 exhibited a mixed form of antagonism. An operational model of allostery was used to analyze these data, which suggested that the predominant modulatory effect of ONC201 was on dopamine efficacy with little to no effect on dopamine affinity. To investigate how ONC201 binds to the D2R, we employed scanning mutagenesis coupled with a D2R-mediated calcium efflux assay. Eight residues were identified as being important for ONC2019s functional antagonism of the D2R. Mutation of these residues followed by assessing ONC201 antagonism in multiple signaling assays highlighted specific residues involved in ONC201 binding. Together with computational modeling and simulation studies, our results suggest that ONC201 interacts with the D2R in a bitopic manner where the imipridone core of the molecule protrudes into the orthosteric binding site, but does not compete with dopamine, whereas a secondary phenyl ring engages an allosteric binding pocket that may be associated with negative modulation of receptor activity. Significance Statement ONC201 is a novel antagonist of the D2 dopamine receptor with demonstrated efficacy in the treatment of various cancers, especially high-grade glioma. In this study, we demonstrate that it antagonizes the D2 receptor with novel bitopic and negative allosteric mechanisms of action, which may explain its high selectivity and some of its clinical anti-cancer properties that are distinct from other D2 receptor antagonists widely used for the treatment of schizophrenia and other neuropsychiatric disorders.

Efficient and precise base editors (BEs) for C-to-G transversion are highly desirable. However, the sequence context affecting editing outcome largely remains unclear. Here we report engineered C-to-G BEs of high efficiency and fidelity, with the sequence context predictable via machine-learning methods. By changing the species origin and relative position of uracil-DNA glycosylase and deaminase, together with codon optimization, we obtain optimized C-to-G BEs (OPTI-CGBEs) for efficient C-to-G transversion. The motif preference of OPTI-CGBEs for editing 100 endogenous sites is determined in HEK293T cells. Using a sgRNA library comprising 41,388 sequences, we develop a deep-learning model that accurately predicts the OPTI-CGBE editing outcome for targeted sites with specific sequence context. These OPTI-CGBEs are further shown to be capable of efficient base editing in mouse embryos for generating Tyr-edited offspring. Thus, these engineered CGBEs are useful for efficient and precise base editing, with outcome predictable based on sequence context of targeted sites., C->G transversions can be highly desirable editing outcomes. Here the authors optimise CGBEs and provide a deep learning model for predicting editing outcomes based on sequence context.

Objectives Previous literature has shown that chronic diseases and psychological distress are correlated. However, the mediating and moderating mechanisms underlying this relationship have not been sufficiently studied. The purpose of this study was to explore the role played by activities of daily living (ADL) and perceived social support. Method Face-to-face questionnaire-based surveys were conducted with 3250 valid participants (age ≥60 years). Participants were assessed using the Barthel Index, Perceived Social Support Scale, and Depression Anxiety Stress Scale-21. Results 1) Chronic diseases had a significant direct effect on psychological distress in older adults; 2) the relationship between chronic diseases and psychological distress was partially mediated by ADL; and 3) the impact of chronic diseases on psychological distress was significantly moderated by perceived social support. More importantly, perceived social support was a protective factor that could effectively alleviate the adverse effects of chronic diseases on psychological distress. Conclusion The results add to the existing literature by uncovering the underlying mechanisms between chronic diseases and mental health. These findings have implications for early intervention and prevention of mental health problems in older adults.

Purpose The aim of this study was to design a quantitative evaluation of the promotion plan for clinical nurse specialists in China. Design The evaluation indexes were selected and established by inquiring 22 experts and using the analytic hierarchy process. The promotion plan was sent to 22 specialized nurses. The reference value was established by comparing the results from predictions made by experts and the self-evaluation of specialized nurses. Methods This study used the Delphi method and mixed qualitative and quantitative methods, which not only determined the entry of the promotion plan but also calculated its weight, and obtained the baseline score through a small range of empirical studies. Results This promotion plan included basic promotion conditions, 5 primary indicators, 15 secondary indicators, and 61 tertiary indicators and was designed by experts who had a high degree of authority in this field. The self-evaluation results of 19 specialist nurses showed a reference value of 30 points per 3 years using the promotion plan. For clinical nursing managers, it is a management tool to evaluate specialist nurses, which can provide a basis for the promotion of specialist nurses. Conclusions The promotion plan for clinical nurse specialists in China formed by this research is quantifiable, scientific, and instructive.

Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase β (IKKβ) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKβ by TNFα induced phosphorylation and TRCP1/2 E3 ligase–mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7–IKKβ axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer. Significance: This study identifies that MAP3K7–IKKβ signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.

Regulated cell death (RCD) is a vital event in various physiological and pathological processes. Ferroptosis is a newly described RCD, which is driven by iron accumulation and unrestricted lipid peroxidation. The interaction between ferroptosis and immunity has been a topic of substantial interest since its discovery in 2012. It has become increasingly evident that ferroptosis is critically involved in the regulation of antitumor immunity and may provide potential strategies in immunotherapy. Ferroptosis could release various damage-associated molecular patterns (DAMPs) or lipid metabolites to regulate the cellular immune response, validating its role as a form of immunogenic cell death (ICD). Specifically, the oxygenated membrane lipids on ferroptotic cells could mediate the phagocytosis by macrophages to maintain the immune responses. Additionally, immune checkpoint inhibitor therapy may sensitize cancer cells to ferroptosis, while ferroptosis might contribute to tumor immune evasion by directly interfering with the function of various immune cells. Based on these insights, we provided a comprehensive review on the interaction patterns between ferroptosis and immunity, which may not only offer insight into the underlying regulatory mechanisms but also facilitating the development of ferroptosis-based antitumor therapeutics.

Background Salmonella enterica is a zoonotic pathogen of substantial concern to human and animal health and is a leading cause of morbidity and mortality in people worldwide. Loop-mediated isothermal amplification (LAMP) technology is a new type of nucleic acid amplification technology, which has the characteristics of high specificity, high sensitivity, simple operation, convenience, and low cost. This study aims to establish a rapid detection method for Salmonella based on LAMP technology. Methods Primers were designed for Salmonella's specific conservative invA gene. Through primer screening and optimization of reaction conditions, and a LAMP method for detecting Salmonella with real-time fluorescence and visual observation results was established. The sensitivity and specificity of the method were assessed, and the accuracy was evaluated through the testing of Salmonella-contaminated and non-contaminated clinical samples. Results The optimal reaction temperature of LAMP was 60-65 °C, and the optimal reaction time was 25-30 minutes. The detection limits of real-time fluorescence and visual observation were both 1.4 pg/µL. There was no cross-reactivity observed with 22 non-Salmonella species, and the specificity was 100%. Additionally, 30 samples contaminated with Salmonella, 30 samples not contaminated with Salmonella, and 8 clinical samples identified as positive by bacterial culture and microbial mass spectrometry were tested. The positive coincidence rate of the detection system was 97.4% by real-time fluorescence and 89.5% by visual observation, the negative coincidence rate was 100%, and the total coincidence rate was 98.5% and 94.1%, respectively. Conclusions In the scene of infection, primary hospital, disaster area treatment and other scenarios, the conditions of environment, equipment and personnel was limited, therefore, the established real-time fluorescence and visual lamp method can provide a powerful means for the rapid detection of Salmonella.