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Hao Zhang,1 Chen Liang,2 Xinxin Hou,3 Ling Wang,1 Dongsheng Zhang41Department of Imaging and Nuclear Medicine, Medical School of Southeast University, Nanjing, Jiangsu, 2Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 3Department of Pathology, Medical School of Henan Polytechnic University, Jiaozuo, Henan, 4Jiangsu Key Laboratory for Biomaterials and Devices, Medical School, Southeast University, Nanjing, People’s Republic of ChinaAbstract: Combination therapy for lung cancer has garnered widespread attention. Radiation therapy, gene therapy, and molecular targeted therapy for lung cancer have certain effects, but the disadvantages of these treatment methods are evident. Combining these methods can decrease their side effects and increase their curative effects. In this study, we constructed a pYr-ads-8-5HRE-cfosp-iNOS-IFNG plasmid (a gene circuit that can express IFNγ), which is a gene circuit, and used that plasmid together with C225 (cetuximab) to prepare gene-loaded immunomagnetic albumin nanospheres (IMANS). Moreover, we investigated the therapeutic effects of gene-loaded IMANS in combination with radiation therapy on human lung cancer in vitro and in vivo. The results showed that this gene circuit was successively constructed and confirmed that the expression of INFγ was increased due to the gene circuit. Gene-loaded IMANS combined with radiation therapy demonstrated improved results in vitro and in vivo. In conclusion, gene-loaded IMANS enhanced the efficacy of combination therapy, solved problems related to gene transfer, and specifically targeted lung cancer cells.Keywords: gene circuit, combination therapy, magnetic albumin nanospheres

Hao Zhang,1 Xinxin Hou,2 Mei Lin,3 Ling Wang,1 Hongbo Li,4 Chenyan Yuan,1 Chen Liang,1 Jia Zhang,5 Dongsheng Zhang1,6 1Medical School of Southeast University, Nanjing, Jiangsu, People’s Republic of China; 2Medical School of Henan Polytechnic University, Jiaozuo, Henan, People’s Republic of China; 3Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu, People’s Republic of China; 4Department of Ultrasound in Medicine, The First Affiliated Hospital (Jiangsu Province Hospital of TCM), Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 5Jiangsu Cancer Hospital, Nanjing, Jiangsu, People’s Republic of China; 6Jiangsu Key Laboratory For Biomaterials and Devices, Nanjing, Jiangsu, People’s Republic of China Abstract: As one of the most common malignant tumors, the clinical and socio-economic consequences of lung cancer are significant. Currently, surgery is the main treatment strategy for this disease, but the survival rates of lung cancer patients are not ideal due to the high recurrence rate of the disease. Therefore, many researchers are exploring new specific therapeutic methods that are highly curative and minimally cytotoxic to healthy tissues. To this end, albumin nanospheres simultaneously were loaded with super-paramagnetic iron oxide nanoparticles (as gene vector and anticancer gene), and plasmid pDONR223-IFNG, and modified with anti-EGFR monoclonal antibody cetuximab as therapy. Targeting agents, namely gene-loaded immunomagnetic albumin nanospheres (cetuximab [C225]-IFNG-IMANS), were prepared for targeted lung carcinoma cells (GLC-82 cell lines). Transmission electron microscopy images showed that the C225-IFNG-IMANS were successfully prepared, and the ability of the nanospheres to target GLC-82 cells in vitro was confirmed by Prussian blue staining, immunofluorescence experiments, and magnetic resonance imaging. Transfection photographs and agarose gel electrophoresis proved that pDONR223-IFNG could be encased in the albumin nanospheres. A Cell Counting Kit-8 assay showed that the combination therapy group had significantly more therapeutic effects on GLC-82 cells than other therapy groups. A flow cytometry assay showed that the apoptotic index of the combined treatment group was 67.68%, whereas the indices of the C225 group, gene therapy group, and magnetic fluid hyperthermia group were 12.2%, 16.34%, and 20.04% respectively. Therefore, the combination of thermal treatment, molecular targeted treatment, and gene treatment synergistically targets GLC-82 cells, and the use of C225-IFNG-IMANS as a gene or drug carrier offers a novel and promising approach for the treatment of lung cancer. Keywords: targeting gene therapy, nano-drug, magnetic nanoparticles

Background: Emerging evidence suggests the potential of hydroxymethylglutaryl-coenzyme A (HMG-CoA, statins) as a therapeutic option for dementia., Objective: The primary objective of this study is to assess the current state of research on statins use in dementia, with a focus on identifying pivotal questions within the field., Methods: A systemic search for publications on statin use in dementia between 2007 and 2023 was conducted, utilizing the Web of Science Core Collection. The scientific output was analyzed from various perspectives through VOSviewer, CiteSpace, and the bibliometrics website (https://bibliometric.com/)., Results: 560 articles authored by 2,977 individuals and 999 institutions across 58 countries were included, which were published in 295 periodicals and cited 21,176 references from 16,424 authors. The annual publication output remained steady, while the number of citations increased consistently. The U.S. and Mayo Clinic emerged as the most significant country and institution, respectively. B. McGuinness and D.L. Sparks were the most eminent authors. Journal of Alzheimer's Disease was the most influential journal. Three sets of keywords and the top 10 references were identified, suggesting pivotal questions within the field., Conclusions: While statins show promising potential as a treatment option for dementia, their use remains uncertain due to the reported short-term cognitive impairment events and questionable long-term protective effects against dementia. The pivotal question is to ascertain the association between statins and cognition. The mechanisms underlying the effects of statins on cognition are multifaceted. This study provides insights into the current status within the field of statin use in dementia.

Objective: To investigate the correlation of peripheral blood T lymphocyte subsets with overall survival (OS) and clinical baseline characteristics in mantle cell lymphoma (MCL)., Methods: The clinical data of 55 MCL patients who were newly diagnosed in the Department of Hematology, Second Hospital of Shanxi Medical University from January 2012 to July 2022 were analyzed retrospectively. The percentages of T lymphocyte subsets and CD4 + /CD8 + ratio in peripheral blood were detected by flow cytometry, and their correlation with clinical characteristics of patients were analyzed. Kaplan-Meier method was used for survival analysis and survival curves were drawn. Log-rank test was used for univariate analysis, while Cox proportional hazards model was used for multivariate analysis., Results: The median follow-up was 40(1-68) months, and the median overall survival (OS) was 47 months. Among the 55 patients, 30(54.5%) patients had a decrease in peripheral blood CD4 + T lymphocyte, while 17(30.9%) patients had a increase in peripheral blood CD8 + T lymphocyte, and 20(36.4%) patients had a decrease in CD4 + /CD8 + ratio. There were no significant correlations between CD4 + /CD8 + ratio and sex, age, Ki-67, B symptoms, leukocytes, hemoglobin, lymphocytes, platelets, albumin, lactate dehydrogenase (LDH), β 2 -microglobulin, splenomegaly, bone marrow invasion, primary site and MIPI score. Survival analysis showed that patients with CD4 + T cell >23.3%, CD8 + T cell ≤33.4% and CD4 + /CD8 + ratio >0.6 had longer OS ( P =0.020, P <0.001, P <0.001). Univariate analysis showed that Ki-67>30%, LDH>250 U/L, splenomegaly, bone marrow involvement, CD4 + T cells ≤23.3%, CD8 + T cells >33.4%, CD4 + /CD8 + ratio ≤0.6 were adverse prognostic factors affecting OS of MCL patients. Multivariate analysis showed that CD4 + /CD8 + ratio ≤0.6 ( HR =4.382, P =0.005) was an independent adverse prognostic factor for OS of MCL patients., Conclusions: Low CD4 + /CD8 + ratio is associated with poor prognosis in MCL, and the CD4 + /CD8 + ratio can be used as an important indicator to evaluate the prognosis risk in MCL patients.

Objective: To explore the antiviral activity of the small-molecule compound AM679 in hepatitis B virus (HBV) replication and infection cell models. Methods: The positive regulatory effect of AM679 on EFTUD2 expression was validated by qPCR and Western blotting. HepAD38 and HepG2-NTCP cells were treated with AM679 (0.5, 1, and 2 nmol/L). Negative control, positive control, and AM679 combined with the entecavir group were set up. HBV DNA intra-and extracellularly, as well as the expression levels of intracellular HBV total RNAs and 3.5kb-RNA changes, were detected with qPCR. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels were measured in the cell supernatant by an enzyme-linked immunosorbent assay (ELISA). The t-test method was used for the statistical analysis of the mean difference between groups. Results: EFTUD2 mRNA and protein expression levels were significantly increased in HepAD38 and HepG2-NTCP cells following AM679 treatment, with a statistically significant difference ( P  < 0.001). Intra-and extracellular indicators such as HBV DNA, HBV RNAs, HBV 3.5kb-RNA, HBsAg, and HBeAg were decreased to varying degrees in both cell models, and the decrease in these indicators was more pronounced with the increase in AM679 concentration and prolonged treatment duration, while the combined use of AM679 and entecavir had a more significant antiviral effect. The HBV DNA inhibition rates in the supernatant of HepAD38 cells with the use of 2 nmol/L AM679 were 21% and 48% on days three and nine, respectively. The AM679 combined with the ETV treatment group had the most significant inhibitory effect (62%), with a P  < 0.01. More active HBV replication was observed after silencing EFTUD2, while the antiviral activity of AM679 was significantly weakened. Conclusion: AM679 exerts anti-HBV activity in vitro by targeting the regulation of EFTUD2 expression.

Organocatalytic desymmetrization reaction is a powerful tool for constructing axial chirality, but the theoretical study on the origin of stereoselectivity still lags behind even now. In this work, the N-heterocyclic carbene (NHC)-catalyzed desymmetrization reaction of biaryl frameworks for the synthesis of axially chiral aldehydes has been selected and theoretically investigated by using density functional theory (DFT). The fundamental pathway involves several steps, i.e., desymmetrization, formation of Breslow oxidation, esterification, and NHC regeneration. The desymmetrization and formation of Breslow processes have been identified as stereoselectivity-determining and rate-determining steps. Further weak interaction analyses proved that the C-H···O hydrogen bond and C-H···π interactions are responsible for the stability of the key stereoselective desymmetrization transition states. This research contributes to understanding the nature of NHC-catalyzed desymmetrization reactions for the synthesis of axially chiral compounds.

Developing and implementing biosafety standards for pathogenic microbiology laboratories is essential to achieving scientific, efficient, and standardized management and operation. This article analyzes the current standardization construction in biosafety in pathogenic microbiology laboratories domestically and internationally. It proposes a framework for the biosafety standard system of pathogenic microbiology laboratories, which mainly includes four parts: basic standards, management standards, technical standards, and industry applications. It provides a reference for the standardization work of pathogenic microbiology laboratories and helps to standardize the biosafety industry in China.

With the acceleration of aging society, delaying aging or promoting healthy aging has become a major demand for human health. 5-Lipoxygenase (5-LOX) is a key enzyme catalyzing arachidonic acid into leukotrienes (LTs), which is a potent mediator of the inflammatory response. Previous studies showed that abnormal activation of 5-LOX and overproduction of LTs are closely related to the occurrence and development of aging-related inflammatory diseases. Therefore, inhibiting 5-LOX activation is a possibly potential strategy for treating age-related diseases. In this paper, the latest research progress in 5-LOX activation, 5-LOX in mediating aging-related diseases and its small molecule inhibitors is briefly reviewed to provide scientific theoretical basis and new ideas for the prevention and treatment of aging-related inflammatory diseases.

Relapsing fever, caused by Borreliae of the relapsing fever groups, is an infectious disease, which would cause spirochaetaemia and repeated fever in human. To comprehensively understand the classification and distribution of relapsing fever, as well as correlated factors, this paper summarizes the progress in research of epidemiology of relapsing fever in the world, and suggests prevention and control measures. The disease is heterogenous and can be divided into three groups according to vectors, i.e. tick-borne relapsing fever, louse-borne relapsing fever and the avian relapsing fever. Tick borne relapsing fever can be further divided into two types: soft tick transmission and hard tick transmission. Soft tick-borne relapsing fever generally has obvious geographical distribution characteristics, while hard tick-borne relapsing fever is widely distributed all over the world. Louse-borne relapsing fever, also known as epidemic forms of relapsing fever, is caused by body lice, and the incidence is usually associated with war, famine, refugees and poor sanitation. The prevention and control of relapsing fever should be based on local conditions.

The catalytic asymmetric dearomatization (CADA) reaction has proved to be a powerful protocol for rapid assembly of valuable three-dimensional cyclic compounds from readily available planar aromatics. In contrast to the well-studied indoles and naphthols, phenols have been considered challenging substrates for intermolecular CADA reactions due to the combination of strong aromaticity and potential regioselectivity issue over the multiple nucleophilic sites (O, C2 as well as C4). Reported herein are the chiral phosphoric acid-catalyzed divergent intermolecular CADA reactions of common phenols with azoalkenes, which deliver the tetrahydroindolone and cyclohexadienone products bearing an all-carbon quaternary stereogenic center in good yields with excellent ee values. Notably, simply adjusting the reaction temperature leads to the chemo-divergent intermolecular (3 + 2) and alkylation dearomatization reactions. Moreover, the stereo-divergent synthesis of four possible stereoisomers in a kind has been achieved via changing the sequence of catalyst enantiomers., (© 2023. Springer Nature Limited.)

Based on the modification of the structure of dolutegravir, we introduced 1,2,3-triazole moieties with different substituted groups and obtained a lot of novel dolutegravir derivatives. The activity of A549 cells treated with the derivatives was examined, and most compounds showed good inhibitory effects. Among them, compounds 4b and 4g were the most effective, and inhibited the growth of A549 cells with IC 50 values of 8.72 ± 0.11 μM and 12.97 ± 0.32 μM, respectively. In addition, compound 4g induced apoptosis and clonal suppression in A549 tumor cells. Compound 4g also activated the LC3 signaling pathway to induce autophagy in tumor cells, and activated the γ-H2AX signaling pathway to induce DNA damage in tumor cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hou, Mao, Guo, Lou, Wang, Li, Wang, Li and Yang.)

Purpose: To evaluate the effects of bleaching combined with Er:YAG laser or Nd:YAG laser on bond strength and microleakage of resin fillings on enamel surface., Methods: Sixty-four pieces of enamel specimens prepared from isolated teeth were randomly divided into 4 groups(n=16): control group, simple bleaching group, bleaching combined with Er: YAG laser group and bleaching combined with Nd:YAG laser group. Then the shear bond strength and the depth of microleakage were tested, and the fracture mode of the specimen was observed under microscope. SPSS 26.0 software package was used for statistical analysis., Results: After bleaching simply, the bond strength of the restoration was significantly decreased, and the marginal microleakage was significantly increased(P＜0.05). There was no significant difference in shear bond strength and microleakage depth between the group bleaching combined with Er: YAG laser and control group(P＞0.05). The shear bond strength after bleaching combined with Nd:YAG laser was significantly reduced (P＜0.05), but there was no significant difference in the depth of microleakage compared with unbleached microleakage(P＞0.05). Bonding interface fracture was the main fracture mode for all groups., Conclusions: Compared to traditional bleaching, bleaching combined with laser has certain clinical advantages due to its less influence on bond strength and microleakage of resin fillings.

Endometriosis is widely perceived as an estrogen-dependent chronic disorder with infertility and pelvic pain. Although the etiology of endometriosis has remained elusive, many studies have proclaimed the relevance of immune system disorders with endometriosis. With the discovery that the dysregulation of multiple biological functions in endometriosis is caused by the aberrant differentiation of T helper cells, a shift towards Th2 immune response may account for the disease progression. This review attempts to present mechanisms of cytokines, chemokines, signal pathways, transcription factors and some other factors related with the derivation of Th1/Th2 immune response involved in the development of endometriosis. The current understanding of treatment approaches and potential therapeutic targets will also be outlined with brief discussion., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Indoleamine 2,3-dioxygenase 1 (IDO1) has attracted much attention in the field of cancer immunotherapy as an immunomodulatory enzyme. To identify potential IDO1 inhibitors, a novel series of compounds with N,N-diphenylurea and triazole structures were synthesized. The designed compounds underwent organic synthesis, and subsequent enzymatic activity experiments targeting IDO1 confirmed their activity at the molecular level. These experiments provided validation for the efficacy of the designed compounds in inhibiting IDO1, compound 3g exhibited an IC 50 value of 1.73 ± 0.97 μM. Further molecular docking study further explained the binding mode and reaction potential of compound 3g with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases., Competing Interests: Author L-FM was employed by the company Henan Wanliu Biotechnology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hou, Wu, Zhan, Gao, Mao, Wang and Yang.)

Background: Cryptotanshinone (CPT) has wide biological functions, including anti-oxidative, antifibrosis, and anti-inflammatory properties. However, the effect of CPT on hepatic fibrosis is unknown., Aim: To investigate the effects of CPT treatment on hepatic fibrosis and its underlying mechanism of action., Methods: Hepatic stellate cells (HSCs) and normal hepatocytes were treated with different concentrations of CPT and salubrinal. The CCK-8 assay was used to determine cell viability. Flow cytometry was used to measure apoptosis and cell cycle arrest. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analyses were used to measure mRNA levels and protein expression of endoplasmic reticulum stress (ERS) signaling pathway related molecules, respectively. Carbon tetrachloride (CCL 4 ) was used to induce in vivo hepatic fibrosis in mice. Mice were treated with CPT and salubrinal, and blood and liver samples were collected for histopathological examination., Results: We found that CPT treatment significantly reduced fibrogenesis by modulating the synthesis and degradation of the extracellular matrix in vitro . CPT inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in cultured HSCs. Furthermore, we found that CPT promoted apoptosis of activated HSCs by upregulating expression of ERS markers (CHOP and GRP78) and activating ERS pathway molecules (PERK, IRE1α, and ATF4), which were inhibited by salubrinal. Inhibition of ERS by salubrinal partially eliminated the therapeutic effect of CPT in our CCL 4 -induced hepatic fibrosis mouse model., Conclusion: CPT can promote apoptosis of HSCs and alleviate hepatic fibrosis through modulating the ERS pathway, which represents a promising strategy for treating hepatic fibrosis., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Doppler ultrasonography is used to study ovarian vascular characteristics. However, the outcomes are reported with a considerable variability in literature. Here we review the differences in Doppler ultrasound-measured ovarian blood flow indices between women with and without ovarian dysfunction and seeks correlations between Doppler measures and ovarian markers., Methods: A literature search was conducted in electronic databases (Google Scholar, Ovid, PubMed, Science Direct, and Springer) to identify studies that used Doppler for ovarian blood flow examination and reported Doppler measures in women with and without ovarian dysfunction and/or the correlations between wDoppler indices and markers of ovarian dysfunction. After quality assessment of included studies, a meta-analysis of weighted mean differences (WMDs) between women with and without ovarian dysfunction in vascularization index (VI), flow index (FI), vascularization flow index (VFI), pulsatility index (PI) and resistance index (RI) was performed. Correlation coefficients between Doppler indices and markers of ovarian dysfunction were pooled to achieve overall estimates., Results: A total of 27 studies [2,377 women with ovarian dysfunction and 308 controls; age 27.7 years, 95% confidence interval (CI): 26.4 to 29.1] were included. These studies were of moderate quality. The VI (WMD 9.75; P<0.0001), FI (WMD 2.73; P<0.0001), and VFI (WMD 1.29; P<0.0001) were significantly higher whereas PI (WMD -1.08; P=0.001) and RI (WMD -0.26; P<0.0001) were significantly lower in women with polycystic ovarian syndrome (PCOS) than in normal women. In women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), antral follicle count was positively correlated with VI (r=0.24; P=0.001), FI (r=0.42; P<0.0001), and VFI (r=0.25; P=0.002). In women with PCOS, testosterone had statistically non-significant correlations with VI (r=0.40; P=0.081), and VFI (r=0.39; P=0.063) and was inversely correlated with PI (r=-0.30; P<0.0001) and RI (r=-0.48; P<0.0001). In women with PCOS, luteinizing hormone (LH) was inversely correlated with PI (r=-0.26; P=0.086) and RI (r=-0.25; P=0.007)., Conclusions: Doppler indices are found significantly different in women with and without ovarian dysfunction and have significant correlations with markers of ovarian dysfunction. These results support the use of Doppler ultrasound to examine ovarian dysfunction. High statistical heterogeneity observed herein should be studies in future investigations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5813/coif). The authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Objective: To explore the changes of cerebral white matter diffusion tensor in epilepsy., Methods: This study was a retrospective study based on diffusion tensor imaging (DTI). Twenty-six epileptic patients and 42 normal controls matched for sex, age and handedness were enrolled in our research. Based on the method of tract-based spatial statistics (TBSS), we analyzed the changes of each relevant parameter index of DTI in white matter of the brain in all subjects, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD)., Results: In comparison with the control group, epileptic patients had decreased FA and elevated MD, AD, and RD in the anterior thalamic radiation, corticospinal tract, forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus and uncinate fasciculus ( P < 0.05)., Conclusion: Widespread white matter integrity was observed in epileptic patients, which may be the structural basis for the development of affective disorders, impaired cognition, and motor abnormalities., Competing Interests: None., (AJTR Copyright © 2022.)

BACKGROUND We aimed to investigate the clinical effects of resin nanoceramic (RNC) computer-aided design/computer-aided manufacture (CAD/CAM) partial crowns on posterior teeth after root canal treatment over a 3-year period. MATERIAL AND METHODS A total of 132 posterior teeth restored with CAD/CAM partial crowns were placed in 128 patients. The observation group (n=66) was restored with RNC restorations, while the control group received lithium disilicate-based glass ceramic (LDGC) CAD restorations. Using Federation dentaire internationale (FDI) World Dental Federation clinical criteria, 2 calibrated evaluators examined the performance of the restorations at baseline, 6, 12, 18, 24, and 36 months. The Kaplan-Meier method and the log-rank test were adopted to analyze the survival rate. The influence of potential risk factors on the main pattern of failure was studied by univariate Cox regression analysis (alpha=0.05). RESULTS At the 3-year followup, the survival rate of the partial crowns was 83.1% in the RNC group, and 93.5% in the LDGC group (P=0.061). Failures were caused by debonding (66.7%), restoration fracture (26.6%), and tooth fracture (6.7%). No significant differences were found between the 2 materials at 36 months, except for the parameters of "surface luster" (P=0.002) and "occlusal contour and wear" (P=0.009). The RNC group was significantly more likely to debond than the LDGC group (hazard ratio=9.22 [1.17,72.74], P=0.01). CONCLUSIONS RNC CAD/CAM-fabricated partial crowns are a potential clinical alternative for endodontically treated posterior teeth, with a survival rate of 83.1% at the 3-year followup. The main pattern of failure was debonding, which might be influenced by surface pretreatment of the RNC material.

Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities in vitro experiments. Among them, compound 14b (IC 50 = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hou, Gong, Mao, Sun and Yang.)

Objective: This study aimed to investigate the effect of cognitive behavioral therapy (CBT) on quality of life, anxiety, and depression in patients with epilepsy., Methods: Each study subject was randomly assigned to a CBT (n=46) or control (n=49) group (1:1 ratio), and the first group underwent an 8-week CBT treatment. Anxiety, depression, and quality of life (QOLIE-31) were assessed at both baseline and endpoint using the Self-Rating Anxiety Scale (SAS), Hamilton Depression Scale (HDMA) and quality of life in Epilepsy-31 (QOLIE-31) scales. The statistical analyses included between-and within-group comparisons of the effects of CBT on these measures and associations with demographic and clinical variables., Results: No differences were found between variables at baseline (P>0.05). The repeated-measures analyses found that CBT group had greater improvement in depression score compared to the control group ( P <0.05). The analysis of anxiety score showed that compared to the control group, CBT intervention had no statistical significance in the total anxiety population. However, the CBT intervention decreased anxiety in women and Combined-drug group ( P <0.05). The CBT group had greater improvement in overall score, medication effect, and seizure worry score than the control group ( P <0.05). Stratified analysis found total and medication effects score of CBT intervention group for the combined-drug group were higher than those of the single drug group ( P <0.05)., Conclusion: Increases in overall scores, seizure worry, cognitive functioning, and medication effect were better in the CBT group. CBT can improve anxiety, depression, and quality of life in patients with epilepsy. Women and combined-drug patients with epilepsy benefit most from CBT., Competing Interests: None., (AJTR Copyright © 2022.)

Alternative splicing is an important mechanism for regulating gene expressions at the post-transcriptional level. In eukaryotes, the genes are transcribed in the nucleus to produce pre-mRNAs and alternative splicing can splice a pre-mRNA to eventually form multiple different mature mRNAs, greatly increasing the number of genes and protein diversity. Alternative splicing is involved in the regulation of various plant life activities, especially the response of plants to abiotic stresses and is also an important process of plant growth and development. This review aims to clarify the usefulness of a genome-wide association analysis in the study of alternatively spliced variants by summarizing the application of alternative splicing, genome-wide association analyses and genome-wide association analyses in alternative splicing, as well as summarizing the related research progress.

This study aims to investigate the expression levels and values of autophagy genes light chain 3 (LC3) and autophagy-related 5 (ATG5) in intestinal-type gastric cancer. Ninety samples of normal gastric mucosa, intraepithelial neoplasia, and gastric cancer tissue were used in this study. The messenger ribonucleic acid (mRNA) and protein expression levels of autophagy genes LC3 and ATG5 were detected using quantitative reverse transcription polymerase chain reaction, Western blot, and the immunohistochemistry method. The correlations of the autophagy genes and certain clinical pathological parameters were analyzed. The results showed that LC3 mRNA expression was 43.76 ± 20.31 in the normal group, 111.29 ± 18.65 in the intraepithelial neoplasia group, and 131.78 ± 26.29 in the gastric cancer group, while ATG5 mRNA expression was 4.52 ± 2.37 in the normal group, 7.09 ± 1.88 in the intraepithelial neoplasia group, and 10.25 ± 2.81 in the gastric cancer group. The differences between the groups were statistically significant (P < 0.05). The protein expression of LC3 in the normal group was 1.05 ± 0.41, 1.53 ± 0.36 in the intraepithelial neoplasia group, and 1.99 ± 0.14 in the gastric cancer group. The protein expression of ATG5 was 0.78 ± 0.24 in the normal group, 1.37 ± 0.39 in the intraepithelial neoplasia group, and 2.04 ± 0.63 in the gastric cancer group. The differences between the groups were statistically significant (P < 0.05). The positive rate of LC3 protein expression was 33.3% in the normal group and 60% in the intraepithelial neoplasia group, and the difference was statistically significant (χ 2 = 4.89; P = 0.04). In the gastric cancer group, the positive rate of LC3 protein expression was 83.3%, making it significantly higher than the intraepithelial neoplasia group, with a statistically significant difference (χ 2 = 4.02, P = 0.045). The positive rate of ATG5 protein expression was 23.3% in the normal group, 50.0% in the intraepithelial neoplasia group, and 76.7% in the gastric cancer group. The expression in the intraepithelial neoplasia group was much higher than in the normal group, with a statistically significant difference (χ 2 = 4.59, P = 0.03), and that of the gastric cancer group was much higher than that of the intraepithelial neoplasia group, with a statistically significant difference (χ 2 = 4.59, P = 0.03). LC3 protein expression was significantly correlated with depth of infiltration, and lymph node status. ATG5 protein expression was significantly correlated with age, depth of infiltration, and lymph node status. There was also a correlation between the LC3 and ATG5 proteins (correlation coefficient r = 0.72, P = 0.001). The enhanced autophagy activity of LC3 and ATG5 may participate in the occurrence and development of intestinal gastric cancer, and they may play a synergistic role in promoting the occurrence and development of intestinal gastric cancer. These findings provide clinical value for the diagnosis of intestinal gastric cancer.

The single crystals of two novel chiral tetranucleate copper(II)-based complexes (TNCu-A and TNCu-B) containing L -methioninol-derived Schiff-bases were obtained. Their single structures were characterized by X-ray single crystal diffraction, infrared (IR) rays, elemental analysis, and liquid chromatography-mass spectrometry analysis. TNCu-A can effectively inhibit human umbilical vein endothelial cells (HUVECs) to form a tubular structure and it induces apoptosis of human triple-negative breast cancer MDA-MB-231 cells and HUVECs in vitro in a mitochondria dependent manner. Moreover, in vivo TNCu-A can remarkably inhibit the growth of triple-negative breast cancer from which MDA-MB-231 cells were xenografted into severely immunodeficient nude mice by inhibiting proliferation, inducing apoptosis of MDA-MB-231 cells by dramatically inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expressions of proapoptotic proteins caspase-9 and Bax, and simultaneously inhibiting tumor angiogenesis by decreasing the density of vascular endothelial cells and suppressing migration and even partially inducing apoptosis.

Background: Atrial fibrillation (AF) recurrence is common in the 3-month blanking-period after catheter ablation, during which electrical cardioversion (ECV) is usually performed to restore sinus rhythm. Whether ECV can affect the clinical outcome of post-ablation AF patients is inconsistent, however. We aimed to explore the 1-year effect of ECV on AF recurrence and rehospitalization in patients experienced recurrence within 3-month after AF catheter ablation., Methods: Patients who experienced recurrence within 3-month after AF catheter ablation procedure were enrolled from the China Atrial Fibrillation Registry (China-AF). A 1:3 Propensity score matching (PSM) method was applying to adjust the confounders between patients who had been treated by ECV or not. Logistic regression models were conducted to evaluate the association of ECV with 1-year AF recurrence and rehospitalization., Results: In this study, 2961 patients experienced AF recurrence within 3-month after the procedure, and 282 of them underwent successful ECV, 2155 patients did not undergo ECV. One-year AF recurrence rates were 56.4% in ECV group versus 65.4% in non-ECV group (p = .003), and were 55.9% versus 65.9%, respectively, after PSM (adjusted odds ratio [OR] 0.66; 95% confidence interval (CI): 0.49-0.88, p = .005). However, the difference of 1-year rehospitalization rates between two groups were not statistically significant before (ECV group: 23.7% vs. non-ECV group: 22.3%, p = .595) and after PSM (ECV group: 24.4% vs. non-ECV group: 21.6%, adjusted OR1.14; 95% CI 0.81-1.62, p = .451)., Conclusions: Successful ECV was associated with lower rate of one-year recurrence in patients with early recurrent AF after catheter ablation., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Objective: To study the polymorphism in P66 and its human B-cell epitopes of Borrelia burgdorferi strains in China., Methods: Polymerase chain reaction (PCR) and sequencing were used to obtain the P66 sequences of 59 Chinese B. burgdorferi . Then the sequences were analyzed by MEGA 5.10 software and compared with the human B-cell epitope sequences from the Immune Epitope Database (IEDB) based on the reference strain of each genotype., Results: Results showed that genetic and amino acid diversity presented in the 66 kD protein of all 59 Chinese strains, especially in Borrelia garinii ( B.g ) and Borrelia afzelii ( B.a ) strains. B.g strains were divided into three subclusters and two scattered strains JC1-7 and JC2-2 according to the amino acid sequences of P66. The P66 sequences of 15 Xinjiang strains represented by XI91-12 in the B.g subcluster 1, changed from CAA to TAA codon at 508aa position, resulting in early termination. Bases A and C were inserted at sequence position 1 523 bp of strains FP1, LB20, LB21, and SZ21 in the B.a genotype, which resulted to early termination at position 511 aa. G base was inserted at 438 bp of LIP94-11 strain, which led to early termination at position 172 aa., Conclusion: In P66 of 59 Chinese strains, polymorphisms were widely distributed. More importantly, the P66 amino acid sequences of B.g strains had a certain regional character. One of the characteristics of Xinjiang B.g isolates might be the variation at the 508aa location in 15 Xinjiang B.g strains, which may be related to the strains' pathogenicity in this area., (Copyright © 2021 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

An increased number of highly active regulatory T cells (Tregs) and macrophages has been found in peritoneal fluid from women with endometriosis. Here, we show that the level of Tregs-derived soluble fibrinogen-like protein 2 (sFGL2) increases in the peritoneal fluid of women with endometriosis. Higher expression of FGL2 and its receptor CD32B is observed in eutopic endometrium and ectopic tissues. The production of sFGL2 in Tregs may be enhanced by several cytokines. sFGL2 selectively induces pro-repair macrophage polarization mainly through the activation of the SHP2-ERK1/2-STAT3 signaling pathway, and the suppression of the NF-κB signaling pathway. Furthermore, sFGL2 induces a much higher level of metallothionein (MT) expression that in turn facilitates pro-repair macrophages polarization. sFGL2-induced pro-repair macrophages promote Th2 and Tregs differentiation, creating a positive feedback loop. These findings suggest that sFGL2 secreted by Tregs skews macrophages toward a pro-repair phenotype via SHP2-ERK1/2-STAT3 signaling pathway, which is involved in the progression of endometriosis.

Aims: This study sought to compare healthcare quality and 30 day, 90 day, and 1 year mortality rates among patients admitted to secondary and tertiary hospitals for heart failure (HF) in Beijing., Methods and Results: This study retrospectively enrolled patients hospitalized with a primary discharge diagnosis of HF during January 2014 to December 2015, from five tertiary and four secondary hospitals, in Beijing, China. Mortality data were extracted from Beijing Death Surveillance Database. HF healthcare quality indices were used to evaluate in-hospital care. Associations between hospital level and mortality rates were assessed using generalized linear mixed models, adjusting for patients' baseline characteristics and intra-hospital correlation. Data from 1413 patients (median [interquartile range] age = 74 [65-80] years, 52.7% female) from secondary hospitals and 1250 patients (median [interquartile range] age = 72 [61-79] years, 43.3% female) from tertiary hospitals were collected. Rates of left ventricular ejection fraction assessment (73.2% vs. 90.1%) and combined use of β-blockers and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (30.1% vs. 49.3%) were lower in secondary hospitals than those in tertiary hospitals, respectively. Patients admitted to secondary hospitals had a higher 90 day mortality [10.8% vs. 5.0%; adjusted odds ratio (OR): 2.06; 95% confidence interval (CI): 1.10-3.84, P = 0.024 and a higher 1 year mortality rate [21.0% vs. 12.1%; adjusted OR: 1.64; 95% CI: 1.02-2.62, P = 0.039], but 30 day mortality rates were not significantly different (5.5% vs. 3.0%; adjusted OR: 1.49; 95% CI: 0.63-3.52, P = 0.368)., Conclusions: Worse quality of care for patients with HF in secondary hospitals was associated with higher 90 day and 1 year mortality rates. Improving care quality in secondary hospitals is crucial to improve prognosis of patients they served., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: To understand the infectious status of Lyme disease among patients with arthritis symptoms in Hainan Province, and to provide a theoretical basis for prevention and control of Lyme disease. Methods: From 2013 to 2018, sampling surveys had been conducted in medical institutions in 8 cities in Hainan Province(Haikou, Sanya, Danzhou, Dongfang, Wenchang, Qionghai, Qiongzhong, Wuzhishan), 2 311 patients serum samples were collected with arthritis symptoms, and descriptive research were conducted base on the collected clinical data. The Indirect Fluorescent-Antibody Test (IFA) method was used for preliminary screening of Lyme disease antibody, the Western Blot (WB) method was used for IFA positive samples confirmation. Statistical analysis using χ 2 test. Results: 2 311 serum samples were tested by IFA, and 166 were positive with the positive rate of 7.18%. Further confirmed by WB method, 62 samples were positive, the positive rate of Lyme disease antibody was 2.68%(62/2 311). The positive rate of Lyme disease antibody among patients with arthritis in different regions of Hainan was statistically significant ( χ ² = 40.636, P <0.001), and the positive rate in Qiongzhong city was the highest (8.81%, 14/159). Danzhou's positive rate was the second highest, 5.62%(5/89). Dongfang city had the lowest positive rate (0.51%, 2/394). The positive rates of Lyme disease serum antibody in men and women were 2.79% (33/1 182) and 2.57% (29/1 129), respectively; the positive rates of antibodies between each age groups were in the range of 1.74% to 3.64%. The antibody positive rate of Lyme disease showed no significant difference between gender and age ( χ ² = 0.110, P =0.740 ; χ ² = 1.938, P =0.747). Conclusion: Patients with arthritis symptoms caused by Borrelia burgdorferi infection were found in 8 cities in Hainan province, but the Lyme disease antibody positive rate was different among cities, with Qiongzhong County being the highest.

Morbidity and mortality caused by infectious diseases rank first among all human illnesses. Many pathogenic mechanisms remain unclear, while misuse of antibiotics has led to the emergence of drug-resistant strains. Infectious diseases spread rapidly and pathogens mutate quickly, posing new threats to human health. However, with the increasing use of high-throughput screening of pathogen genomes, research based on big data mining and visualization analysis has gradually become a hot topic for studies of infectious disease prevention and control. In this paper, the framework was performed on four infectious pathogens (Fusobacterium, Streptococcus, Neisseria, and Streptococcus salivarius) through five functions: 1) genome annotation, 2) phylogeny analysis based on core genome, 3) analysis of structure differences between genomes, 4) prediction of virulence genes/factors with their pathogenic mechanisms, and 5) prediction of resistance genes/factors with their signaling pathways. The experiments were carried out from three angles: phylogeny (macro perspective), structure differences of genomes (micro perspective), and virulence and drug-resistance characteristics (prediction perspective). Therefore, the framework can not only provide evidence to support the rapid identification of new or unknown pathogens and thus plays a role in the prevention and control of infectious diseases, but also help to recommend the most appropriate strains for clinical and scientific research. This paper presented a new genome information visualization analysis process framework based on big data mining technology with the accommodation of the depth and breadth of pathogens in molecular level research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Sun, Hou, Du, Wang, Du, Yu, Cai, Yu, Li, Luo, Shen, Lu, Li, Zhang, Gao, Ma, Lin and Cao.)

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies with poor prognosis and lack of effective targeted therapies. In this study, we investigated the tumor suppressive role of the cell death inducing DFF like effector A (CIDEA) in ESCC. Firstly, public datasets and ESCC tissue microarray analysis showed that CIDEA was frequently down-regulated at both the mRNA and protein level. This was significantly associated with low differentiation and TNM stage in ESCC, and indicated poor prognosis for ESCC patients. Bisulfite genomic sequencing (BGS) and methylation-specific PCR (MSP) analysis revealed that the down-regulation of CIDEA was associated with hypermethylation of its promoter, which was also correlated with the poor prognosis in ESCC patients. In vitro and in vivo functional studies demonstrated that CIDEA decreased cell growth, foci formation, DNA replication, and tumorigenesis in nude mice. Further study revealed that, during starvation or cisplatin induced DNA damage, CIDEA facilitated the G1-phase arrest or caspase-dependent mitochondrial apoptosis through the JNK-p21/Bad pathway. Therefore, CIDEA is a novel tumor suppressor gene that plays an important role in the development and progression of ESCC, and may provide a potential therapeutic target for patients with ESCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Li, Yan, Hou, Jia, Chang, Guan and Qin.)

Germination is a plant developmental process by which radicle of mature seeds start to penetrate surrounding barriers for seedling establishment and multiple environmental factors have been shown to affect it. Little is known how high salinity affects seed germination of C4 plant, Zea mays. Preliminary germination assay suggested that isolated embryo alone was able to germinate under 200 mM NaCl treatment, whereas the intact seeds were highly repressed. We hypothesized that maize endosperm may function in perception and transduction of salt signal to surrounding tissues such as embryo, showing a completely different response to that in Arabidopsis. Since salt response involves ABA, we analysed in vivo ABA distribution and quantity and the result demonstrated that ABA level in isolated embryo under NaCl treatment failed to increase in comparison with the water control, suggesting that the elevation of ABA level is an endosperm dependent process. Subsequently, by using advanced profiling techniques such as RNA sequencing and SWATH-MS-based quantitative proteomics, we found substantial differences in post-transcriptional and translational changes between salt-treated embryo and endosperm. In summary, our results indicate that these regulatory mechanisms, such as alternative splicing, are likely to mediate early responses to salt stress during maize seed germination., (© 2020 John Wiley & Sons Ltd.)

Background: Post hoc analysis of the landmark atrial fibrillation follow-up investigation of rhythm management trial revealed that amiodarone was associated with higher risks of mortality, intensive care unit admission, and non-cardiovascular death. We aim to evaluate the association between amiodarone use and patient survival under updated medical mode and level using data from the China Atrial Fibrillation (China-AF) Registry study., Methods: Clinical data of 8161 non-valvular atrial fibrillation (NVAF) patients who were antiarrhythmic drug (AAD)-naive before enrollment into the China-AF Registry, recruited between August 2011 and February 2017, were collected. The primary outcome was all-cause mortality. A Cox proportional hazard regression model was used to evaluate the association between amiodarone use and the outcome. We also calculated the rate of sinus rhythm maintenance at the penultimate follow-up., Results: Compared with 6167 patients of non-AAD group, 689 patients of the amiodarone group were younger (mean age 65.6 vs. 68.6 years), more frequently completed high school education, had fewer comorbidities such as chronic heart failure, prior bleeding, and stroke, and were more likely to be treated in tertiary hospitals while less hospitalization. The proportion of persistent AF was much lower among users of amiodarone, who were also less likely to be taking oral anticoagulants. The patients in the amiodarone group had a statistically insignificant lower incidence of all-cause mortality (2.44 vs. 3.91 per 100 person-years) over a mean follow-up duration of 300.6 ± 77.5 days. After adjusting for potential confounders, amiodarone use was not significantly associated with a lower risk of all-cause mortality (adjusted hazard ratio, 0.79; 95% confidence interval, 0.42-1.49). Sub-group analysis revealed the consistent results. The rate of sinus rhythm maintenance at the penultimate follow-up in the amiodarone group was significantly higher than in the non-AAD group., Conclusions: Our study indicated that amiodarone use was not significantly associated with a lower risk of 1-year all-cause mortality compared with a non-AAD strategy in "real-world" patients with NVAF., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

The fruiting body of Hericium erinaceus has been used to treat digestive system disorder-related diseases for over 2000 years in China. A novel polysaccharide, HEFP-2b, was obtained from H. erinaceus fruiting bodies. Physical and chemical analysis showed that HEFP-2b consisted of fucose, galactose, glucose, and mannose in molar ratio of 11.81:22.82:44.28:21.09, and that its molecular weight was 3.252 × 10 4  Da. The backbone of HEFP-2b consisted of →6)-linked-α-D-Glcp-(1→ and →4)-β-D-Galp-(1→ and →3,6) -α-D-Manp linkage, with two side-branching units of (1→ and →6)-β-D-Galp and (1→ and →4)-α-D-Manp, terminated by Glc and Fuc. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle arrest experiments revealed that HEFP-2b considerably inhibited the growth of colon cancer cells (HCT-116) in vitro. The growth inhibitory effects of HEFP-2b correlated with their ability to arrest the cell cycle at the S-phase. Our results will provide valuable information for future studies on HEFP-2b as a novel health-promoting functional food ingredient that can be used for treating colon cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The fruiting bodies of Hericium erinaceus (Bull.) Pers. are commonly used in China in the treatment of digestive system diseases. In this work, the polysaccharides from the fruiting bodies of Hericium erinaceus (HEFPs) were extracted, and their effects on human colorectal cancer cells (HCT-116 and DLD1) were investigated in vitro. Our results showed that HEFPs were mainly composed of arabinose, galactose, glucose, and mannose at a molar ratio of 8.99 : 11.15 : 1.2 : 1.97. They significantly inhibited the growth of these cells by inducing apoptosis by the modulation of Bax and Bcl-2 expression, which in turn induced the loss of mitochondrial membrane potential, leading to the activation of cleaved-caspase-9 and cleaved-caspase-3. These results suggested that HEFPs induced apoptosis via the caspase-9-depedent intrinsic mitochondrial pathway. Furthermore, HEFPs increased the level of reactive oxygen species (ROS) in HCT-116 and DLD1 cells. The addition of the antioxidant N-acetyl-l-cysteine reduced the ability of HEFPs to trigger the intrinsic mitochondrial pathway, indicating the role of ROS generation in the upstream pathway of HEFP-induced apoptosis. Therefore, the results described in this study could be of interest for further studies in finding functional foods or alternative therapeutic agents against colorectal cancer.

Objective: To evaluate the protective efficacy and safety of Brucella 104M against aerosol challenge in BALB/c mice and characterize its immunological effects. Methods: Female mice of 6-8 weeks old were immunized with Brucella abortus strain 104M by intratracheal aerosol delivery or intranasal instillation or subcutaneous injection route. Six mice of each group were sacrificed at 4, 8, 16, 24 weeks after immunization. At each time point, the clinical manifestations of mice were investigated, the serum, spleen and lung samples of mice were collected, body weight, spleen weight, bacteria loads in spleens, the anti- Brucella antibodies titers in serum and the cytokines concentrations of IFN-γ, IL-18 in serum or lung homogenate of the mice were detected. Twenty two weeks after immunization, all the mice were challenged with Brucella A19 through intratracheal aerosol delivery. Results: Compared with the control group, neither abnormal clinical symptoms nor significant changes in body weight were found in 104M immunization groups, at each time point when immunized through either nose dropping route, subcutaneous injection or aerosol routes; and the spleen weight of immunization groups were lower than control group after challenge ( P <0.05): *M1 (0.26±0.16)g

The single crystals of two novel copper(ii)-based complexes containing l-methioninol-derived Schiff bases were obtained and characterized. The nanoparticles of these complexes were prepared and their cellular uptake was measured in MDA-MB-231 cells and HUVECs. It was found that these complexes could remarkably induce apoptosis, inhibit proliferation, suppress migration and metastasis, and inhibit angiogenesis and the growth of triple-negative breast cancer derived from MDA-MB-231 cells in vitro. Meanwhile, these complexes exhibit anticancer and antiangiogenic functions by activating the important protein molecules VEGFR2, FAK, AKT and Erk1/2 or their phosphorylated molecules p-VEGFR2, p-FAK, p-AKT, and p-Erk1/2 in the VEGF/VEGFR2 signaling pathway, collapsing the mitochondrial membrane potential, and damaging the level of reactive oxygen species.

Background: The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease-driving mechanisms and tissue targeting., Objective: Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments., Methods: Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non-lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real-time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS-involved skin compartments were also recognized by immunohistochemistry., Results: Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin-A, calgranulin-B and serpin-B4 were detected in the hair root sheath, koebnerisin and connexin-32 in stratum granulosum, transcobalamin-1 in stratum spinosum/hair root sheath, small prolin-rich protein-3 in apocrine sweat gland ducts/sebaceous glands-ducts and matrix metallopeptidase-9 in resident monocytes., Conclusion: Our findings highlight a panel of immune-related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands., (© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

BACKGROUND There is a growing recognition of sex-related disparities in atrial fibrillation (AF). However, limited data is available in Chinese AF patients. MATERIAL AND METHODS We compared symptoms, quality of life (QoL), and treatment of AF according to sex from the China AF Registry study. RESULTS We studied 14 723 patients with non-valvular AF, of whom 5645 patients (38.3%) were female. Women were older than men (67.5±10.6 vs . 62.2±12.2). Compared to men, women had more comorbidities and a higher proportion of CHA₂DS₂-VASC score ≥2. Women with AF experienced more severe or disabling symptoms than men (33.7% vs . 22.9% in age <75 group; 40.3% vs . 28.7% in age ≥75 group; both P <0.0001). After multivariate analysis, women with AF still had lower QoL (OR 0.69; 95%CI, 0.63-0.76; P <0.0001). Women tended to have lower rates of ablation and rhythm-control drug use in those aged <75 years. Oral anticoagulant use was low and had no sex difference in AF patients with a CHA₂DS₂-VASC score ≥2. CONCLUSIONS In Chinese AF patients, women were older and more symptomatic, and had worse QoL. Despite all these differences, women tended to receive less rhythm-control treatment in those aged <75 years. Oral anticoagulant was substantially underused in high stroke risk patients, regardless of sex.

BACKGROUND Results of the landmark Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial comparing rhythm control and rate control strategies has led to dramatic changes in the pharmacological management of non-valvular atrial fibrillation (NVAF) patients. We sought to investigate the effect of antiarrhythmic drugs (AADs) on the clinical outcomes of NVAF patients using "real-world" data from China. MATERIAL AND METHODS We evaluated the association between AAD usage and clinical outcomes using clinical data of 8161 NVAF patients who were AAD-naive before enrollment in the China Atrial Fibrillation Registry, recruited between August 2011 and February 2017. The primary outcome was all-cause mortality. RESULTS Compared with 6167 patients who never used any AADs, 1994 patients in the AAD group had lower incidence (per 100 person-years) of all-cause mortality (1.44 versus 3.91), cardiovascular death (0.45 versus 2.31), ischemic stroke (1.36 versus 2.03), and cardiovascular hospitalization (9.83 versus 10.22) over a mean follow-up duration of 316.7±90.4 days. After adjusting for potential confounders, AAD usage was associated with a lower risk of all-cause mortality [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.31-0.81] and decreased risk of cardiovascular death (HR: 0.30, 95% CI: 0.13-0.68). Subgroup analysis revealed AAD was associated with higher risk of cardiovascular hospitalization among female patients. CONCLUSIONS AAD usage was associated with lower risk of 1-year all-cause mortality and cardiovascular death in "real-world" patients with NVAF.

Activation of Toll-like receptor (TLR)-2 and subsequent inflammatory response contribute to lesion development in acne vulgaris. A cross-talk between aryl hydrocarbon receptor (AhR), a cytosolic receptor protein that responds to environmental and physiological stress, and TLRs has recently been reported. In this study, we explored the possible role of AhR in the effects induced on cultured human SZ95 sebocytes by peptidoglycan (PGN), a classic TLR2 agonist. PGN-induced secretion of inflammatory factors TNF-α and IL-8 in human SZ95 sebocytes was suppressed after knockdown of AhR and pretreatment with the AhR antagonist CH223191. In addition, the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhanced TNF-α and IL-8 secretion in PGN-pretreated sebocytes. Furthermore, PGN-induced expression of myeloid differentiation factor 88 (MyD88), phospho-p38MAPK (p-p38MAPK), and p-p65NF-κB was strengthened by TCDD and repressed by CH223191. AhR inhibition by transfecting shRNA blocked the ability of PGN to stimulate phosphorylation of p38MAPK and p65NF-κB in SZ95 sebocytes. Overall, these data demonstrate that AhR is able to modulate PGN-induced expression of TNF-α and IL-8 in human SZ95 sebocytes involving the MyD88-p65NF-κB/p38MAPK signaling pathway, which probably indicates a new mechanism in TLR2-mediated acne., (The Author(s). Published by S. Karger AG, Basel.)

Decidual macrophages (dMΦ) are distinct from the conventional macrophages present in other tissues and express M2 macrophage markers, but the molecular mechanisms of formation and the roles of M2 MΦ during pregnancy have not been completely elucidated. The crosstalk between decidual natural killer cells (dNK) and dMΦ plays an important role in the maintenance of maternal-fetal immune tolerance. Here, CXCL16 derived from first-trimester trophoblast cells induces the polarization of human M2 macrophages. The M2 MΦ polarized by CXCL16 exhibit decreased interleukin-15 production, which facilitates the inactivation of NK cells. The cytotoxicity of NK cells is attenuated by the CXCL16-polarized M2 MΦ. The data shown in the present study provide evidence to support the hypothesis that CXCL16 secreted by trophoblast cells is a key molecule involved in decidual M2 MΦ polarization, which in turn regulates the killing ability of NK cells, thereby contributing to the homeostatic and immune-tolerant milieu required for successful fetal development.

Background: The nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome composed of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 is engaged in the inflammatory response of many kidney diseases and can be activated by purinergic 2X7 receptor (P2X7R). This study was conducted to explore whether P2X7R plays a pathogenic role in the podocyte damage of obesity-related glomerulopathy (ORG) and whether this role is mediated by the activation of NLRP3 inflammasome., Methods: A mouse model of ORG was established by high-fat diet feeding. The conditionally immortalized mouse podocytes were cultured with leptin or with leptin and P2X7R antagonist (KN-62 or A438079). The mRNA and protein expression of the P2X7R and NLRP3 inflammasome components including NLRP3, ASC, and caspase-1, as well as the podocyte-associated molecules including nephrin, podocin, and desmin in mouse renal cortex or cultured mouse podocytes were tested by real-time-polymerase chain reaction and Western blot analysis, respectively., Results: The significantly upregulated expression of P2X7R and NLRP3 inflammasome components and the NLRP3 inflammasome activation were observed in the renal cortex (in fact their location in podocytes was proved by confocal microscopy) of ORG mice in vivo, which were accompanied with the morphological changes of podocyte damage and the expression changes of podocyte-associated molecules. Similar changes in the expression of P2X7R and NLRP3 inflammasome components as well as in the expression of podocyte-associated molecules were also observed in the cultured podocyte studies treated by leptin in vitro, and all of the above changes were significantly attenuated by the P2X7R antagonist KN-62 or A438079., Conclusions: P2X7R could trigger the activation of NLRP3 inflammasome, and the activated P2X7R/NLRP3 inflammasome in podocytes might be involved in the podocyte damage of ORG., Competing Interests: There are no conflicts of interest

Background/aims: It is known that chronic low-grade inflammation contributes to the initiation and development of both diabetes and diabetic nephropathy (DN), so we designed this study to investigate the role of P2X7R and NLRP3 inflammasome in DN pathogenesis and the antagonistic effects of artificially cultivated Ophiocordyceps sinensis (ACOS)., Methods: A rat model of DN caused by high-fat-diet feeding and low-dose streptozotocin injection and a mouse podocyte injury model induced by high-glucose (HG) stimulation were established, and the intervention effects of ACOS on them were observed. The biological parameters of serum and urine and the pathological manifestations of kidney tissue were examined. The expression of mRNA and protein of P2X7R and NLRP3 inflammasome (NLRP3, ASC, and caspase-1) and downstream effectors (IL-1 β and IL-18), as well as podocyte-associated molecules, was determined by real-time quantitative PCR and Western blot assay, respectively., Results: The DN rats showed to have developed insulin resistance, elevated fasting blood glucose, increased urinary protein excretion, and serum creatinine level as well as corresponding glomerular pathological alterations including podocyte damages. ACOS significantly antagonized the above changes. The experiments in vivo and in vitro both displayed that the mRNA and protein expression of P2X7R, NLRP3, ASC, caspase1 (procaspase-1 mRNA in the gene level and active caspase-1 subunit P10 in the protein level), IL-1 β , and IL-18 was significantly upregulated and the mRNA and protein expression of podocyte-associated molecules was significantly changed (downregulation of nephrin, podocin, and WT-1 expression and upregulation of desmin expression) indicating podocyte injury in the kidney tissue of DN rats and in the HG-stressed mouse podocytes, respectively. ACOS also significantly antagonized all the above changes., Conclusion: Our research work suggests that P2X7R and NLRP3 inflammasome are involved in the pathogenesis of DN, and ACOS can effectively inhibit the high expression of P2X7R and the activation of NLRP3 inflammasome, which may contribute to the therapeutic effects of Ophiocordyceps sinensis .

Objective: Liver cirrhosis (LC) was associated with an increased risk of osteoporosis; however, the association between LC and fracture risk was inconclusive. Therefore, this systematic review and meta-analysis aims to explore the association between LC and fracture risk., Design: To identify related literature, a systematic search of PubMed, EMBASE, Web of science and the Cochrane Library from 1965 to July 2017 without language limitation was performed. The random-effects model described by DerSimonian and Laird was used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Eventually, 5 cohort and 3 case-control studies were identified, which included 321 035 subjects and 31 272 fracture cases. The pooled OR of the association between LC and any fracture risk, hip fracture, spine/trunk fracture and limb fracture was 1.94 (95% CI, 1.59-2.37), 2.11 (95% CI, 1.34-3.32), 2.00 (95% CI, 1.50-2.67) and 1.82 (95% CI, 1.65-2.01), respectively., Conclusion: In conclusion, this study indicates that cirrhotic patients have an increased risk of fracture. Preventive measures should be instituted as early as possible., (© 2018 John Wiley & Sons Ltd.)