Search

Abstract The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.

Purpose: This study aims to investigate patient characteristics with lens zonular ligament abnormalities in Acute Primary Angle Closure (APAC), identifying related risk factors, and evaluating the efficacy of Pilocarpine, a miotic agent. Design: Retrospective case-control study. Methods: Conducted as a retrospective case-control study at Hebei Provincial Eye Hospital from January 1, 2019, to December 31, 2021, the study included APAC cases undergoing ultrasound phacoemulsification with or without glaucoma surgery. Zonular ligament status was determined by intraoperative indicators such as lens equator visibility post-mydriasis and anterior capsule wrinkling during capsulorhexis. Patients were categorized into APAC and APAC with Lens Subluxation (APACLS) groups. Demographic details, Central Anterior Chamber Depth (ACD), Axial Length (AL), ACD difference between eyes (ACDD), Lens Thickness (LT), Lens Position (LP), and Relative Lens Position (RLP) were recorded and compared. Pilocarpine's impact on intraocular pressure reduction was assessed. Statistical analysis involved bilateral t-tests (for normally distributed data comparing both eyes in each group), non-parametric tests (for comparing two groups with non-normally distributed data), binary logistic regression, and Receiver Operating Characteristic (ROC) curve analysis for cutoff value determination related to zonular abnormalities. Results: The APAC and APACLS groups showed no significant difference in age of onset (70.11 ± 8.67 years vs. 70.11 ± 8.67 years, P = 0.159) or axial length of the eye (22.35 ± 0.64 mm vs. 22.36 ± 0.78 mm, P = 0.929). In the APACLS group, LT was greater (5.24 ± 0.37 mm vs. 5.01 ± 0.36 mm, P = 0.011), ACD was shallower (1.42 ± 0.24 mm vs. 1.69 ± 0.24 mm, P = 0.000), and ACDD was larger (0.38 ± 0.22 mm vs. 0.18 ± 0.18 mm, P = 0.000). The LP was lower (4.04 ± 0.32 vs. 4.20 ± 0.22, P = 0.013), and RLP was also lower (0.18 ± 0.02 vs. 0.19 ± 0.01, P = 0.015) in the APACLS group. A shallow ACD and a large ACDD were identified as risk factors associated with lens zonular abnormalities in the affected eyes (ACD OR value 63.97, P = 0.027; ACDD OR value 0.029, P = 0.027). Using ROC curve analysis, the cutoff value for ACDD was determined to be 0.375 mm, and for ACD, it was 1.6 mm. After pupil constriction with Pilocarpine eye drops, the proportion of patients whose intraocular pressure normalized was 75.36 % (52/69) in the APAC group and 71.43 % (25/35) in the APACLS group. Conclusion: ACD and ACDD in the affected eye are indicative of increased risk for APACLS. An ACD 0.375 mm should prompt consideration of zonular ligament abnormalities. Pilocarpine as a miotic treatment is safe and effective for such patients.

Development of low temperature catalytic pyrolysis technology for heated tobacco sheets is expected to increase the aroma of heated tobacco products and improve their overall smoking quality. In this study, the low temperature pyrolysis performances of heated tobacco sheets catalyzed by various anionic sodium salts were investigated using TG-DTG, Py-GC-MS technology and smoke routine chemical composition analysis. The results showed that the total weight loss between 100°C and 300°C increased by 7.8%–13.15% after adding various anionic sodium salts, among which, sodium acetate and sodium tartrate showed a relatively higher weight loss. The relative content of free hydroxyacetone, furfuryl alcohol, butyrolactone and megastigmatrienone in the pyrolysis gas increased, while the relative content of free nicotine decreased. With the change of anionic species, the catalytic decomposition ability of cellulose, lignin, and other substances may change, resulting in the distribution alteration of compounds in the pyrolysis gas. After adding sodium acetate and sodium citrate, the release of total particulate matter (TPM), glycerol, and nicotine in flue gas increased. Overall, the addition of sodium acetate and sodium citrate showed a higher low temperature pyrolysis performance of heated tobacco sheets. The research results in this paper provide data support for changing the low temperature catalytic pyrolysis performance of heated tobacco sheets by adjusting the type of anions in sodium salts.

Abstract As the next generation of green power system, smart grids have gradually enhanced the operation efficiency of power system. Meanwhile, the application of communication and intelligent technologies make the power grid more vulnerable to the emerging cyber‐physical attacks, such as the false data injection attack (FDIA). Particularly, the deception property of the FDIA on the output measurement estimation can fool the current security mechanism without triggering an alarm. Motivated by this problem, this paper aims at developing a novel detection and recovery mechanism against FDIA in smart grid. Based on the established state space grid model derived from the three‐phase sinusoidal voltage equations, an improved principal component analysis (PCA)‐based detection method is proposed. By introducing the mathematical transformation principle method, the detection performance such as detection rate and false positive rate can be improved. To keep the stable running of power system, a genetic optimization algorithm‐based linear quadratic regulator (LQR) defense method is developed. In addition, to improve the response performance to external attacks, an artificial intelligence method named genetic optimization algorithm is introduced to optimize the robust performance of the proposed defense method. Finally, the simulation results on the IEEE 6‐bus and 118‐bus grid system demonstrate the superiority of the proposed genetic algorithm optimization‐based LQR defense method.

Micro/nanoplastics (MNPs), as emerging pollutants, have been detected in both the maternal and fetal sides of the placenta in pregnant women, and their reproductive toxicity has been demonstrated in in vivo and in vitro experimental models. The Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy has been innovatively devised to facilitate valid risk assessment, encompassing a comprehensive evaluation of reliability, correlation, outcome fitness, and integrity across four dimensions based on the included published evidence and our own findings. This study serves as an application case of TRAEC, with 40 items of research evidence on the toxicity of MNPs to the placenta, which were rigorously screened and incorporated into the final scoring system. The final score for this TRAEC case study is 5.63, suggesting a moderate-to-low risk of reproductive toxicity associated with MNPs in the placenta, which may potentially increase with decreasing particle size. It is essential to emphasize that the findings also report original data from assays indicating that exposure to high-dose groups (100 μg/mL, 200 μg/mL) of 50 nm and 200 nm polystyrene nanoplastics (PS-NPs) induces HTR8/SVneo cell cycle arrest and cell apoptosis, which lead to reproductive toxicity in the placenta by disrupting mitochondrial function. Overall, this study employed the TRAEC strategy to provide comprehensive insight into the potential reproductive health effects of ubiquitous MNPs.

Thin polysilicon (poly-Si)-based passivating contacts can reduce parasitic absorption and the cost of n-TOPCon solar cells. Herein, n+-poly-Si layers with thicknesses of 30~100 nm were fabricated by low-pressure chemical vapor deposition (LPCVD) to create passivating contacts. We investigated the effect of n+-poly-Si layer thickness on the microstructure of the metallization contact formation, passivation, and electronic performance of n-TOPCon solar cells. The thickness of the poly-Si layer significantly affected the passivation of metallization-induced recombination under the metal contact (J0,metal) and the contact resistivity (ρc) of the cells. However, it had a minimal impact on the short-circuit current density (Jsc), which was primarily associated with corroded silver (Ag) at depths of the n+-poly-Si layer exceeding 40 nm. We introduced a thin n+-poly-Si layer with a thickness of 70 nm and a surface concentration of 5 × 1020 atoms/cm3. This layer can meet the requirements for low J0,metal and ρc values, leading to an increase in conversion efficiency of 25.65%. This optimized process of depositing a phosphorus-doped poly-Si layer can be commercially applied in photovoltaics to reduce processing times and lower costs.

For the aroma enhancement research of heated cigarettes, it is worth exploring whether tobacco can be pyrolyzed into pyrolysis liquids containing a large number of volatile aroma components. In this study, tobacco pyrolysis liquids were prepared in subcritical/supercritical ethanol, and their applications in the aroma enhancement of heated cigarettes were investigated. The optimal conditions of supercritical liquefaction reactions were determined by optimizing the reaction time, liquid/solid mass ratio and temperature conditions. Moreover, the effect of supercritical liquefaction conditions on volatile aroma components in tobacco pyrolysis liquids was investigated by GC-MS. The results indicated that the reaction temperature had the most significant impact on the tobacco pyrolysis reaction, and higher reaction temperature promoted the pyrolysis conversion of tobacco, resulting in enhanced tobacco conversion and a high content of volatile components in the tobacco pyrolysis liquid. The optimal reaction conditions for the preparation of tobacco pyrolysis liquid were found to be a temperature of 220°C, a liquid/solid mass ratio = 15, and a 2-h reaction time. Meanwhile, the content of ester compounds and nicotine in the tobacco pyrolysis liquid increased significantly with the increase of reaction temperature. Sub/supercritical ethanol treatment significantly destroyed the surface structure of tobacco, and the degree of tobacco depolymerization increased when temperature rised. The analysis of aroma compounds in the smoke of heated cigarettes indicated that the tobacco pyrolysis liquid could significantly increase the release of aromatic substances and has a significant aroma-enhancing effect. This article proposed and prepared tobacco pyrolysis liquid in subcritical/supercritical ethanol and explored its potential application in the aroma enhancement of heated cigarettes, offering a new route for flavor enhancement technology for this type of product.

Although great progress has been made in the diagnosis and treatment of acute myocardial infarction (AMI) in recent years, its morbidity and mortality are still relatively high. In this study, we explain that the function of Sestrin2 gene in Anxiety and Depression Myocardial infarction and its possible mechanism. 26 patients with Anxiety and Depression Myocardial infarction (ADMI) and 26 normal volunteers were collected from our hospital. All mice anaesthetized using 50 mg/kg of pentobarbital sodium and the left anterior descending arteries (LAD) were ligated to induce myocardial infarction. H9c2 cells were stimulated with 5% oxygen (O2) and 5% carbon dioxide (CO2) and 90% N2 for 24 h. The serum expression of Sestrin2 in patients with ADMI was up-regulated. Sestrin2 gene up-regulation reduced collagen I/II and KEAP1 mRNA expressions, and increased GPX4 and Nrf2 mRNA expressions in vitro model of AMI. Down-regulation of Sestrin2 increased collagen I/II and KEAP1 mRNA expressions, and decreased GPX4 and Nrf2 mRNA expressions in vitro model of AMI. These data confirmed that Sestrin2 reduced inflammation and ferroptosis in model of ADMI by LKB1-mediated AMPK activation. This infers that Sestrin2 is potential target to be used in the treatment of premature AMI.

Abstract Background Anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several mesenchymal tumors, with significant implications for diagnosis, therapy and prognosis. However, few studies have investigated the correlation between ALK expression status and clinicopathological characteristics in patients with gastrointestinal stromal tumors (GISTs). Methods A total of 506 GIST patients were enrolled. Sanger sequencing was employed to detect c-KIT and PDGFRA gene mutations. The tissue microarray (TMA) technique and immunohistochemistry were employed to identify the ALK (clone: 1A4 and D5F3) expression status in the tumor tissues. The ALK gene variants of IHC-positive cases were analyzed by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). The clinicopathological data were analyzed using SPSS Statistics 26.0. Results Among the 506 GIST patients, the c-KIT mutation accounted for 84.2% (426/506), followed by PDGFRA mutation (10.3%, 52/506), while the wild-type accounted for the least (5.5%, 28/506). ALK-positive expression was detected in PDGFRA-mutant GISTs (7.7%, 4/52) but negative for c-KIT-mutant or wild-type GISTs by IHC. Four ALK IHC-positive patients were all male. The tumors all occurred outside the stomach. The predominant patterns of growth were epithelioid (2/4), spindle (1/4), and mixed type (1/4). They were all identified as high-risk classification according to the National Institutes of Health (NIH) classification. Aberrant ALK mutations were not identified by DNA-based NGS except in one of the 4 cases with amplification by FISH. Conclusion Our study revealed 7.7% (4/52) of ALK expression in PDGFRA-mutant GISTs, indicating that molecular tests were required to rule out the possibility of PDGFRA-mutant GISTs when encountering ALK-positive mesenchymal tumors with CD117-negative or weakly positive in immunohistochemical staining.

Abstract Background It has previously been observed that the prognostic value of tumor size varied according to different stages patients enrolled in gastric cancer. We aimed to investigate the influence of T stage on the prognostic and predicting value of tumor size. Material and methods A total of 13,585 patients with stage I–III gastric cancer were selected from the Surveillance, Epidemiology, and End Results Program (SEER) database. Univariate and multivariate cox regression analysis stratified by T stage were performed. C-index and time-dependent receiver operating characteristic curve (ROC) curve were applied to assess discrimination ability of tumor size and other factors. Nomograms were constructed to further assess the performance of tumor size in a specific model. Calibration ability, discrimination ability, reclassification ability and clinical benefits were executed to judge the performance of models. Results Stratified analyses according to T stage illustrated that with the increase of T stage, the effect of tumor size on overall survival (OS) and cancer-specific survival (CSS) significantly decreased. Moreover, tumor size showed superior discrimination ability in T1 gastric cancer, outperformed other prognostic factors in predicting both CSS (C-index: 0.666, AUC: 0.687) and OS (C-index: 0.635, AUC: 0.660). The cox regression model included tumor size showed better performance than the model excluded tumor size in every aspect. Conclusion T stage had a negative impact on the predicting value of tumor size. Tumor size showed significant prognostic value in T1 gastric cancer, which may be effective in clinical practice.

Ischemic stroke (IS) remains a serious threat to human health. Neuroinflammatory response is an important pathophysiological process after IS. Circular RNAs (circRNAs), a member of the non-coding RNA family, are highly expressed in the central nervous system and widely involved in regulating physiological and pathophysiological processes. This study reviews the current evidence on neuroinflammatory responses, the role of circRNAs in IS and their potential mechanisms in regulating inflammatory cells, and inflammatory factors affecting IS damage. This review lays a foundation for future clinical application of circRNAs as novel biomarkers and therapeutic targets.

Abstract Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a refractory and recurrent subtype of B-cell ALL enriched with kinase-activating rearrangements. Incomplete understanding of the heterogeneity within the tumor cells presents a major challenge for the diagnosis and therapy of Ph-like ALL. Here, we exhibited a comprehensive cell atlas of one Ph-like ALL patient with a novel TPR-PDGFRB fusion gene at diagnosis and relapse by using single-cell RNA sequencing (scRNA-seq). Twelve heterogeneous B-cell clusters, four with strong MKI67 expression indicating highly proliferating B cells, were identified. A relapse-enriched B-cell subset associated with poor prognosis was discovered, implicating the transcriptomic evolution during disease progression. Integrative single-cell analysis was performed on Ph-like ALL and Ph+ ALL patients, and revealed Ph-like specific B-cell subpopulations and shared malignant B cells characterized by the ectopic expression of the inhibitory receptor CLEC2D. Collectively, scRNA-seq of Ph-like ALL with a novel TPR-PDGFRB fusion gene provides valuable insights into the underlying heterogeneity associated with disease progression and offers useful information for the development of immunotherapeutic techniques in the future.

Microorganisms play an important role in plant growth, health and ecological function. It is necessary to explore the microbial community because of the significant ecological and economic value of apples (Malus x domestica). However, the related bacterial communities in different ecological habitats are not clear in the unique scion/rootstock combinations of apples. In this study, the Illumina Miseq platform was used to analyze the bacterial communities in different niches (bulk soil, rhizosphere soil and roots) of two scion/rootstock combinations [Fuji/Malus xiaojinensis Cheng et Jiang (Mx) and Fuji/Malus baccata (L.) Borkh. (Mb)]. The relationship between the microbial community, soil properties, and plant characters was explored. The results showed that the diversity of the bacterial community decreased from bulk soil to rhizosphere soil and then to roots. In addition, at the phylum level, Proteobacteria, Actinobacteria and Acitinobacteria were dominant and had notable divergence in different ecological niches. Distinct niches had remarkable effects on the diversity and composition of the bacterial community according to PCoA. The rootstock genotype had an effect on the bacterial composition but no effect on the diversity. pH, soil organic matter (SOM), alkaline hydrolyzable nitrogen (AN) were the main factor affecting the structure of bacterial community in rhizosphere soil, as shown by Pearson analysis. Bacteria taxa in the roots were affected by starch, fructose, sucrose and sorbitol. This study showed the microbial community structure in different ecological niches of different scion/rootstock combinations and provided some evidence for understanding the microbial-plant interaction of apple rootstocks.

Abstract Purpose To study the relationship between the TyG index and the risk of AAC. Methods We enrolled 1,486 participants from the National Health and Nutrition Examination Survey (NHANES). The TyG index was calculated in the log-transformed of triglycerides multipled by glucose, and the presence of AAC was diagnosed as AAC score above than 0. Results Our suggested found that TyG level was positively correlated with the presence of AAC and log-transformed AAC score. After adjusted for other variables, comparing with the lowest quartile of TyG index, the highest quartile of TyG level was significantly associated with the presence of AAC (OR 2.12, 95%CI 1.05–4.35, p = 0.038) and severe AAC (OR 2.12, 95%CI 1.05–4.35, p = 0.038). Conclusions TyG index was significantly associated with the risk of AAC and severe AAC, which could be a marker in clinical practice.

Abstract Background Lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease (CAD). Recent studies have indicated that statins tend to increase Lp(a) levels by 10–20%. However, the association of statin-mediated increases in Lp(a) levels with CAD has not been determined. Methods This study included 488 patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Lp(a) levels were measured at baseline and 1 month after statin therapy. The study endpoints were major adverse cardiovascular events (MACE). Hazard ratios for the MACE were adjusted for potential confounder using Cox regression. Results After statin therapy, the mean level of Lp(a) increased by 19.3% from baseline. Lp(a) levels increased in 307 patients (62.9%) with a median elevation of 4.1 mg/dL. Patients with an increase in Lp(a) were at higher risk for MACE than those without an increase in Lp(a) (p = 0.044). Subgroup analyses revealed that a mild-to-moderate increase in Lp(a) was not associated with MACE, whereas there was a strong correlation between the highest quartile increase in Lp(a) (≥ 10.1 mg/dL) and MACE (HR = 2.29, 95%CI = 1.36–3.84, p = 0.002). This correlation was independent of baseline Lp(a) levels but not independent of on-statin Lp(a) levels. Conclusions Severe increases in Lp(a) following statin therapy raise the risk of MACE, but a mild-to-moderate increase in Lp(a) may not affect the cardiovascular prognosis of CAD patients. Even if the baseline Lp(a) levels are low, it is necessary to continue testing for Lp(a) concentration at least once after statin.

One new lignan sinensiol H (1) and two new bisnorlignans, sinensiols I and J (2 and 3), along with three known compounds were isolated from the whole plants of Selaginella sinensis. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopy as well as high-resolution mass spectrometry. The absolute configuration of 1 was established by ECD calculation. Compounds 2 and 3 represent rare examples of naturally occurring 9,9'-bisnorlignans. All the isolated compounds were assayed for their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages.

Abstract Serum branched chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the levels of these amino acids in women with gestational diabetes mellitus (GDM) and examined their changes in response to an oral glucose tolerance test (OGTT). 110 women were enrolled and underwent a 75-g OGTT during their second trimester; 43 women were diagnosed with GDM and 67 women did not have GDM (non-GDM women). During the OGTT, fasting, 1-h, and 2-h blood samples were obtained. BCAA and AAA levels were measured by liquid chromatography-tandem mass spectrometry. The differences in BCAA and AAA levels between GDM and non-GDM women were not evident during fasting but became significant after glucose loading. Glucose ingestion decreased the levels of BCAAs and AAAs in both groups. Notably, GDM women showed a delayed and blunted decrease in these amino acids compared to non-GDM women. The risks of 2-h changes in BCAAs and AAAs for GDM women were significant. We identified that the differences in BCAA and AAA levels between GDM women and controls, which were not evident during fasting, could be provoked by performing an OGTT.

Abstract Background Long anterior lens zonules (LAZs) is a rare disease that was mostly conducted among African Americans. Through the observation of a Chinese patient, we discoverd that the disease may show different characteristics in Asians. Case presentation A patient with vision loss due to a macular hole was found to have several special clinical signs during vitrectomy combined with phacoemulsification and intraocular lens implantation surgery in our hospital, including radially oriented lines on the anterior capsule with pigment, a shallow anterior chamber, slightly high intraocular pressure, and radial retinal stripes in the peripheral retina. Finally, he was diagnosed with long anterior lens zonule syndrome. Conclusion Clinicians need to pay more attention to the rare disease LAZs. It is important to tear the appropriate size of the anterior capsule so as to avoid radial capsular tearing and intraocular lens dislocation.

Abstract Epicardial adipose tissue (EAT) can play an important role in the occurrence and development of atrial fibrillation and stroke. In this study, we explored the relationship between left atrial epicardial adipose tissue (LA-EAT) and left atrial appendage flow velocity (LAA-FV) in patients with nonvalvular atrial fibrillation (NV-AF). A total of 145 patients with NV-AF who underwent their first radiofrequency ablation were enrolled. They underwent left aortopulmonary vein computed tomography angiography (CTA) and transesophageal echocardiography (TEE) before AF ablation. Left atrial (LA) electroanatomical mapping was performed intraoperatively to assess left atrial voltage. Univariate regression analysis showed that LAA-FV was lower in patients with a low voltage zone (LAA-FV; 35.02 ± 10.78 cm/s vs. 50.60 ± 12.17 cm/s, P

The skin is the largest organ in humans. It comprises about 16% of our body. Many diseases originate from the skin, including acne vulgaris, skin cancer, fungal skin disease, etc. As a common skin cancer in China, melanoma alone grows at year rate of nearly 4%. Therefore, it is crucial to develop an objective, reliable, accurate, non-invasive, and easy-to-use diagnostic method for skin diseases to support clinical decision-making. Raman spectroscopy is a highly specific imaging technique, which is sensitive, even to the single-cell level in skin diagnosis. Raman spectroscopy provides a pattern of signals with narrow bandwidths, making it a common and essential tool for researching individual characteristics of skin cells. Raman spectroscopy already has a number of clinical applications, including in thyroid, cervical and colorectal cancer. This review will introduce the advantages and recent developments in Raman spectroscopy, before focusing on the advances in skin diagnosis, including the advantages, methods, results, analysis, and notifications. Finally, we discuss the current limitations and future progress of Raman spectroscopy in the context of skin diagnosis.

Single-cell volumetric imaging is essential for researching individual characteristics of cells. As a nonscanning imaging technique, light field microscopy (LFM) is a critical tool to achieve real-time three-dimensional imaging with the advantage of single-shot. To address the inherent limits including nonuniform resolution and block-wise artifacts, various modified LFM strategies have been developed to provide new insights into the structural and functional information of cells. This review will introduce the principle and development of LFM, discuss the improved approaches based on hardware designs and 3D reconstruction algorithms, and present the applications in single-cell imaging.

BackgroundEpicardial adipose tissue (EAT) is directly related to coronary artery disease (CAD), but little is known about its role in hemodynamically significant CAD. Therefore, our goal is to explore the impact of EAT volume on hemodynamically significant CAD.MethodsPatients who underwent coronary computed tomography angiography (CCTA) and received coronary angiography within 30 days were retrospectively included. Measurements of EAT volume and coronary artery calcium score (CACs) were performed on a semi-automatic software based on CCTA images, while quantitative flow ratio (QFR) was automatically calculated by the AngioPlus system according to coronary angiographic images.ResultsThis study included 277 patients, 112 of whom had hemodynamically significant CAD and showed higher EAT volume. In multivariate analysis, EAT volume was independently and positively correlated with hemodynamically significant CAD [per standard deviation (SD) cm3; odds ratio (OR), 2.78; 95% confidence interval (CI), 1.86–4.15; P

Background: The extensive usage of pesticides has led to a ubiquitous exposure in the Chinese general population. Previous studies have demonstrated developmental neurotoxicity associated with prenatal exposure to pesticides. Objectives: We aimed to delineate the landscape of internal pesticides exposure levels from pregnant women’s blood serum samples, and to identify the specific pesticides associated with the domain-specific neuropsychological development. Methods: Participants included 710 mother-child pairs in a prospective cohort study initiated and maintained in Nanjing Maternity and Child Health Care Hospital. Maternal spot blood samples were collected at enrollment. Leveraging on an accurate, sensitive and reproducible analysis method for 88 pesticides, a total of 49 pesticides were measured simultaneously using gas chromatography-triple quadrupole tandem mass spectrometry (GC–MS/MS). After implementing a strict quality control (QC) management, 29 pesticides were reported. We assessed neuropsychological development in 12-month-old (n = 172) and 18-month-old (n = 138) children using the Ages and Stages Questionnaire (ASQ), Third Edition. Negative binomial regression models were used to investigate the associations between prenatal exposure to pesticides and ASQ domain-specific scores at age 12 and 18 months. Restricted cubic spline (RCS) analysis and generalized additive models (GAMs) were fitted to evaluate non-linear patterns. Longitudinal models with generalized estimating equations (GEE) were conducted to account for correlations among repeated observations. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were applied to examining the joint effect of the mixture of pesticides. Several sensitivity analyses were performed to assess the robustness of the results. Results: We observed that prenatal exposure to chlorpyrifos was significantly associated with a 4 % decrease in the ASQ communication scores both at age 12 months (RR, 0.96; 95 % CI, 0.94–0.98; P 0.05). Longitudinal analyses implicated the consistent findings. Conclusion: This study gave an integrated picture of pesticides exposure in Chinese pregnant women. We found significant inverse associations between prenatal exposure to chlorpyrifos, mirex, atrazine, dimethipin and the domain-specific neuropsychological development (i.e., communication, gross motor and fine motor) of children at 12 and 18 months of age. These findings identified specific pesticides with high risk of neurotoxicity, and highlighted the need for priority regulation of them.

Abstract Background Lipoprotein(a) [Lp(a)] elevation is an important risk factor for coronary artery disease (CAD). However, the correlation between Lp(a) elevations and the risk of recurrent cardiovascular events in patients with established cardiovascular disease is controversial. Some studies have shown that Low-density lipoprotein cholesterol (LDL-C) levels may influence the association between Lp(a) and cardiovascular risk. Our study aims to explore the correlation between Lp(a) elevations and cardiovascular risk in patients with different LDL-C levels. Methods We included 516 patients who received coronary stents due to acute coronary syndrome (ACS) and followed them for three years. They were divided into low-Lp(a) group and high-Lp(a) group according to Lp(a) levels, and the incidence of major adverse cardiovascular events (MACE) and acute coronary events (ACE) was compared between the two groups. Then the patients were divided into three subgroups (S1:LDL-C ≥ 1.8 mmol/L; S2:1.4 ≤ LDL-C

There is an argument that BPA substitutes may have the same or more deleterious health effects as BPA due to their structural similarity. This study explored the association between urinary BPA substitutes and precocious puberty among girls by including 120 girls with precocious puberty (cases) aged 2–10 years enrolled at Nanjing Children’s Hospital Department of Endocrinology in China between April 2021 to September 2021 and 145 healthy girls (controls) recruited from a primary school. Logistic regression was used to evaluate the effect of single exposures, and Bayesian kernel machine regression (BKMR) and quantile-based g-computation were used for the mixed effect. In the multivariate logistic regression, BPS (bisphenol S), TBBPA (tetrabromobisphenol A), and BPFL (bisphenol-FL) were significantly associated with increased risk of precocious puberty (odds ratio (OR) = 1.75, 95% confidence interval (CI): 1.13, 2.76, p = 0.014), (OR = 1.46, CI: 1.06, 2.05; p = 0.023), and (OR = 1.47, CI: 1.01, 2.18; p = 0.047), respectively. The BMKR and quantile-based g-computation models revealed consistent associations for single exposures and there was insufficient evidence for the associations of the mixed exposure of bisphenols with precocious puberty. In conclusion, BPA substitutes such as BPS, TBBPA, and BPFL may be associated with an increased risk of precocious puberty in girls.

To the best of the author’s knowledge, studies of mature plasmacytoid dendritic cell proliferation associated with T lymphoblastic lymphoma were extremely rare in the literature. Here, we report a patient who underwent both mature plasmacytoid dendritic cell proliferation and T lymphoblastic lymphoma. With the findings of lymph node biopsy taken from the right cervical and inguinal regions, we identified eye-catching mature plasmacytoid dendritic cells that were considered to be responsible for this lesion at the beginning, until the immunostaining of Ki67 and TDT showed a small group of positive cells hiding in these plasmacytoid dendritic cells. A bone marrow biopsy was also performed on this patient. Microscopically, the hematopoietic tissue was almost completely replaced by lymphoblastoid cells with condensed chromatin, inconspicuous nucleoli and scanty cytoplasm, which were basically the same as those seen in the lymph nodes in morphology. However, there was no sign of plasmacytoid dendritic cells or Langerhans cells in the bone marrow biopsy. With the help of bone marrow biopsy, our final diagnosis of the lymph node was T lymphoblastic lymphoma coexisting with mature plasmacytoid dendritic cell proliferation. Although accumulations of plasmacytoid dendritic cells may occur in some infections or reactive lymphadenopathy, the presence of extensive nodules or infiltration of plasmacytoid dendritic cells strongly reminds the pathologist to carefully evaluate the bone marrow or peripheral blood status of the patient to exclude a hidden myeloid or other neoplasm.

Abstract Background Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to investigate the relationship of cytochrome P450 (CYP450) gene polymorphisms with blood concentrations of HCQ and its metabolites and adverse drug reactions (ADRs) in patients with SLE and RA. Methods A cohort of 146 patients with SLE and RA treated with HCQ was reviewed. The ADRs of the patients were recorded. The blood concentrations of HCQ and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Genotyping of single nucleotide polymorphisms (SNPs) in CYP450, a metabolic enzyme involved in the HCQ metabolic pathway, was performed using a MassARRAY system. The chi-square test, T-test, and one-way analysis of variance were used to analyse data. Results Among 29 candidate SNPs, we found that CYP3A4 (rs3735451) was significantly associated with blood levels of HCQ and its metabolites in both the unadjusted model and adjusted model (patients taking HCQ for > 10 years) (P

Abstract Background Rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients. Methods DNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling. Results We identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32). Conclusions The HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.

AimsAntithrombotic secondary prevention in stable cardiovascular disease (SCVD) patients at high ischemic risk remains unclear. We compared the efficacy and safety of aspirin monotherapy, clopidogrel monotherapy, ticagrelor monotherapy, rivaroxaban monotherapy, clopidogrel plus aspirin, ticagrelor plus aspirin, and rivaroxaban plus aspirin in the high-risk ischemic cohorts.Methods and resultsEleven randomized controlled trials were included (n = 111737). The primary outcomes were major cardiovascular and cerebrovascular events (MACEs) and major bleeding. A random effects model was used for frequentist network meta-analysis. Odds ratio (OR) and 95% credible intervals (CI) were reported as a summary statistic. Compared with aspirin monotherapy, rivaroxaban plus aspirin [OR 0.79 (95% CI, 0.69, 0.89)], ticagrelor plus aspirin [0.88 (0.80, 0.98)], clopidogrel plus aspirin [0.56 (0.41, 0.77)] were associated with a reduced risk of MACEs, but rivaroxaban monotherapy [0.92 (0.79, 1.07)], ticagrelor monotherapy [0.68 (0.45, 1.05)], and clopidogrel monotherapy [0.67 (0.43, 1.05)] showed no statistically significant difference. However, rivaroxaban monotherapy and all dual antithrombotic strategies increased the risk of major bleeding to varying degrees, with ticagrelor plus aspirin associated with the highest risk of major bleeding. The net clinical benefit favored clopidogrel or ticagrelor monotherapy, which have a mild anti-ischemic effect without an increase in bleeding risk.ConclusionThe present network meta-analysis suggests that clopidogrel or ticagrelor monotherapy may be recommended first in this cohort of SCVD at high ischemic risk. But clopidogrel plus aspirin or rivaroxaban plus aspirin can still be considered for use in patients with recurrent MACEs.

BackgroundPatients with Lynch syndrome are at an increased risk of developing simultaneous or metachronous tumors, while sarcomas have been occasionally reported. Sarcomas are generally not considered part of the common Lynch syndrome tumor spectrum. However, more and more studies and case reports suggested that sarcoma could be a rare clinical manifestation of Lynch syndrome, leading to new treatment strategies for sarcoma.Case summaryWe report the case of a 74-year-old male patient with Lynch syndrome who had rectal mucinous adenocarcinoma and prostate adenocarcinoma and then developed undifferentiated sarcoma of the left neck two years later. Mismatch repair deficiency (dMMR) was confirmed by immunohistochemical staining for the mismatch repair proteins MSH2, MSH6, MLH1 and PMS2. The result of polymerase chain reaction (PCR) microsatellite instability (MSI) testing of sarcoma showed high-level microsatellite instability (MSI-H). Additionally, a pathogenic germline mutation in MSH2 (c.2459-12A>G) was detected by next-generation sequencing (NGS). Taking into account HE morphology, immunohistochemical phenotype, MSI status, NGS result, medical history and germline MSH2 gene mutation, the pathological diagnosis of left neck biopsy tissue was Lynch syndrome related undifferentiated sarcoma with epithelioid morphology. The patient has been receiving immunotherapy (sintilimab) combined with chemotherapy (tegafur, gimeracil and oteracil potassium capsules) and currently has stable disease. We also reviewed the literature to understand the association between sarcoma and Lynch syndrome.ConclusionSarcoma may now be considered a rare clinical manifestation of Lynch syndrome. Attention and awareness about the association between Lynch syndrome and sarcoma need to be increased. Therefore, timely detection of MMR proteins and validation at the gene level for suspicious patients are the keys to avoiding missed or delayed diagnosis and to identifying patients suited for immunotherapy, which may also help to provide appropriate genetic counseling and follow-up management for patients.

BackgroundCoronary microvascular dysfunction (CMD) may play an important role in various cardiovascular diseases, including HFpEF and both obstructive and non-obstructive coronary artery disease (CAD). To date, there has been no bibliometric analysis to summarize this field. Here, we aim to conduct a bibliometric analysis of CMD to determine the current status and frontiers in this field.Materials and methodsPublications about CMD were taken from the Web of Science Core Collection database (WOSCC). WOSCC’s literature analysis wire, the VOSviewer 1.6.16, and CiteSpace 5.1.3 were used to conduct the analysis.ResultsA total of 785 publications containing 206 reviews and 579 articles are included in the sample. The leading authors are Iacopo Olivotto, Paolo G. Camici, and Carl J. Pepine. The most productive institutions are the University of Florence, Cedars Sinai Medical Center, and Harvard University. The most productive countries are the USA, Italy, and England. There are a total of 237 journals that contribute to this field, and the leading journals in our study were the International Journal of Cardiology, the European Heart Journal and the JACC. From 2012 to 2021, the top three most-cited articles focused on the association between HFpEF and CMD. The important keywords are heart failure, hypertrophic cardiomyopathy, chest pain, women, coronary flow reserve (CFR), endothelial dysfunction and prognostic value. “Positron emission tomography” shows the strongest burst strength, followed by “blow flow” and “artery.” The keywords that started to burst from 2015 are particularly emphasized, including “heart failure,” “coronary flow reserve,” and “management.”ConclusionStudies about CMD are relatively limited, and the largest contribution comes from the USA, Italy and England. More studies are needed, and publications from other countries should be enhanced. The main research hotspots in the CMD field include CMD in patients with HFpEF, sex differences, the new methods of diagnosis for CMD, and the effective treatment of CMD. Attention should be given to CMD in patients with HFpEF, and untangling the association between CMD and HFpEF could be helpful in the development of physiology-stratified treatment for patients with CMD and HFpEF.

Abstract This letter presents a robust active contour model driven by the local threshold preprocessing fitting energies to actualize fast segmentation of inhomogenous images. First, the local threshold preprocessing is carried out to compute two local intensity means. Second, these two means are sorted and serve as the local area fitting centres, which makes the contour move along the internal or external target boundaries. Finally, the above local area fitting centres are used to build the model's energy functional based on the symmetric cross entropy. Experimental results of the real inhomogenous images confirm that the presented model can segment inhomogenous images much faster and is robust to the setting up of the original contour.

Abstract Background Recent studies suggest that there is a link between the gut microbiota and glucose metabolism. This study aimed to compare the gut microbiota during early pregnancy of women with hyperglycymia to those with normal blood glucose. Methods Gut microbial composition was analysed in 22 women with hyperglycaemia and 28 age-matched healthy controls during their first prenatal visits (

Aims: To determine the association between urinary levels of perchlorate, nitrate and thiocyanate, and the prevalence of cardiovascular diseases (CVD) among general population. Methods: A total of 16, 570 participants were enrolled from the National Health and Nutrition Examination Surveys (NHANES). Urinary levels of perchlorate, nitrate and thiocyanate were measured using ion chromatography coupled with electrospray tandem mass spectrometry. Multivariable linear regressions and logistic regressions were performed to explore the associations of exposure to perchlorate, nitrate and thiocyanate, and the prevalence of total and specific CVD, including chronic heart failure (CHF), coronary heart disease (CHD), angina, heart failure and stroke. Restricted cubic splines were used to explore the nonlinearity. Results: Participants with CVD had a lower urinary level of nitrate and thiocyanate (all P

Background and PurposeMounting researches have illuminated that the neutrophil-related ratios were related to the prognosis of acute ischemic stroke (AIS). However, few have compared their predictive value and accuracy. To make such comparison and identify the best indicator on the 90-day outcome, we investigated biomarkers including neutrophil ratio (Nr), neutrophil count (Nc), lymphocyte (L), neutrophil-to-lymphocyte ratio (NLR), platelet (P or PLT), platelet-to-neutrophil ratio (PNR), NLR-to-platelet ratio (NLR/PLT), eosinophil (E), neutrophil-to-eosinophil ratio (NER), monocyte (M), and monocyte-to-neutrophil ratio (MNR).MethodsThis retrospective study recruited 283 AIS and 872 healthy controls (HCs) receiving intravenous thrombolysis (IVT). Blood samples were collected after 24 h of admission before IVT. Propensity Score Matching (PSM) was used to explore whether these ratios differentiated AIS and HCs. We applied univariate and multivariate analyses to evaluate the prediction effect of these ratios separately or added in the model and figured out a clinical prediction model. To estimate the discrimination and calibration of the new models, the receiver operating characteristics (ROC) curve analysis, DeLong method, and likelihood ratio test (LR test) were utilized.ResultsPSM showed that Nr, Nc, NLR, P, PNR, NLR/PLT, NER, and MNR facilitates the differentiation of the HCs and AIS. Among the eight biomarkers, PNR and MNR could differentiate the 90-day outcome, and it was found out that PNR performed better. Univariate regression analysis demonstrated that PNR was the only independent predictor which needs no adjustment. Besides, the multivariate regression analysis, Delong method, and LR test indicated that among the neutrophil-related ratios, NLR, PNR, NLR/PLT, NER, and MNR exerted little influence on the discrimination but could enhance the calibration of the base model, and NER proved to work best.ConclusionLow PNR was the best indicator among the neutrophil-related ratios tin predicting a poor 90-day outcome of AIS patients. Moreover, high NER performed best when predicting the 90-day outcome to improve the calibration of the base model.

Background and PurposeBlood eosinophil counts are thought to be associated with atherosclerosis in acute ischemic stroke (AIS) and AIS severity. We aimed to investigate 1): the temporal profile of eosinophil in AIS patients treated with recombinant tissue plasminogen activator (r-tPA); 2): The association between dynamic eosinophil and 3-month outcomes in different AIS etiologies; 3): incremental predictive ability of dynamic eosinophil adding to conventional model; and 4): the longitudinal change of neutrophil-to-lymphocyte ratio (NLR) and compared its prognostic value with eosinophils.MethodsA total of 623 AIS patients with intravenous thrombolysis in two hospitals were included. Blood samples were obtained on admission, within 24 h after an intravenous thrombolysis and on the seventh day. A multivariate logistic regression model with restricted cubic spline was performed to explore the association between dynamic eosinophil and a 3-month poor outcome. C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were adopted to explore the incremental predictive ability.ResultsPercent change in eosinophil counts after intravenous thrombolysis was median −25.00% (IQR −68.25%–+14.29%). Decrease in eosinophil >75% after intravenous thrombolysis was associated with 2.585 times risk for poor outcome and 13.836 times risk for death. However, the association were weak for patients outside of cardioembolic stroke. Adding eosinophil changes to a conventional model improved the discriminatory ability of poor outcome (NRI = 53.3%; IDI = 2.2%) and death (NRI = 101.0%; IDI = 6.9%).ConclusionsDynamic decrease in eosinophil after intravenous thrombolysis predicts a 3-month poor outcome and death in AIS patients with r-tPA treatment and improved the predictive ability of conventional model. However, this result needs to be interpreted carefully in non-cardioembolic AIS patients.

Background and Purpose: The eosinophil-to-neutrophil ratio (ENR) was recently reported as a novel inflammatory marker in acute ischemic stroke (AIS). However, few studies reported the predictive value of ENR in AIS patients, especially for those with intravenous thrombolysis.Methods: Two hundred sixty-six AIS patients receiving intravenous thrombolysis were retrospectively recruited in this study and followed up for 3 months and 1 year. The Modified Rankin Scale (mRS) and the time of death were recorded. Poor outcome was defined as mRS 3–6. After excluding patients who were lost to follow-up, the remaining 250 patients were included in the 3-month prognosis analysis and the remaining 223 patients were included in the 1-year prognosis analysis.Results: ENR levels in the patients were lower than those in the healthy controls. The optimal cutoff values for the ability of ENR × 102 to predict 3-month poor outcome were 0.74 with 67.8% sensitivity and 77.3% specificity. Patients with ENR × 102 ≥ 0.74 have a lower baseline National Institutes of Health Stroke Scale (NIHSS) score (median: 7 vs. 11, p < 0.001). After multivariate adjustment, patients with ENR × 102 ≥ 0.74 were more likely to come to a better 3-month outcome (OR = 0.163; 95% CI, 0.076–0.348, p < 0.001). At the 1-year follow-up, the patients with ENR × 102 ≥ 0.74 showed a lower risk of mortality (HR = 0.314; 95% CI, 0.135–0.731; p = 0.007).Conclusions: A lower ENR is independently associated with a 3-month poor outcome and a 3-month and 1-year mortality in AIS patients treated with intravenous thrombolysis.

Abstract Background The red cell index (RCI) was described as a biomarker for evaluating respiratory function in previous studies, but the relationship between RCI and stroke, remained a mystery. The present study aimed to probe the association between RCI at 24‐hr and 3‐month mortality and functional outcomes among acute ischemic stroke (AIS) patients treated with recombinant tissue plasminogen activator (r‐tPA). Methods A total of 217 AIS patients between January 2016 and January 2019 were recruited in this retrospective study. AIS patients were grouped in terms of RCI tertiles. Predictive factors were confirmed via multivariate logistic regression analysis. The receiver operating characteristic (ROC) was used to assess the ability of RCI in predicting mortality. In addition, the risk of 3‐month all‐cause mortality was evaluated by Cox proportional hazard model. Results We grouped AIS patients into tertiles with the purpose of comparing clinical factors and RCI levels. Multivariate logistic regression analysis presented that RCI (odds ratio [OR] = 1.443, 95% confidence interval [CI] [1.167–1.786], p = 0.001) was an independent biomarker for 3‐month all‐cause mortality. The best cutoff value of RCI was 2.41 (area under the curve [AUC] = 0.639, 95% CI [0.501–0.778], p = .032), with a sensitivity of 40.9% and a specificity of 89.7%. Cox survival analysis demonstrated a positive significant correlation between RCI (hazard ratio [HR] = 1.332, 95% CI [1.148–1.545], p

Isofenphos-methyl (IFP) is a very active and persistent chiral insecticide. However, IFP has lower activity against acetylcholinesterases (AChEs). Previously, it was confirmed that phosphorothioate organophosphorus pesticides with N-alkyl (POPN) require activation by oxidative desulfuration and N-dealkylation. In this work, we demonstrated that IFP could be metabolized in human liver microsomes to isofenphos-methyl oxon (IFPO, 52.7%), isocarbophos (ICP, 14.2%) and isocarbophos oxon (ICPO, 11.2%). It was found that (R)-IFP was preferentially degraded compared to the (S)-enantiomer, and the enantiomeric fraction (EF) value reached 0.61 at 60 min. However, (S)-enantiomers of the three metabolites, were degraded preferentially, and the EF values ranged from 0.34 to 0.45. Cytochrome P450 (CYP) isoforms CYP3A4, CYP2E1, and CYP1A2 and carboxylesterase enzyme have an essential role in the enantioselective metabolism of IFP; but, the enzymes that participate in the degradation of IFP metabolites are different. The AChE inhibition bioassay indicated that ICPO is the only effective inhibitor of AChE. The covalent molecular docking has proposed that the metabolites of IFP and its analogs after N-dealkylation and oxidative desulfuration will possess the highest inhibitory activity against AChE. This study is the first to demonstrate that ICPO can be regarded as a potential biomarker for the biomonitoring of IFP and ICP exposure in humans. Keywords: Isofenphos-methyl, Chiral, Metabolites, Biomarker, Molecular docking

The gene mutations of the ATP-binding-cassette transporter subfamily D member 1 (ABCD1) can lead to the inherited neuro-metabolic malfunction disease X-linked adrenoleukodystrophy (X-ALD). Human urine cells from a 6-year-old male X-ALD patient harboring a ABCD1 gene frameshift (c.2013insA, Xq28) were reprogrammed into the induced pluripotent stem cell (iPSC) line WMUi014-A with Sendai virus reprogramming kit containing OCT4, SOX2, c-MYC, and KLF4 Yamanaka factors. The established iPSCs in vitro stably expressed pluripotent markers, had differentiation potential into three germ layers, and maintained a normal 44 + XY karyotype.

Since immune infiltration is closely associated with the progression and prognosis of atherosclerosis, we aimed to describe the abundance of 24 immune cell types within atherosclerotic tissues. In the current study, we used the Immune Cell Abundance Identifier (ImmuCellAI), a web-based tool, to estimate the abundance of 24 immune cells based on the microarray profiles of atherosclerotic carotid artery samples to analyze the proportions and the dysregulation of immune cell types within carotid atherosclerosis. We found that atherosclerotic immune cells had a diverse landscape dominated by T cells and myeloid cells and that macrophages and dendritic cells (DCs) showed different abundance in normal and atherosclerotic tissues. Moreover, the expression of macrophages was closely related to the level of the expression of DCs and of exhausted T cells, while the expression of T-helper type 1 (Th1) cells was strongly correlated with the expression of T-helper type 2 (Th2) cells and effector memory cells. Our data confirm a distinct profile of atherosclerosis-infiltrating immune cell subpopulations, which may inspire an immunological direction for research on atherosclerosis.

Background Long‐term antithrombotic strategies for patients with chronic coronary syndrome with high‐risk factors represent an important treatment dilemma in clinical practice. Our aim was to conduct a network meta‐analysis to evaluate the efficacy and safety of long‐term antithrombotic strategies in patients with chronic coronary syndrome. Methods and Results Four randomized studies were included (n=75167; THEMIS [Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study], COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies], PEGASUS‐TIMI 54 [Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54], and DAPT [Dual Anti‐platelet Therapy]). The odds ratios (ORs) and 95% CIs) were calculated as the measure of effect size. The results of the network meta‐analysis showed that, compared with aspirin monotherapy, the ORs for trial‐defined major adverse cardiovascular and cerebrovascular events were 0.86; (95% CI, 0.80–0.93) for ticagrelor plus aspirin, 0.89 (95% CI, 0.78–1.02) for rivaroxaban monotherapy, 0.74 (95% CI, 0.64–0.85) for rivaroxaban plus aspirin, and 0.72 (95% CI, 0.60,–0.86) for thienopyridine plus aspirin. Compared with aspirin monotherapy, the ORs for trial‐defined major bleeding were 2.15 (95% CI, 1.78–2.59]) for ticagrelor plus aspirin, 1.51 (95% CI, 1.23–1.85) for rivaroxaban monotherapy, and 1.68 (95% CI, 1.37–2.05) for rivaroxaban plus aspirin. For death from any cause, the improvement effect of rivaroxaban plus aspirin was detected versus aspirin monotherapy (OR, 0.76; 95% CI, 0.65–0.90), ticagrelor plus aspirin (OR, 0.79; 95% CI, 0.66–0.95), rivaroxaban monotherapy (OR, 0.82; 95% CI, 0.69–0.97), and thienopyridine plus aspirin (OR, 0.58; 95% CI, 0.41–0.82) regimens. Conclusions All antithrombotic strategies combined with aspirin significantly reduced the incidence of major adverse cardiovascular and cerebrovascular events and increased the risk of major bleeding compared with aspirin monotherapy. Considering the outcomes of all ischemic and bleeding events and all‐cause mortality, rivaroxaban plus aspirin appears to be the preferred long‐term antithrombotic regimen for patients with chronic coronary syndrome and high‐risk factors.

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer with a mortality rate of approximately 3–6/100,000 and is the third leading cause of cancer-related death worldwide. Although several small-molecule drugs have been developed for the treatment of HCC, the choice of an agent for patients who require systemic chemotherapy at an advanced stage is still limited. The Hippo pathway is an evolutionarily conserved tumor suppressive pathway commonly dysregulated in HCC, which makes it a promising target for anti-HCC therapies. Homoharringtonine (HHT) is an FDA-approved anti-leukemia drug with proven strong anti-tumor activity in solid tumors. In this study, we found that HHT could significantly inhibit HCC cell growth by suppressing cell proliferation and colony formation. Moreover, HHT repressed cell invasion and migration remarkably. Additionally, HHT induced cell cycle arrest at S phase and promoted apoptosis. Most importantly, we showed that HHT-induced apoptosis was a consequence of the Hippo pathway activation. Consistently, the MST1/2 inhibitor, XMU-MP-1, could restore cell viability and reverse HHT-induced cell apoptosis. Furthermore, in vivo results confirmed the tumor inhibitory effect of HHT. Taken together, our findings suggest that HHT is a potential alternative therapeutic agent for the treatment of HCC.

Germacrone, a monocyclic sesquiterpene, exerts marked antitumor effects in a variety of cancers, including hepatocellular carcinoma, gastric cancer, and breast cancer. However, the mechanism underlying the effects of germacrone on gastric cancer remains unclear. In this study, we show that germacrone inhibited gastric cancer cell proliferation in a dose-dependent manner, and induced G0/G1-phase cell cycle arrest and apoptosis in these cells. Moreover, germacrone increased the expression of LC3II/LC3I. And LC3II/LC3I was significant increased after germacrone treatment compared with germacrone and bafilomycin A1 (Baf A1) treatment, which suggested germacrone promoted the formation of autophagosomes. Proteomic analysis was then used to identify molecular targets of germacrone in gastric cancer. A total of 596 proteins were screened, and the top hit was identified as late endosomal/lysosomal adaptor and MAPK and MTOR activator 5 (LAMTOR5, also named HBXIP). Overexpression of HBXIP delayed the germacrone-induced cell cycle arrest, induction of apoptosis, and inhibition of autophagy. Combined, our results indicate that germacrone suppresses gastric cancer cell proliferation by inhibiting HBXIP, and this process is related to G0/G1-phase arrest and apoptosis.

Isofenphos-methyl (IFP), a chiral organophosphorus pesticide, is one of the main chemicals used to control underground insects and nematodes. Recently, the use of IFP on vegetables and fruits has been prohibited due to its high toxicity. In this study, we investigated the enantioselective distribution and metabolism of IFP and its metabolites, namely, isofenphos-methyl oxon (IFPO) and isocarbophos oxon (ICPO), in male Sprague Dawley (SD) rats. Forty eight hours (48 h) after exposure, ICPO was the main detectable compound in blood (up to 75%) and urine (up to 77%), and we found that (S)-ICPO was significantly more stable than (R)-ICPO (p 0.05). We found that cytochrome P450 (CYP) (i.e. CYP2C11, CYP2D2 and CYP3A2 enzymes and carboxylesterases) is responsible for the enantioselective metabolism of IFP in liver. In addition, rats exposed to (S)-IFP exhibited hepatic lipid peroxidation, liver inflammation and hepatic fibrosis. This study provides useful information and a reference for the biomonitoring and risk assessment of IFP and organophosphorus pesticide exposure.

Biological diversity plays an important role in the stability of ecosystems. The Mu Us Desert (MUD), located in Northern China, is an aeolian desert. Although it has been governed by a series of ecological restoration programs, the MUD still has limited biological diversity. Populus euphratica (P. euphratica), a xerophytic plant, has great potential to improve the biological diversity of the MUD. However, the survival rate of P. euphratica in the MUD has been very low. The current study tried to explore the mechanism of the high death rate of P. euphratica in the microbiome perspective. The correlation study between soil community composition and soil properties showed that water-filled pore space (WFPS), pH, EC, AP, NO3–, and NH4+ possess higher potential to change the bacterial community (18%) than the fungal community (9%). Principal coordinate analysis indicated that the composition of both bacteria (Proteobacteria and Bacteroidetes) and fungi (Ascomycota) in the root soil can be increased by P. euphratica. By systematically comparing between the fungal diversity in the root soil around P. euphratica and the pathogenic fungus extract from the pathogenic site of P. euphratica, we found that the high death rate of P. euphratica was associated with specific pathogenic fungus Alternaria alternate and Didymella glomerata. In addition, the microbiome composition analysis indicated that P. euphratica planting could also influence the portions of bacteria community, which also has great potential to lead to future infection. However, as the extraction and separation of bacteria from plants is challenging, the correlation between pathogenic bacteria and the high death rate of P. euphratica was not studied here and could be explored in future work.

Objectives The relationship between lipid levels and arterial stiffness remains controversial. Therefore, we aimed to determine the relationship between lipid profiles and brachial–ankle pulse wave velocity (baPWV) as an indicator of arterial stiffness. Methods A total of 909 participants aged 24 to 84 years were stratified into four baPWV quartiles in our study. Serum lipids, baPWV, and other variables of the participants were measured. Univariable and multivariable linear regression analyses were used to examine the relationships between lipid parameters and baPWV. Results The highest baPWV quartile group had higher aspartate transaminase, alanine aminotransferase, plasma glucose, total cholesterol, triglyceride (TG), and low-density lipoprotein cholesterol levels and maximum ankle–brachial index, and lower high-density lipoprotein cholesterol levels and estimated glomerular filtration rate. Univariate regression analysis showed that total cholesterol, TG, and low-density lipoprotein cholesterol levels were positively related and high-density lipoprotein cholesterol levels were negatively related to baPWV. After adjusting for age, body mass index, smoking status, aspartate transaminase, alanine aminotransferase, plasma glucose, and estimated glomerular filtration rate, only TG levels were correlated with baPWV (β = 0.075). Conclusions Four lipid variates are associated with arterial stiffness, and TG levels are positively related to arterial stiffness, independent of cardiovascular risks and liver function.

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), which plays a crucial role in lipoprotein metabolism, has been also regarded as an important marker for atherosclerosis. Available evidence indicated that 2-h postchallenge plasma glucose (2-hPG) could be another biomarker for atherosclerosis. However, currently the association between circulating PCSK9 and 2-hPG remains unclear. Here, we explored this potential link in a Chinese Han population. Methods Totally, 600 Chinese Han subjects from Nanjing district, China, were enrolled for the 75-g oral glucose tolerance test (OGTT), and they included normal glucose tolerance (NGT, n = 200), impaired glucose regulation (IGR, n = 200), and type 2 diabetes (T2DM, n = 200). Anthropometric and biochemical determinations such as serum lipid measurements were made. A sandwich ELISA assay was performed to measure serum PCSK9 levels in all subjects. Results Serum PCSK9 concentrations were higher in IGR group (77.63 ± 28.14 ng/ml) and T2DM group (90.62 ± 39.96 ng/ml) than in NGT group (65.33 ± 32.68 ng/ml), and it was significantly higher in T2DM group than in IGR group (p