Risk/benefit trade-off of habitual physical activity and air pollution on mortality: A large-scale prospective analysis in the UK Biobank.

BACKGROUND: Previous observational studies have indicated associations of physical activity (PA) and air pollution with mortality. A few studies have evaluated air pollution and PA interactions for health. Still, the trade-off between the harmful effects of air pollution exposure and the protective effects of PA remains controversial and unclear. OBJECTIVE: This study aimed to investigate the joint association of air pollution and PA with mortality risks. METHODS: This prospective cohort study included 322,092 participants from 2006 to 2010 and followed up to 2021 in the UK Biobank study. The concentrations of air pollutants (2006-2010), including particulate matter (PM) with diameters <=2.5 mm (PM2.5), <=10 mm (PM10), and between 2.5 and 10 mm (PM2.5-10), and nitrogen oxides (NO2 and NOx) were obtained. Information on PA measured by the International Physical Activity Questionnaire short form (2006-2010) and wrist-worn accelerometer (2013-2015) were collected. All-cause and cause-specific mortalities were recorded. Cox proportional hazard models were used to investigate the associations of air pollution exposure and PA with mortality risks. The additive and multiplicative interactions were also examined. RESULTS: During a mean follow-up of 11.83 years, 16629 deaths were recorded. Compared with participants reporting low PA, higher PA was negatively associated with all-cause [hazard ratio (HR), 0.74; 95% CI, 0.71-0.78], cancer (HR, 0.85; 95% CI, 0.80-0.90), CVD (HR, 0.79; 95% CI, 0.71-0.87), and respiratory disease-specific mortality (HR, 0.51; 95% CI, 0.44-0.60). Exposure to PM2.5 (HR, 1.05; 95% CI, 1.00-1.09) and NOx (HR, 1.06; 95% CI, 1.02-1.10) was connected with increased all-cause mortality risk, and significant PM2.5-associated elevated risks for CVD mortality and NOx-associated elevated risks for respiratory disease mortality were observed. No obvious interaction between PA and PM2.5 or NOx exposure was detected. CONCLUSIONS: Our study provides additional evidence that higher PA and lower air pollutant levels are independently connected with reduced mortality risk. The benefits of PA are not significantly affected by long-term air pollution exposure, indicating PA can be recommended to prevent mortality regardless of air pollution levels. Our findings highlight the importance of public health policies and interventions facilitating PA and reducing air pollution in reducing mortality risks and maximizing health benefits. Future investigation is urgently needed to identify these findings in areas with severe air pollution conditions.

Nitrogen-Based Gas Molecule Adsorption on a ReSe2 Monolayer via Single-Atom Doping: A First-Principles Study.

Two-dimensional materials have shown immense promise for gas-sensing applications due to their remarkable surface-to-volume ratios and tunable chemical properties. However, despite their potential, the utilization of ReSe2 as a gas-sensing material for nitrogen-containing molecules, including NO2, NO, and NH3, has remained unexplored. The choice of doping atoms in ReSe2 plays a pivotal role in enhancing the gas adsorption and gas-sensing capabilities. Herein, the adsorption properties of nitrogen-containing gas molecules on metal and non-metal single-atom (Au, Pt, Ni, P, and S)-doped ReSe2 monolayers have been evaluated systematically via ab initio calculations based on density functional theory. The findings strongly suggest that intrinsic ReSe2 has better selectivity toward NO2 than toward NO and NH3. Moreover, our results provide compelling evidence that all of the dopants, with the exception of S, significantly enhance both the adsorption strength and charge transfer between ReSe2 and the investigated molecules. Notably, P-decorated ReSe2 showed the highest adsorption energy for NO2 and NO (-1.93 and -1.52 eV, respectively) with charge transfer above 0.5e, while Ni-decorated ReSe2 exhibited the highest adsorption energy for NH3 (-0.76 eV). In addition, on the basis of transition theory, we found that only Au-ReSe2 and Ni-ReSe2 can serve as reusable chemiresisitve gas sensors for reliable detection of NO and NH3, respectively. Hence, our findings indicate that gas-sensing applications can be significantly improved by utilizing a single-atom-doped ReSe2 monolayer.

The role of transcription factor FOXA1/C2/M1/O3/P1/Q1 in breast cancer.

Breast cancer is a common malignancy with the highest mortality rate among women worldwide. Its incidence is on the rise year after year, accounting for more than one-tenth of new cancers worldwide. Increasing evidence suggests that forkhead box (FOX) transcription factors play an important role in the occurrence and development of breast cancer. However, little is known about the relationship between the expression, prognostic value, function, and immune infiltration of FOX transcription factors in tumor microenvironment. We used bioinformatics to investigate expression and function of FOX factor in breast cancer. Our results revealed the expression levels of FOXA1 and FOXM1 were significantly higher in breast cancer tissues than in normal tissues. The high expression of mRNA in FOXA1 (P < .05), FOXM1 (P < .01), and FOXP1 (P < .05) groups was related to tumor stage. Survival analysis results showed that increased FOXP1 mRNA levels were significantly associated with overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) in all patients with breast cancer (P < .05). Patients with the FOXA1 high-expression group had better RFS and DMFS than the low-expression group (P < .05), while patients with FOXM1 high-expression group had worse RFS, OS, and DMFS than the low-expression group (P < .05). Meanwhile, mutation analysis showed that genetic alterations in FOX transcription factors were significantly associated with shorter OS and progression-free survival (P < .05), but not with disease-free survival (P = .710) in patients with breast cancer. FOXP1, FOXA1, and FOXM1 may be used as potential biomarkers to predict the prognosis of patients with breast cancer. Functional enrichment indicated that FOX was mainly involved in cell division, cell senescence, cell cycle, and prolactin signaling pathway. In patients with breast cancer, FOXC2 expression was negatively correlated with the infiltration of B cells and positively correlated with the infiltration of neutrophils and dendritic cells. However, FOXM1 was negatively correlated with the infiltration of CD8 + T cells and macrophages and positively correlated with the infiltration of neutrophils and dendritic cells. These findings provided novel insights into the screening of prognostic biomarkers of the FOX family in breast cancer and laid a foundation for further research on the immune infiltration of the FOX transcription factor family members in tumors.

LncRNA PART1 Attenuates Myocardial Ischemia-Reperfusion Injury by Regulating TFAP2C/DUSP5 Axis via miR-302a-3p.

BACKGROUND AND OBJECTIVES: Myocardial ischemia-reperfusion injury (MIRI) refers to the damage of cardiac function caused by restoration of blood flow perfusion in ischemic myocardium. However, long non-coding RNA prostate androgen regulated transcript 1 (PART1)'s role in MIRI remain unclear. METHODS: Immunofluorescence detected LC3 expression. Intermolecular relationships were verified by dual luciferase reporter assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and transferase-mediated dUTP nick-end labeling (TUNEL) assays analyzed cell viability and apoptosis. The release of lactate dehydrogenase was tested via enzyme-linked immunosorbent assay (ELISA). Left anterior descending coronary artery surgery induced a MIRI mouse model. Infarct area was detected by 2,3,5-triphenyltetrazolium chloride staining. Hematoxylin and eosin staining examined myocardial injury. ELISA evaluated myocardial marker (creatine kinase MB) level. RESULTS: PART1 was decreased in hypoxia/reoxygenation (H/R) induced AC16 cells and MIRI mice. PART1 upregulation attenuated the increased levels of Bax, beclin-1 and the ratio of LC3II/I, and enhanced the decrease of Bcl-2 and p62 expression in H/R-treated cells. PART1 upregulation alleviated H/R-triggered autophagy and apoptosis via miR-302a-3p. Mechanically, PART1 targeted miR-302a-3p to upregulate transcription factor activating enhancer-binding protein 2C (TFAP2C). TFAP2C silencing reversed the protected effects of miR-302a-3p inhibitor on H/R treated AC16 cells. We further established TFAP2C combined to dual-specificity phosphatase 5 (DUSP5) promoter and activated DUSP5. TFAP2C upregulation suppressed H/R-stimulated autophagy and apoptosis through upregulating DUSP5. Overexpressed PART1 reduced myocardial infarction area and attenuated MIRI in mice. CONCLUSION: PART1 improved the autophagy and apoptosis in H/R-exposed AC16 cells through miR-302a-3p/TFAP2C/DUSP5 axis, which might provide novel targets for MIRI treatment.

Gra-CRC-miRTar: The pre-trained nucleotide-to-graph neural networks to identify potential miRNA targets in colorectal cancer.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second deadliest cancer worldwide representing a major public health problem. In recent years, increasing evidence has shown that microRNA (miRNA) can control the expression of targeted human messenger RNA (mRNA) by reducing their abundance or translation, acting as oncogenes or tumor suppressors in various cancers, including CRC. Due to the significant up-regulation of oncogenic miRNAs in CRC, elucidating the underlying mechanism and identifying dysregulated miRNA targets may provide a basis for improving current therapeutic interventions. In this paper, we proposed Gra-CRC-miRTar, a pre-trained nucleotide-to-graph neural network framework, for identifying potential miRNA targets in CRC. Different from previous studies, we constructed two pre-trained models to encode RNA sequences and transformed them into de Bruijn graphs. We employed different graph neural networks to learn the latent representations. The embeddings generated from de Bruijn graphs were then fed into a Multilayer Perceptron (MLP) to perform the prediction tasks. Our extensive experiments show that Gra-CRC-miRTar achieves better performance than other deep learning algorithms and existing predictors. In addition, our analyses also successfully revealed 172 out of 201 functional interactions through experimentally validated miRNA-mRNA pairs in CRC. Collectively, our effort provides an accurate and efficient framework to identify potential miRNA targets in CRC, which can also be used to reveal miRNA target interactions in other malignancies, facilitating the development of novel therapeutics.

A green tea extract confection decreases circulating endotoxin and fasting glucose by improving gut barrier function but without affecting systemic inflammation: A double-blind, placebo-controlled randomized trial in healthy adults and adults with metabolic syndrome.

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P = .023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P < .0001) and γ-valerolactones (P = .0001). Fecal calprotectin (P = .029) and myeloperoxidase (P = .048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P = .043) but not sucralose/erythritol (P > .05) was decreased by GTE regardless of health status. No between-treatment differences (P > .05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P = .029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation.

METTL3 and METTL14-mediated N6-methyladenosine modification of SREBF2-AS1 facilitates hepatocellular carcinoma progression and sorafenib resistance through DNA demethylation of SREBF2.

As the most prevalent epitranscriptomic modification, N6-methyladenosine (m6A) shows important roles in a variety of diseases through regulating the processing, stability and translation of target RNAs. However, the potential contributions of m6A to RNA functions are unclear. Here, we identified a functional and prognosis-related m6A-modified RNA SREBF2-AS1 in hepatocellular carcinoma (HCC). The expression of SREBF2-AS1 and SREBF2 in HCC tissues and cells was measured by RT-qPCR. m6A modification level of SREBF2-AS1 was measured by methylated RNA immunoprecipitation assay. The roles of SREBF2-AS1 in HCC progression and sorafenib resistance were investigated by proliferation, apoptosis, migration, and cell viability assays. The regulatory mechanisms of SREBF2-AS1 on SREBF2 were investigated by Chromatin isolation by RNA purification, RNA immunoprecipitation, CUT&RUN, and bisulfite DNA sequencing assays. Our findings showed that the expression of SREBF2-AS1 was increased in HCC tissues and cells, and positively correlated with poor survival of HCC patients. m6A modification level of SREBF2-AS1 was also increased in HCC and positively correlated with poor prognosis of HCC patients. METTL3 and METTL14-induced m6A modification upregulated SREBF2-AS1 expression through increasing SREBF2-AS1 transcript stability. Functional assays showed that only m6A-modified, but not non-modified SREBF2-AS1 promoted HCC progression and sorafenib resistance. Mechanistic investigations revealed that m6A-modified SREBF2-AS1 bound and recruited m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1 to SREBF2 promoter, leading to DNA demethylation at SREBF2 promoter and the upregulation of SREBF2 transcription. Functional rescue assays showed that SREBF2 was the critical mediator of the oncogenic roles of SREBF2-AS1 in HCC. Together, this study showed that m6A-modified SREBF2-AS1 exerted oncogenic roles in HCC through inducing DNA demethylation and transcriptional activation of SREBF2, and suggested m6A-modified SREBF2-AS1 as a prognostic biomarker and therapeutic target for HCC.

Disulfiram: A novel repurposed drug for cancer therapy.

ABSTRACT: Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), an Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.

CTRP9 prevents atherosclerosis progression through changing autophagic status of macrophages by activating USP22 mediated-de-ubiquitination on Sirt1 in vitro.

BACKGROUND: Atherosclerosis (AS) is commonly regarded as a key driver accounted for the leading causes of morbidity and mortality among cardiovascular and cerebrovascular diseases. A growing body of evidence indicates that autophagy in macrophages involved in AS might be a potential therapeutic target. C1q/TNF-related protein 9 (CTRP9) has been proven to delay the progression of cardiovascular diseases. However, the relations between CTRP9 and Sirt1, as well as their effects on macrophages autophagy have not been fully explored. METHODS: Macrophages were differentiated from mononuclear cells collected from peripheral blood samples of healthy donors. The in vitro AS models were constructed by ox-LDL treatment. Cell viability was determined by CCK-8 assay. Immunofluorescence assay of LC3 was implemented for evaluating autophagy activity. Oil Red O staining was performed for lipid accumulation detection. ELISA, cholesterol concentration assay and cholesterol efflux analysis were conducted using commercial kits. Cycloheximide assay was implemented for revealing protein stability. RT-qPCR was used for mRNA expression detection, and western blotting was performed for protein level monitoring. RESULTS: CTRP9 attenuated impaired cell viability, autophagy inhibition and increased lipid accumulation induced by ox-LDL. Moreover, CTRP9 maintained Sirt1 protein level through enhancing its stability through de-ubiquitination, which was mediated by upregulated USP22 level. CRTP9 exerted its protective role in promoting autophagy and reducing lipid accumulation through the USP22/Sirt1 axis. CONCLUSION: Collectively, CTRP9 alleviates lipid accumulation and facilitated the macrophages autophagy by upregulating USP22 level and maintaining Sirt1 protein expression, thereby exerting a protective role in AS progression in vitro.

Dexmedetomidine Prevents Chronic Incisional Pain After Brain Tumor Resection: A Secondary Analysis of the Randomized Control Trial.

BACKGROUND: Dexmedetomidine was reported to reduce postoperative acute pain after neurosurgery. However, the efficacy of dexmedetomidine for preventing chronic incisional pain is uncertain. METHODS: This article is a secondary analysis of a randomized, double-blind, placebo-controlled trial. Eligible patients were randomly allocated to either the dexmedetomidine group or the placebo group. Patients assigned to the dexmedetomidine group were given a 0.6 µg kg -1 dexmedetomidine bolus followed by a 0.4 µg kg -1 h -1 maintenance dose until dural closure; placebo patients were given comparable amounts of normal saline. The primary end point was the incidence of incisional pain at 3 months after craniotomy evaluated by numerical rating scale scores and defined as any score >0. The secondary end points were postoperative acute pain scores, sleep quality, and Short-Form McGill Pain Questionnaire (SF-MPQ-2) at 3 months after craniotomy. RESULTS: From January 2021 to December 2021, a total of 252 patients were included in the final analysis: the dexmedetomidine group (n = 128) and the placebo group (n = 124). The incidence of chronic incisional pain was 23.4% (30 of 128) in the dexmedetomidine group versus 42.7% (53 of 124) in the placebo group (risk ratio, 0.55; 95% confidence interval, 0.38-0.80; P = .001). The overall severity of chronic incisional pain was mild in both groups. Patients in the dexmedetomidine group had lower acute pain severity on movement than those in the placebo group for the first 3 days after surgery (all adjusted P < .01). Sleep quality did not differ between groups. However, the SF-MPQ-2 total sensory ( P = .01) and neuropathic pain descriptor ( P = .023) scores in the dexmedetomidine group were lower than those in the placebo group. CONCLUSIONS: Prophylactic intraoperative dexmedetomidine infusion reduces the incidence of chronic incisional pain as well as acute pain score after elective brain tumor resections.

Intraoperative blood pressure and cardiac complications after aneurysmal subarachnoid hemorrhage: a retrospective cohort study.

BACKGROUND: Previous studies report that intraoperative hypotension worsens outcomes after aneurysmal subarachnoid hemorrhage (aSAH). However, the hypotensive harm threshold for major adverse cardiovascular events (MACE) remains unclear. METHODS: The authors included aSAH patients who had general anesthesia for aneurysmal clipping/coiling. MACE were defined by a composite of acute myocardial injury, acute myocardial infarction, and other cardiovascular complications identified by electrocardiogram and echocardiography. The authors initially used logistic regression and change-point analysis based on the second derivative to identify mean arterial pressure (MAP) of 75 mmHg as the harm threshold. Thereafter, our major exposure was MAP below 75 mmHg characterized by area, duration, and time-weighted average. The area below 75 mmHg represents the severity and duration of exposure and was defined as the sum of all areas below a specified threshold using the trapezoid rule. Time-weighted average MAP was derived by dividing area below the threshold by the duration of anesthesia. All analyses were adjusted for baseline risk factors including age greater than 70 years, female sex, severity of intracerebral hemorrhage, history of cardiovascular disease, and preoperative elevated myocardial enzymes. RESULTS: Among 1029 patients enrolled, 254 (25%) developed postoperative MACE. Patients who experienced MACE were slightly older (59±11 vs. 54±11 years), were slightly more often women (69 vs. 58%), and had a higher prevalence of cardiovascular history (65 vs. 47%). Adjusted cardiovascular risk increased nearly linearly over the entire range of observed MAP. However, there was a slight inflexion at MAP of 75 mmHg. MACE was significantly associated with area [adjusted odds ratios (aOR) 1.004 per 10 mmHg.min, 95% CI: 1.001-1.007, P =0.002), duration (aOR 1.031 per 10 min, 95% CI: 1.009-1.054, P =0.006), and time-weighted average (aOR 3.516 per 10 mmHg, 95% CI: 1.818-6.801, P <0.001) of MAP less than 75 mmHg. CONCLUSIONS: Lower blood pressures were associated with cardiovascular complications over the entire observed range, but worsened when MAP was less than 75 mmHg. Pending trial data to establish causality, it may be prudent to keep MAP above 75 mmHg in patients having surgical aSAH repairs to reduce the risk of MACE.

Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

Intravenous tranexamic acid for intracerebral meningioma resections: A randomized, parallel-group, non-inferiority trial.

STUDY OBJECTIVES: Tranexamic acid (TXA) is an antifibrinolytic that is widely used to reduce surgical bleeding. However, TXA occasionally causes seizures and the risk might be especially great after neurosurgery. We therefore tested the hypothesis that TXA does not meaningfully increase the risk of postoperative seizures within 7 days after intracranial tumor resections. DESIGN: Randomized, double-blind, placebo-controlled, non-inferiority trial. SETTING: Beijing Tiantan Hospital, Capital Medical University. PATIENTS: 600 patients undergoing supratentorial meningioma resection were included from October 2020 to August 2022. INTERVENTIONS: Patients were randomly assigned to a single dose of 20 mg/kg of TXA after induction (n = 300) or to the same volume of normal saline (n = 300). MEASUREMENT: The primary outcome was postoperative seizures occurring within 7 days after surgery, analyzed in both the intention-to-treat and per-protocol populations. Non-inferiority was defined by an upper limit of the 95% confidence interval for the absolute difference being <5.5%. Secondary outcomes included incidence of non-epileptic complication within 7 days, changes in hemoglobin concentration, estimated intraoperative blood loss. Post hoc analyses included the types and timing of seizures, oozing assessment, and a sensitivity analysis for the primary outcome in patients with pathologic diagnosis of meningioma. MAIN RESULTS: All 600 enrolled patients adhered to the protocol and completed the follow-up for the primary outcome. Postoperative seizures occurred in 11 of 300 (3.7%) of patients randomized to normal saline and 13 of 300 (4.3%) patients assigned to tranexamic acid (mean risk difference, 0.7%; 1-sided 97.5% CI, -∞ to 4.3%; P = 0.001 for noninferiority). No significant differences were observed in any secondary outcome. Post hoc analysis indicated similar amounts of oozing, calculated blood loss, recurrent seizures, and timing of seizures. CONCLUSION: Among patients having supratentorial meningioma resection, a single intraoperative dose of TXA did not significantly reduce bleeding and was non-inferior with respect to postoperative seizures after surgery. REGISTRY INFORMATION: This trial was registered at clinicaltrials.gov (NCT04595786) on October 22, 2020, by Dr.Yuming Peng.

Metabolomics-based investigation of the chemical composition changes in Mongolian medicinal plant Euphorbia pekinensis before and after processing with Chebulae Fructus.

Euphorbia pekinensis (EP), known for its diuretic properties, is clinically utilized for treating conditions such as edema and malignant tumors. However, in its raw form, Euphorbia pekinensis is toxic, and oral administration of this crude medicine can lead to gastrointestinal stimulation, resulting in abdominal pain and diarrhea. In Mongolian medicine's ethnomedicinal system, a distinctive processing method called "Chebulae Fructus processing" is employed. Chebulae Fructus is used to mitigate the toxicity of EP and alleviate its purgative effects. Nevertheless, the detoxification mechanism associated with this processing method remains unexplored. It is hypothesized that processing with Chebulae Fructus may alter the chemical composition of EP, and the residual components of Chebulae Fructus within processed Chinese medicine might exhibit pharmacological antagonistic effects, thereby achieving the purpose of processing and reducing toxicity. To investigate this further, a combination of UPLC-QTOF-MS-based metabolomics technology and multivariate statistical analysis was employed to analyze and compare the chemical composition of raw and processed EP. Differential variables contributing to group separation were identified based on specific criteria, including VIP (Variable Importance in Projection) values of ≥ 1 in PLS-DA models, p-values < 0.05, and fold changes (FC) > 1.2 or < 0.8. The resulting differentially expressed features were then identified through database matching, literature review, or manual annotation. In total, 47 components were identified from the PEP samples in both positive and negative ionization modes, primarily belonging to flavonoids, terpenoids, organic acids, glycosides, and fatty acids. Among the raw EP group and PEP S4 group, 10 differential compounds were identified. Notably, one toxic terpene and one phenylpropanoid from EP were downregulated, while two bioactive components from Chebulae Fructus were upregulated in the processed group. The possible conversion reactions of these two processing Q-markers were also elucidated. The characteristic processing with Chebulae Fructus resulted in a change in the composition of this Mongolian medicine EP. Furthermore, this study provides a scientific foundation for optimizing the processing technology of EP and offers insights into the processing of other ethnomedicines with toxic properties.

Incorporating environmental capacity considerations to prioritize control factors for the management of heavy metals in soil.

Heavy metals (HMs) pollution threatens food security and human health. While previous studies have evaluated source-oriented health risk assessments, a comprehensive integration of environmental capacity risk assessments with pollution source analysis to prioritize control factors for soil contamination is still lacking. Herein, we collected 837 surface soil samples from agricultural land in the Nansha District of China in 2019. We developed an improved integrated assessment model to analyze the pollution sources, health risks, and environmental capacities of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. The model graded pollution source impact on environmental capacity risk to prioritize control measures for soil HMs. All HMs except Pb exceeded background values and were sourced primarily from natural, transportation, and industrial activities (31.26%). Approximately 98.92% (children), 97.87% (adult females), and 97.41% (adult males) of carcinogenic values exceeded the acceptable threshold of 1E-6. HM pollution was classified as medium capacity (3.41 kg/hm2) with mild risk (PI = 0.52). Mixed sources of natural backgrounds, transportation, and industrial sources were identified as priority sources, and As a priority element. These findings will help prioritize control factors for soil HMs and direct resources to the most critical pollutants and sources of contamination, particularly when resources are limited.

Bioactivities and Mechanisms of Action of Diphyllin and Its Derivatives: A Comprehensive Systematic Review.

Natural products are treasure houses for modern drug discovery. Diphyllin is a natural arylnaphthalene lignan lactone isolated from the leaf of Astilboides tabularis. Studies have found that it possesses plenty of bioactivity characteristics. In this paper, we reviewed the structure, bioactivity, and mechanism of action of diphyllin and its derivatives. The references were obtained from PubMed, Web of Science, and Science Direct databases up to August 2023. Papers without a bio-evaluation were excluded. Diphyllin and its derivatives have demonstrated V-ATPase inhibition, anti-tumor, anti-virus, anti-biofilm, anti-inflammatory, and anti-oxidant activities. The most studied activities of diphyllin and its derivatives are V-ATPase inhibition, anti-tumor activities, and anti-virus activities. Furthermore, V-ATPase inhibition activity is the mechanism of many bioactivities, including anti-tumor, anti-virus, and anti-inflammatory activities. We also found that the galactosylated modification of diphyllin is a common phenomenon in plants, and therefore, galactosylated modification is applied by researchers in the laboratory to obtain more excellent diphyllin derivatives. This review will provide useful information for the development of diphyllin-based anti-tumor and anti-virus compounds.

m6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis.

N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic RNAs. Although the important roles of m6A in RNA fate have been revealed, the potential contribution of m6A to RNA function in various diseases, including hepatocellular carcinoma (HCC), is still unclear. In this study, we identified a novel m6A-modified RNA AC026356.1. We found that AC026356.1 was increased in HCC tissues and cell lines. High expression of AC026356.1 was correlated with poor survival of HCC patients. m6A modification level of AC026356.1 was also increased in HCC and more significantly correlated with poor survival of HCC patients. Functional assays showed that m6A-modified AC026356.1 promoted HCC cellular proliferation, migration, and liver metastasis. Gene set enrichment analysis showed that AC026356.1 activated IL11/STAT3 signaling. Mechanistic investigation showed that m6A-modified AC026356.1 bound to IGF2BP1. The interaction between m6A-modified AC026356.1 and IGF2BP1 promoted the binding of IL11 mRNA to IGF2BP1, leading to increased IL11 mRNA stability and IL11 secretion. Functional rescue assays showed that depletion of IL11 reversed the oncogenic roles of AC026356.1. These findings revealed the potential influences of m6A modification on RNA biological functions and suggested that targeting m6A modification may be a novel strategy for HCC treatment.

Human papillomavirus infections among women with cervical lesions and cervical cancer in Yueyang, China: a cross-sectional study of 3674 women from 2019 to 2022.

PURPOSE: To investigate the distribution of the incidence and genotypes of human papillomavirus (HPV) among women with cervical cancer (CC) and precancerous cervical lesions in Yueyang City, China, to develop prevention and control strategies for CC. METHODS: A total of 3674 patients with cervical lesions and cervical cancer who attended 7 hospitals in Yueyang City between September 2019 and September 2022 were included. They included 1910 cervical intraepithelial neoplasia (CIN) I, 718 CIN II, 576 CIN II and 470 CC, respectively. The HPV genotyping of the above patients was detected by Real time-PCR in the laboratory department of each hospital. RESULTS: The total HPV prevalence was 74.69% (95% CI 73.28-76.09%) in 3674 patients. The incidence of high- and low-risk HPV was 73.46% and 7.21%, respectively. The prevalence of HPV in CIN I, CIN II, CIN III, and invasive CC (ICC) groups was 66.65% (1273/1910, 95% CI 64.53-68.77%), 80.78% (580/718, 95% CI 77.89-83.67%), 83.88% (483/576, 95% CI 80.84-86.87%), and 86.81% (408/470, 95% CI 83.74-89.88%), respectively. The top three HPV subtypes in ICC are HPV16, HPV52, and HPV58. The prevalence of HPV 16 increased with increasing disease severity, with this genotype being present in 12.57%, 20.89%, 36.98%, and 50.85% of CIN I, CIN II, CIN III, and ICC cases, respectively (p < 0.001). Single HPV infection was predominant in cervical lesions, with a prevalence of 48.50% (95% CI 46.89-50.12%). The HPV prevalence varied by age, being highest among women with ICC, CIN I, CIN II and CIN III aged ≥ 60 years, 50-59 years, 40-49 years, and 40-49 years, respectively. CONCLUSION: The prevalence of HPV in patients with cervical lesions in Yueyang City was very high, with HPV 16, 52, 58, 53, and 51 being the five most common HPV genotypes in patients with cervical lesions.

MoTe2/InN van der Waals heterostructures for gas sensors: a DFT study.

Vertical van der Waals (vdW) heterostructures have shown potential for gas sensing owing to their remarkable sensitivity. However, the optimization process for achieving the best gas sensing performance is complicated by the heterostructure's reliance on both physical and electrical characteristics. This study employs density functional theory (DFT) to analyse the structural and electronic parameters of a MoTe2/InN vdW heterostructure. The findings of this study indicate that the vdW heterostructure has a type-II band alignment with higher adsorption energy towards NH3, NO2, and SO2 than the individual monolayers. In specific, the heterostructure is well suited for NO2 detection but has limitations in reliably detecting NH3 and SO2 due to longer recovery times. We find significant hybridization between the adsorbate and interacting surfaces' orbitals and a notable presence of NO2 molecular orbitals in proximity to the Fermi level. Additionally, dielectric and work function modulations offer a viable means to develop optical-based gas sensors that can selectively detect NO2. Our research provides valuable insights into vdW heterostructure design for high-performance gas sensors.

Effect of dexmedetomidine on postoperative delirium in patients undergoing awake craniotomies: study protocol of a randomized controlled trial.

INTRODUCTION: Postoperative delirium (POD) is a common complication, and it has a high incidence in neurosurgery patients. Awake craniotomy (AC) has been widely performed in patients with glioma in eloquent and motor areas. Most of the surgical procedure is frontotemporal craniotomy, and the operation duration has been getting longer. Patients undergoing AC are high-risk populations for POD. Dexmedetomidine (Dex) administration perioperatively might help to reduce the incidence of POD. The purpose of this study is to investigate the effect of Dex on POD in patients undergoing AC. METHODS: The study is a prospective, single-center, double-blinded, paralleled-group, randomized controlled trial. Patients undergoing elective AC will be randomly assigned to the Dex group and the control group. Ten minutes before urethral catheterization, patients in the Dex group will be administered with a continuous infusion at a rate of 0.2 µg/kg/h until the end of dural closure. In the control group, patients will receive an identical volume of normal saline in the same setting. The primary outcome will be the cumulative incidence and severity of POD. It will be performed by using the confusion assessment method in the first 5 consecutive days after surgery. Secondary outcomes include quality of intraoperative awareness, stimulus intensity of neurological examination, pain severity, quality of recovery and sleep, and safety outcomes. DISCUSSION: This study is to investigate whether the application of Dex could prevent POD in patients after undergoing AC and will provide strong evidence-based clinical practice on the impact of intraoperative interventions on preventing POD in AC patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05195034. Registered on January 18, 2022.