Nomogram based on liver stiffness and spleen area with ultrasound for posthepatectomy liver failure: A multicenter study.

BACKGROUND: Liver stiffness (LS) measurement with two-dimensional shear wave elastography (2D-SWE) correlates with the degree of liver fibrosis and thus indirectly reflects liver function reserve. The size of the spleen increases due to tissue proliferation, fibrosis, and portal vein congestion, which can indirectly reflect the situation of liver fibrosis/cirrhosis. It was reported that the size of the spleen was related to posthepatectomy liver failure (PHLF). So far, there has been no study combining 2D-SWE measurements of LS with spleen size to predict PHLF. This prospective study aimed to investigate the utility of 2D-SWE assessing LS and spleen area (SPA) for the prediction of PHLF in hepatocellular carcinoma (HCC) patients and to develop a risk prediction model. AIM: To investigate the utility of 2D-SWE assessing LS and SPA for the prediction of PHLF in HCC patients and to develop a risk prediction model. METHODS: This was a multicenter observational study prospectively analyzing patients who underwent hepatectomy from October 2020 to March 2022. Within 1 wk before partial hepatectomy, ultrasound examination was performed to measure LS and SPA, and blood was drawn to evaluate the patient's liver function and other conditions. Least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis was applied to identify independent predictors of PHLF and develop a nomogram. Nomogram performance was validated further. The diagnostic performance of the nomogram was evaluated with receiver operating characteristic curve compared with the conventional models, including the model for end-stage liver disease (MELD) score and the albumin-bilirubin (ALBI) score. RESULTS: A total of 562 HCC patients undergoing hepatectomy (500 in the training cohort and 62 in the validation cohort) were enrolled in this study. The independent predictors of PHLF were LS, SPA, range of resection, blood loss, international normalized ratio, and total bilirubin. Better diagnostic performance of the nomogram was obtained in the training [area under receiver operating characteristic curve (AUC): 0.833; 95% confidence interval (95%CI): 0.792-0.873; sensitivity: 83.1%; specificity: 73.5%] and validation (AUC: 0.802; 95%CI: 0.684-0.920; sensitivity: 95.5%; specificity: 52.5%) cohorts compared with the MELD score and the ALBI score. CONCLUSION: This PHLF nomogram, mainly based on LS by 2D-SWE and SPA, was useful in predicting PHLF in HCC patients and presented better than MELD score and ALBI score.

FGF4 ameliorates the liver inflammation by reducing M1 macrophage polarization in experimental autoimmune hepatitis.

BACKGROUND: The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH. METHODS: We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages. RESULTS: We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation. CONCLUSION: We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K-AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

Core biomarkers analysis benefit for diagnosis on human intrahepatic cholestasis of pregnancy.

BACKGROUND: The pregnant women with intrahepatic cholestasis were at high risk of fetal distress, preterm birth and unexpected stillbirth. Intrahepatic cholestasis of pregnancy (ICP) was mainly caused by disorder of bile acid metabolism, whereas the specific mechanism was obscure. METHODS: We performed proteomics analysis of 10 ICP specimens and 10 placenta specimens from patients without ICP through data-independent acquisition (DIA) technique to disclose differentially expressed proteins. We executed metabolomic analysis of 30 ICP specimens and 30 placenta specimens from patients without ICP through UPLC-MS/MS to identify differentially expressed metabolites. Enrichment and correlation analysis was used to obtain the direct molecular insights of ICP development. The ICP rat models were constructed to validate pathological features. RESULTS: The heatmap of proteomics analysis showed the top 30 up-regulated and 30 down-regulated proteins. The metabolomic analysis revealed 20 richer and 4 less abundant metabolites in ICP samples compared with placenta specimens from patients without ICP, and enrichment pathways by these metabolites included primary bile acid biosynthesis, cholesterol metabolism, bile secretion, nicotinate and nicotinamide metabolism, purine metabolism and metabolic pathways. Combined analysis of multiple omics results demonstrated that bile acids such as Glycohyocholic acid, Glycine deoxycholic acid, beta-Muricholic acid, Noncholic acid, cholic acid, Gamma-Mercholic Acid, alpha-Muricholic acid and Glycochenodeoxycholic Aicd were significantly associated with the expression of GLRX3, MYL1, MYH7, PGGT1B, ACTG1, SP3, LACTB2, C2CD5, APBB2, IPO9, MYH2, PPP3CC, PIN1, BLOC1S1, DNAJC7, RASAL2 and ATCN3 etc. The core protein ACAT2 was involved in lipid metabolic process and animal model showed that ACAT2 was up-regulated in placenta and liver of pregnant rats and fetal rats. The neonates had low birth weight and Safranin O-Fast green FCF staining of animal models showed that poor osteogenic and chondrogenic differentiation of fetal rats. CONCLUSION: Multiple metabolites-alpha-Muricholic acid, beta-Muricholic acid, Glycine deoxycholic acid and Glycochenodeoxycholic Acid etc. were perfect biomarkers to predict occurrence of ICP. Bile acids were significantly associated with varieties of protein expression and these proteins were differentially expressed in ICP samples. Our study provided several biomarkers for ICP detection and potential therapeutic targets for ICP development.

Structure-Based Drug Design of 2-Amino-[1,1'-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of CCNE1-Amplified Breast Cancer.

CCNE1 amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for CCNE1 amplification holds promise for the treatment of CCNE1-amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound 8ma exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the CCNE1-amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.

Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Mussel Foot Protein-Inspired Adhesive Tapes with Tunable Underwater Adhesion.

Instant and strong adhesion to underwater adherends is a big challenge due to the continuous interference of water. Mussel foot protein-bioinspired catechol-based adhesives have garnered great interest in addressing this issue. Herein, a novel self-made catecholic compound with a long aliphatic chain was utilized to prepare thin (∼0.07 mm) and optically transparent (>80%) wet/underwater adhesive tapes by UV-initiated polymerization. Its adhesion activity was water-triggered, fast (<1 min), and strong (adhesion strength to porcine skin: ∼1.99 MPa; interfacial toughness: ∼610 J/m2, burst pressure: ∼1950 mmHg). The effect of the catechol/phenol group and positively charged moiety on the wet/underwater adhesion to abiotic/biotic substrates was investigated. On the wet/underwater adherends, the tape with catechol groups presented much higher interfacial toughness, adhesion strength, and burst pressure than the analogous tape with phenol groups. The tape with both the catechol group and cationic polyelectrolyte chitosan had a more impressive improvement in its adhesion to wet/underwater biological tissues than to abiotic substrates. Therefore, catechol and a positive moiety in the tape would synergistically enhance its wet/underwater adhesion to various substrates, especially to biological tissues. The instant, strong, and noncytotoxic tape may provide applications in underwater adhesion for sealing and wound closure.

Exosomal miR-486 derived from bone marrow mesenchymal stem cells promotes angiogenesis following cerebral ischemic injury by regulating the PTEN/Akt pathway.

Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have been shown to promote angiogenesis after ischemic stroke, in which microRNAs (miRs) are believed to play an important role in exosome-mediated therapeutic effects, though the mechanism is still not clear. In this study, a series of molecular biological and cellular assays, both in vitro and in vivo, were performed to elucidate the role of exosomal miR-486 in angiogenesis following cerebral ischemic and its molecular mechanisms. Our results revealed that BMSC-Exos significantly improved neurological function and increased microvessel density in ischemic stroke rats. In vitro assays showed that BMSC-Exos promoted the proliferation, migration, and tube formation ability of oxygen-glucose deprivation/reoxygenation (OGD/R) injured rat brain microvascular endothelial cells (RBMECs). Importantly, BMSC-Exos increased the expression of miR-486 and phosphorylated protein kinase B (p-Akt) and down-regulated the protein level of phosphatase and tensin homolog (PTEN) in vivo and in vitro. Mechanistic studies demonstrated that transfection with miR-486 mimic enhanced RBMECs angiogenesis and increased p-Akt expression, while inhibited PTEN expression. On the other hand, the miR-486 inhibitor induced an opposite effect, which could be blocked by PTEN siRNA. It was thus concluded that exosomal miR-486 from BMSCs may enhance the functional recovery by promoting angiogenesis following cerebral ischemic injury, which might be related to its regulation of the PTEN/Akt pathway.

Preoperative Ultrasound Radomics to Predict Posthepatectomy Liver Failure in Patients With Hepatocellular Carcinoma.

PURPOSE: Posthepatectomy liver failure (PHLF) is a major cause of postoperative mortality in hepatocellular carcinoma (HCC) patients. The study aimed to develop a method based on the two-dimensional shear wave elastography and clinical data to evaluate the risk of PHLF in HCC patients with chronic hepatitis B. METHODS: This multicenter study proposed a deep learning model (PHLF-Net) incorporating dual-modal ultrasound features and clinical indicators to predict the PHLF risk. The datasets were divided into a training cohort, an internal validation cohort, an internal independent testing cohort, and three external independent testing cohorts. Based on ResNet50 pretrained on ImageNet, PHLF-Net used a progressive training strategy with images of varying granularity and incorporated conventional B-mode and elastography images and clinical indicators related to liver reserve function. RESULTS: In total, 532 HCC patients who underwent hepatectomy at five hospitals were enrolled. PHLF occurred in 147 patients (27.6%, 147/532). The PHLF-Net combining dual-modal ultrasound and clinical indicators demonstrated high effectiveness for predicting PHLF, with AUCs of 0.957 and 0.923 in the internal validation and testing sets, and AUCs of 0.950, 0.860, and 1.000 in the other three independent external testing sets. The performance of PHLF-Net outperformed models of single- and dual-modal US. CONCLUSIONS: Preoperative ultrasound imaging combining clinical indicators can effectively predict the PHLF probability in patients with HCC. In the internal and external validation sets, PHLF-Net demonstrated its usefulness in predicting PHLF.

Study on the impact of comprehensive geriatric assessment on anxiety and depression in chronic obstructive pulmonary disease patients.

BACKGROUND: Psychological factors such as anxiety and depression will not only aggravate the symptoms of chronic obstructive pulmonary disease (COPD) patients and reduce the quality of life of patients, but also affect the treatment effect and long-term prognosis. Therefore, it is of great significance to explore the clinical application of senile comprehensive assessment in the treatment of COPD and its influence on psychological factors such as anxiety and depression. AIM: To explore the clinical application of comprehensive geriatric assessment in COPD care and its impact on anxiety and depression in elderly patents. METHODS: In this retrospective study, 60 patients with COPD who were hospitalized in our hospital from 2019 to 2020 were randomly divided into two groups with 30 patients in each group. The control group was given routine nursing, and the observation group was given comprehensive assessment. Clinical symptoms, quality of life [COPD assessment test (CAT) score], anxiety and depression Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) were compared between the two groups. RESULTS: CAT scores in the observation group decreased from an average of 24.5 points at admission to an average of 18.3 points at discharge, and in the control group from an average of 24.7 points at admission to an average of 18.3 points at discharge. The average score was 22.1 (P < 0.05). In the observation group, HAMA scores decreased from 14.2 points at admission to 8.6 points at discharge, and HAMD scores decreased from 13.8 points at admission to 7.4 points at discharge. The mean HAMD scores in the control group decreased from an average of 14.5 at admission to an average of 12.3 at discharge, and from an average of 14.1 at admission to an average of 11.8 at discharge. CONCLUSION: The application of comprehensive geriatric assessment in COPD care has a significant effect on improving patients' clinical symptoms and quality of life, and can effectively reduce patients' anxiety and depression.

Study on factors influencing carbon dioxide emissions and carbon peak heterogenous pathways in Chinese provinces.

Implementing a Carbon Peak Action Plan at the regional level requires comprehensive consideration of the developmental heterogeneity among different provinces, which is an effective pathway for China to realize the goal of carbon peak by 2030. However, there is currently no clear provincial roadmap for carbon peak, and existing studies on carbon peak pathways inadequately address provincial heterogeneity. Therefore, this paper employs the Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) model to decompose assess 8 factors influencing carbon emissions of 30 provinces. According to scenario analysis, the paper explores the differentiated pathways for provincial carbon peaks based on policy expectation indicators (including population, economy, and urbanization rate) and comprises policy control indicators (including the energy structure, energy efficiency, industrial structure, transportation structure, and innovation input). The results indicate that population, per capita GDP, urbanization rate, and innovation input are the primary factors for influencing (negatively) the growth of carbon emissions. In contrast, the optimization and upgrading of the industrial structure, energy intensity, energy structure, and transportation structure have mitigating effects on carbon emissions, especially for the first two factors. The forecasting results reveal that robust regulations of the energy and industry can effectively accelerate carbon peak at a reduced magnitude. If developed at BAU, China cannot achieve carbon peak by 2030, continuing an upward trend. However, by maximizing the adjustment strength of energy and industrial transformation within the scope of provincial capabilities, China could achieve carbon peak as early as 2025, with a peak of 12.069 billion tons. In this scenario, 24 provinces could achieve carbon peak before 2030. Overall, this study suggests the feasibility of differentiated pathway to achieve carbon peaks in China, exploring the carbon peak potential and paths of 30 provinces, and identifying provinces where carbon peak is more challenging. It also provides a reference for the design of carbon peak roadmaps at both provincial and national levels and offers targeted recommendations for the implementation of differentiated policy strategies for the government.

Methyl-Sensitive Amplification Polymorphism (MSAP) Analysis Provides Insights into the DNA Methylation Changes Underlying Adaptation to Low Temperature of Brassica rapa L.

BACKGROUND: DNA methylation can change rapidly to regulate the expression of stress-responsive genes. Previous studies have shown that there are significant differences in the cold resistance of winter rapeseed (Brassica rapa L.) after being domesticated in different selection environments; however, little is known about the epigenetic regulatory mechanisms of its cold resistance formation. METHODS: Four winter rapeseed materials ('CT-2360', 'MXW-1', '2018-FJT', and 'DT-7') domesticated in different environments were selected to analyze the DNA methylation level and pattern changes under low temperature using methylation-sensitive amplified polymorphism technology with 60 primer pairs. RESULTS: A total of 18 pairs of primers with good polymorphism were screened, and 1426 clear bands were amplified, with 594 methylation sites, accounting for 41.65% of the total amplified bands. The total methylation ratios of the four materials were reduced after low-temperature treatment, in which the DNA methylation level of 'CT-2360' was higher than that of the other three materials; the analysis of methylation patterns revealed that the degree of demethylation was higher than that of methylation in 'MXW-1', '2018-FJT', and 'DT-7', which were 22.99%, 19.77%, and 24.35%, respectively, and that the methylation events in 'CT-2360' were predominantly dominant at 22.95%. Fifty-three polymorphic methylated DNA fragments were randomly selected and further analyzed, and twenty-nine of the cloned fragments were homologous to genes with known functions. The candidate genes VQ22 and LOC103871127 verified the existence of different expressive patterns before and after low-temperature treatment. CONCLUSIONS: Our work implies the critical role of DNA methylation in the formation of cold resistance in winter rapeseed. These results provide a comprehensive insight into the adaptation epigenetic regulatory mechanism of Brassica rapa L. to low temperature, and the identified differentially methylated genes can also be used as important genetic resources for the multilateral breeding of winter-resistant varieties.

Research on The Status Quo and Influencing Factors of Knowledge and Practice of Disaster Emergency Rescue of Nurses in Grade A Hospitals.

Context: Man-made disasters and natural disasters bring huge losses to human life and property. High-quality nursing teams play an important role in reducing casualty and disability rates in disaster areas, reducing the prognosis of the injured, accelerating community recovery and even promoting social rehabilitation. This work aimed to analyze the current situation and influencing factors of disaster emergency rescue (DER) of nurses in Hunan Province by surveying their knowledge, attitude, and practice of DER in Grade A hospitals. Methods: 1260 nurses working in 13 Grade A hospitals in Hunan Province from March to October 2022 were selected as subjects by a random sampling method and conducted by a questionnaire survey. The general data of the subjects were collected by "behaviors", forming the "nurses' knowledge, attitude, and practice questionnaire, and their DER knowledge, attitude and behavior were evaluated. Results: 1260 questionnaires were distributed, and 1,256 were effectively received, with a recovery rate of 99.68%. The total score of DER-related knowledge of 1.256 investigators was 136.82 ± 9.73 points. Among them, the highest and lowest scores were observed in the Triage (26.79 ± 2.09 points) and the sanitary and anti-epidemic (17.97 ± 1.28 points). The scores of DER attitude of 1256 respondents were close, which were arranged as about 3.87 ± 0.39 (with a range of 4.34 ~ 4.20). 1,256 investigators expressed the highest score in participating in the DER-related courses (4.93 ± 0.34 points) and the lowest score in participating in the on-site DER (2.01 ± 0.13 points). The results showed that they were correlated with gender, educational background, working years, department, and out-of-hospital emergency rescue experience (P ≤ .05), but not with age. The scores of DER-related knowledge and behaviors of hospital nurses were higher in men than in women. The higher the education, the higher the score, and the more the working years. Emergency and ICU nurses scored higher than those in other general departments. In addition, nurses with out-of-hospital emergency rescue experience scored higher than those without. Conclusion: The overall DER-related knowledge, attitude, and practice of hospital nurses is not high. Nursing managers should incorporate disaster nursing into emergency rescue nurses' training, strengthen clinical nurses' training and exercise in DER-related knowledge, pay special attention to DER drills and practices, and provide reasonable and correct DER guidance. Furthermore, it should cultivate the noble social citizenship qualities of clinical nursing nurses, such as the sense of mission to save the dying and heal the injured, the sense of satisfaction in realizing self-worth, and the sense of social responsibility. In addition, it is suggested that a reasonable incentive and reward system be established to encourage hospital nurses to participate in the DER. Due to the limitations of this study, the sample size can be expanded and included in the nurse interview considered in the future to supplement the survey data and further study and analyze nurses' rescue mentality, cognitive influencing factors, and intervention measures to provide more reference for human resource reserve and management of disaster rescue care.

Amphiphilic Janus cotton gauze with enhanced moisture management and blood coagulation for rapid hemostasis and wound healing.

Cotton gauze is commonly used in initial emergency care. However, its high hydrophilicity and limited clotting capacity can lead to the excessive absorption of blood, resulting in unnecessary blood loss. Herein, an amphiphilic Janus cotton gauze with excellent moisture management and enhanced blood coagulation has been developed via in situ generating bioactive glass (BG) onto the cotton gauze (CG), and then attaching cardanol (CA) onto one side of the BG-loaded CG (CG@BG) via click reaction. The Janus gauze (CA-CG@BG) has asymmetric wetting properties with a hydrophilic side (CA-CG@BGHL) and a hydrophobic side (HBCA-CG@BG). When applied to hemostatic, the porous and active BG on CA-CG@BGHL can rapidly initiate coagulation cascade to form a robust thrombus. CA on HBCA-CG@BG can entangled with each other, creating a hydrophobic barrier that prevents blood from flowing out. The hemostatic performance of CA-CG@BG is superior to that of CG in both rats and pigs. Interestingly, CA-CG@BG possesses unidirectional exudate removal. When applied to wound healing, the exudate can penetrate the hydrophobic HBCA-CG@BG to the hydrophilic CA-CG@BGHL, resulting in faster wound healing than CG. CA-CG@BG exhibits excellent cytocompatibility and hemocompatibility. This unique Janus dressing shows promise as a potential material for clinical applications in the future.

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

Effect of Enterostomal Therapist-Led Visual Health Education Combined with Peer Education on the Self-Nursing Ability, Quality of Life and Peristomial Complications in Patients with a Permanent Colostomy.

Objective: This study aimed to analyse the impact of enterostomal therapist-led visual health education combined with peer education on the postoperative self-nursing ability, quality of life and peristomial complications in patients with a permanent colostomy. Methods: Patients with a permanent colostomy admitted to Second Hospital of Hebei Medical University between March 2021 and March 2023 were selected and divided into the study group (60 patients) and the control group (60 patients). Enterostomal therapist-led visual health education combined with peer education was adopted in the study group, and regular education was adopted in the control group. The clinical effects between the two groups were compared. Results: Repeated measurement analysis of variance showed that the two educational methods had different effects on the quality of life (Ftreatment = 342.734, p < 0.001), self-nursing ability (Ftreatment = 256.321, p < 0.001), adaptability (Ftreatment = 321.734, p < 0.001) of patients with a permanent colostomy. After the 3-month intervention, the differences in all aspects of the quality of life, self-nursing ability and adaptability between the two groups were statistically significant, and the score of the study group was higher than that of the control group (p < 0.05). Compared with the control group, the study group had a lower incidence of the five complications (p < 0.05) and higher nursing satisfaction (Z = -2.968, p < 0.05). Conclusion: Enterostomal therapist-led visual health education combined with peer education can improve the quality of life of patients with a permanent colostomy, improve their positive mood, reduce their negative mood, improve their adaptability to the stoma, reduce complications and improve their daily living conditions. In the future, the clinical application of visual health education and peer education in patients with permanent colostomy should be increased.

Postprandial Plasma Glucose between 4 and 7.9 h May Be a Potential Diagnostic Marker for Diabetes.

Postprandial glucose levels between 4 and 7.9 h (PPG4-7.9h) correlate with mortality from various diseases, including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4-7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG4-7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG4-7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG4-7.9h predicted using this model. A receiver operating characteristic curve analysis showed that predicted PPG4-7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. A simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG4-7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG4-7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants.

Association between baseline blood pressure variability and left heart function following short-term extreme cold exposure.

Extreme cold exposure has been widely considered as a cardiac stress and may result in cardiac function decompensation. This study was to examine the risk factors that contribute to changes in cardiovascular indicators of cardiac function following extreme cold exposure and to provide valuable insights into the preservation of cardiac function and the cardiac adaptation that occur in real-world cold environment. Seventy subjects were exposed to cold outside (Mohe, mean temperature -17 to -34°C) for one day, and were monitored by a 24-h ambulatory blood pressure device and underwent echocardiography examination before and after extreme cold exposure. After exposure to extreme cold, 41 subjects exhibited an increase in ejection fraction (EF), while 29 subjects experienced a decrease. Subjects with elevated EF had lower baseline coefficients of variation (CV) in blood pressure compared to those in the EF decrease group. Additionally, the average real variability (ARV) of blood pressure was also significantly lower in the EF increase group. Multivariate regression analysis indicated that both baseline CV and ARV of blood pressure were independent risk factors for EF decrease, and both indicators proved effective for prognostic evaluation. Correlation analysis revealed a correlation between baseline blood pressure CV and ARV, as well as EF variation after exposure to extreme cold environment. Our research clearly indicated that baseline cardiovascular indicators were closely associated with the changes in EF after extreme cold exposure. Furthermore, baseline blood pressure variability could effectively predict alterations in left cardiac functions when individuals were exposed to extreme cold environment.

Exploring the Mechanism of Isoforskolin against Asthma Based on Network Pharmacology and Experimental Verification.

In this study, network pharmacology combined with biological experimental verification was utilized to screen the targets of isoforskolin (ISOF) and investigate the potential underlying mechanism of ISOF against asthma. Asthma-related targets were screened from the Genecards and DisGeNET databases. SEA and Super-PRED databases were used to obtain the targets of ISOF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to identify enriched regulatory pathways of key targets in ISOF acting on asthma. Then, a protein-protein interaction (PPI) network was constructed via STRING database and hub genes of ISOF against asthma were further screened using molecular docking. Finally, CCK-8, qPCR, and Western blotting were performed to confirm the targets of ISOF in treating asthma. A total of 96 drug potential therapeutic targets from the relevant databases were screened out. KEGG pathway enrichment analysis predicted that the target genes might be involved in the PI3K-Akt pathway. The core targets of ISOF in treating asthma were identified by the PPI network and molecular docking, including MAPK1, mTOR, and NFKB1. Consistently, in vitro experiments showed that ISOF acting on asthma was involved in inflammatory response by reducing the expression of MAPK1, mTOR, and NFKB1. The present study reveals that MAPK1, mTOR, and NFKB1 might be key targets of ISOF in asthma treatment and the anti-asthma effect might be related to the PI3K-AKT signaling pathway.

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway.

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.