Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic simulation.

CONTEXT: SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol). For the SHP2 target, the FMO method prediction has a high correlation between the binding affinity of the protein-ligand interaction and experimental values (R2 = 0.55), demonstrating a significant advantage over the MM/PBSA (R2 = 0.02) and MM/GBSA (R2 = 0.15) methods. Therefore, we employed Dock-FMO virtual screening of ChemDiv database of ∼2,990,000 compounds to identify a novel SHP2 allosteric inhibitor bearing hydroxyimino acetamide scaffold. Experimental validation demonstrated that the new compound (E)-2-(hydroxyimino)-2-phenyl-N-(piperidin-4-ylmethyl)acetamide (7188-0011) effectively inhibited SHP2 in a dose-dependent manner. Molecular dynamics (MD) simulation analysis revealed the binding stability of compound 7188-0011 and the SHP2 protein, along with the key interacting residues in the allosteric binding site. Overall, our work has identified a novel and promising allosteric inhibitor that targets SHP2, providing a new starting point for further optimization to develop more potent inhibitors. METHODS: All the molecular docking studies were employed to identify potential leads with Maestro v10.1. The protein-ligand binding affinities of potential leads were further predicted by FMO calculations at MP2/6-31G* level using GAMESS v2020 system. MD simulations were carried out with AmberTools18 by applying the FF14SB force field. MD trajectories were analyzed using VMD v1.9.3. MM/GB(PB)SA binding free energy analysis was carried out with the mmpbsa.py tool of AmberTools18. The docking and MD simulation results were visualized through PyMOL v2.5.0.

Household air pollution and attributable burden of disease in rural China: A literature review and a modelling study.

Household air pollution prevails in rural residences across China, yet a comprehensive nationwide comprehending of pollution levels and the attributable disease burdens remains lacking. This study conducted a systematic review focusing on elucidating the indoor concentrations of prevalent household air pollutants-specifically, PM2.5, PAHs, CO, SO2, and formaldehyde-in rural Chinese households. Subsequently, the premature deaths and economic losses attributable to household air pollution among the rural population of China were quantified through dose-response relationships and the value of statistical life. The findings reveal that rural indoor air pollution levels frequently exceed China's national standards, exhibiting notable spatial disparities. The estimated annual premature mortality attributable to household air pollution in rural China amounts to 966 thousand (95% CI: 714-1226) deaths between 2000 and 2022, representing approximately 22.2% (95% CI: 16.4%-28.1%) of total mortality among rural Chinese residents. Furthermore, the economic toll associated with these premature deaths is estimated at 486 billion CNY (95% CI: 358-616) per annum, constituting 0.92% (95% CI: 0.68%-1.16%) of China's GDP. The findings quantitatively demonstrate the substantial disease burden attributable to household air pollution in rural China, which highlights the pressing imperative for targeted, region-specific interventions to ameliorate this pressing public health concern.

Early-onset Marfan syndrome with aortic dilatation and giant pulmonary artery aneurysm: A case report.

A 30-year-old woman with ankylosing spondylitis was referred to our clinic with abnormal fetal echocardiography findings, including ascending aortic dilatation, giant main pulmonary artery aneurysm, and aortic and pulmonary valve stenosis at 22 weeks of gestation. The full-term male neonate was born by cesarean section and was transferred to the cardiac intensive care unit soon after delivery for respiratory distress with low percutaneous oxygen saturation. Based on cardiovascular and genetic analysis findings, the patient was diagnosed with Marfan syndrome. Surgery was performed; however, the patient died due to cardiac arrest. In conclusion, main pulmonary artery dilatation and aneurysms are uncommon in Marfan syndrome; therefore, presentation with these findings during the fetal life, as in the present case, is likely a sign of severe Marfan syndrome-related cardiac involvement.

SIRT3 and SIRT4 double-genes remodeled the mitochondrial network to induce hepatocellular carcinoma cell line differentiation and suppress malignant phenotypes.

Tumor cells with damaged mitochondria undergo metabolic reprogramming, but gene therapy targeting mitochondria has not been comprehensively reported. In this study, plasmids targeting the normal hepatocyte cell line (L-O2) and hepatocellular carcinoma cell line were generated using three genes SIRT3, SIRT4, and SIRT5. These deacetylases play a variety of regulatory roles in cancer and are related to mitochondrial function. Compared with L-O2, SIRT3 and SIRT4 significantly ameliorated mitochondrial damage in HCCLM3, Hep3B and HepG2 cell lines and regulated mitochondrial biogenesis and mitophagy, respectively. We constructed double-gene plasmid for co-express SIRT3 and SIRT4 using the internal ribosome entry site (IRES). The results indicated that the double-gene plasmid effectively expressed SIRT3 and SIRT4, significantly improved mitochondrial quality and function, and reduced mtDNA level and oxidative stress in HCC cells. MitoTracker analysis revealed that the mitochondrial network was restored. The proliferation, migration capabilities of HCC cells were reduced, whereas their differentiation abilities were enhanced. This study demonstrated that the use of IRES-linked SIRT3 and SIRT4 double-gene vectors induced the differentiation of HCC cells and inhibited their development by ameliorating mitochondrial dysfunction. This intervention helped reverse metabolic reprogramming, and may provide a groundbreaking new framework for HCC treatment.

Effect of Missed Post-Procedure Creatinine Measurement on Sub-Acute Kidney Injury Following Coronary Angiography.

Serum creatinine (SCr) levels are essential for the diagnosis of kidney disease after coronary angiography (CAG). However, the influence of missed post-procedure SCr measurement in this situation is unclear. The present study included 14,127 patients undergoing CAG as part of the Cardiorenal ImprovemeNt registry II. Patients were divided into two groups according to whether a post-procedure SCr was measured within 3 days. The primary endpoint was acute kidney disease (AKD). Logistic regression was used to evaluate the relationship between post-procedure SCr and AKD. Of the 14,127 patients (61.6 ± 9.8 years, 34.2% females), 55.4% (n = 7822) did not have a post-procedure SCr measurement. The incidence of AKD was higher in the missed post-procedure SCr group (15.7 vs 11.9%; median follow-up 6.54 years). Multivariate logistic regression showed that missed post-procedure SCr measurement was associated with significantly higher risk of AKD (adjusted odds ratio [aOR]: 1.26, 95% CI: 1.10-1.45, P < .001). The results were more significant in patients with normal renal function at baseline (aOR: 1.36, 95% CI: 1.16-1.60, P < .001). In our study, over half of the patients undergoing CAG missed their post-procedure SCr measurement. The missed post-procedure SCr group had a significantly higher risk of developing AKD compared with those with a post-procedure SCr measurement.

A Patient Similarity Network (CHDmap) to Predict Outcomes After Congenital Heart Surgery: Development and Validation Study.

Background: Although evidence-based medicine proposes personalized care that considers the best evidence, it still fails to address personal treatment in many real clinical scenarios where the complexity of the situation makes none of the available evidence applicable. "Medicine-based evidence" (MBE), in which big data and machine learning techniques are embraced to derive treatment responses from appropriately matched patients in real-world clinical practice, was proposed. However, many challenges remain in translating this conceptual framework into practice. Objective: This study aimed to technically translate the MBE conceptual framework into practice and evaluate its performance in providing general decision support services for outcomes after congenital heart disease (CHD) surgery. Methods: Data from 4774 CHD surgeries were collected. A total of 66 indicators and all diagnoses were extracted from each echocardiographic report using natural language processing technology. Combined with some basic clinical and surgical information, the distances between each patient were measured by a series of calculation formulas. Inspired by structure-mapping theory, the fusion of distances between different dimensions can be modulated by clinical experts. In addition to supporting direct analogical reasoning, a machine learning model can be constructed based on similar patients to provide personalized prediction. A user-operable patient similarity network (PSN) of CHD called CHDmap was proposed and developed to provide general decision support services based on the MBE approach. Results: Using 256 CHD cases, CHDmap was evaluated on 2 different types of postoperative prognostic prediction tasks: a binary classification task to predict postoperative complications and a multiple classification task to predict mechanical ventilation duration. A simple poll of the k-most similar patients provided by the PSN can achieve better prediction results than the average performance of 3 clinicians. Constructing logistic regression models for prediction using similar patients obtained from the PSN can further improve the performance of the 2 tasks (best area under the receiver operating characteristic curve=0.810 and 0.926, respectively). With the support of CHDmap, clinicians substantially improved their predictive capabilities. Conclusions: Without individual optimization, CHDmap demonstrates competitive performance compared to clinical experts. In addition, CHDmap has the advantage of enabling clinicians to use their superior cognitive abilities in conjunction with it to make decisions that are sometimes even superior to those made using artificial intelligence models. The MBE approach can be embraced in clinical practice, and its full potential can be realized.

Contribution of genetic variants to congenital heart defects in both singleton and twin fetuses: a Chinese cohort study.

BACKGROUND: The contribution of genetic variants to congenital heart defects (CHDs) has been investigated in many postnatal cohorts but described in few prenatal fetus cohorts. Overall, specific genetic variants especially copy number variants (CNVs) leading to CHDs are somewhat diverse among different prenatal cohort studies. In this study, a total of 1118 fetuses with confirmed CHDs were recruited from three units over a 5-year period, composing 961 of singleton pregnancies and 157 of twin pregnancies. We performed chromosomal microarray analysis on all cases to detect numerical chromosomal abnormalities (NCAs) and pathogenic/likely pathogenic CNVs (P/LP CNVs) and employed whole-exome sequencing for some cases without NCAs and P/LP CNVs to detect P/LP sequence variants (P/LP SVs). RESULTS: Overall, NCAs and P/LP CNVs were identified in 17.6% (197/1118) of cases, with NCA accounting for 9.1% (102/1118) and P/LP CNV for 8.5% (95/1118). Nonisolated CHDs showed a significantly higher frequency of NCA than isolated CHD (27.3% vs. 4.4%, p < 0.001), but there was no significant difference in the frequency of P/LP CNVs between isolated and nonisolated CHD (11.7% vs. 7.7%). A total of 109 P/LP CNVs were identified in 95 fetuses, consisting of 97 (89.0%) de novo, 6 (5.5%) parental inherited and 6 (5.5%) with unavailable parental information. The 16p11.2 proximal BP4-BP5 deletion was detected in 0.9% (10/1118) of all cases, second only to the most common 22q11.21 proximal A-D deletion (2.1%, 23/1118). Most of the 16p11.2 deletions (8/10) detected were de novo, and were enriched in CHD cases compared with a control cohort from a previous study. Additionally, SV was identified in 12.9% (8/62) of cases without NCA and P/LP CNV, most of which were de novo with autosomal dominant inheritance. CONCLUSIONS: Our cohort study provides a deep profile of the contribution of genetic variants to CHDs in both singleton and twin fetuses; NCA and P/LP CNV contribute to 9.1% and 8.5% of CHD in fetuses, respectively. We confirmed the 16p11.2 deletion as a CHD-associated hotspot CNV, second only to the 22q11.21 deletion in frequency. Most 16p11.2 deletions detected were de novo. Additionally, P/LP SV was identified in 12.9% (8/62) of fetuses without NCA or P/LP CNV.

Extracellular vesicles from normal tissues orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis.

Extracellular vesicles (EVs) exist throughout our bodies. We recently revealed the important role of intracardiac EVs induced by myocardial ischemia/reperfusion on cardiac injury and dysfunction. However, the role of EVs isolated from normal tissues remains unclear. Here we found that EVs, derived from murine heart, lung, liver and kidney have similar effects on macrophages and regulate the inflammation, chemotaxis, and phagocytosis of macrophages. Interestingly, EV-treated macrophages showed LPS resistance with reduced expressions of inflammatory cytokines and enhanced phagocytic activity. Furthermore, we demonstrated that the protein content in EVs contributed to the activation of inflammation, while the RNA component mainly limited the excessive inflammatory response of macrophages to LPS. The enrichment of miRNAs, including miR-148a-3p, miR-1a-3p and miR-143-3p was confirmed in tissue EVs. These EV-enriched miRNAs contributed to the inflammation remission in LPS induced macrophages through multiple pathways, including STAT3, P65 and SAPK/JNK. Moreover, administration of both EVs and EV-educated macrophages attenuated septic injury and cytokine storm in murine CLP models. Taken together, the present study disclosed that EVs from normal tissues can orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis. Therefore, tissue derived EVs or their derivatives may serve as potential therapeutic strategies in inflammatory diseases.

Development and validation of a combined cuproptosis and immunogenic cell death prognostic model for diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide with a high degree of heterogeneity. Cuproptosis and immunogenic cell death (ICD) have been considered to be vital for tumor progression. However, current understanding of cuproptosis and immunogenic cell death in DLBCL is still very limited. We aim to explore a prognostic model combining cuproptosis and immunogenic cell death in DLBCL. METHODS: Pearson's correlation analysis was utilized to acquire lncRNAs associated with cuproptosis and immunogenic cell death. Prognostic biomarker identification and model construction involved the use of univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. We assessed the predictive capability of the risk model by conducting Kaplan-Meier analysis and time-dependent ROC analysis. The analysis and comparison of immune infiltration and drug sensitivity were conducted in this study. Moreover, RT-qPCR was employed to validate the expression of lncRNAs associated with cuproptosis and immunogenic cell death in DLBCL cell lines. RESULTS: We identified 4 prognosis-related lncRNAs (ANKRD10-IT1, HOXB-AS1, LINC00520 and LINC01165) that were correlated with cuproptosis and immunogenic cell death. The model was verified to have a good and independent predictive ability in the prognostic prediction of DLBCL patients. Moreover, significant difference was observed in immune infiltration and drug sensitivity between high- and low-risk groups. CONCLUSION: Our discoveries could enhance the comprehension of the role of cuproptosis and ICD in DLBCL, potentially offering novel viewpoints and knowledge for personalized and precise treatment of DLBCL individuals.

The relationship between serum creatinine/cystatin C ratio and mortality in hypertensive patients.

BACKGROUND AND AIMS: Sarcopenia is a disease characterized by loss of skeletal muscle mass and function that is closely associated with cardiovascular disease. The serum creatinine/cystatin C (Cr/CysC) ratio has been shown to be a simplified indicator for identifying low muscle mass (LMM) or sarcopenia. The aim of this study was to investigate whether the Cr/CysC ratio helps to predict prognostic information in hypertensive patients. METHODS AND RESULTS: This cohort study included 2509 patients with hypertension from the National Health and Nutrition Survey 1999-2002. To evaluate the association between Cr/CysC ratio and mortality, we used Kaplan Meier estimates to calculate cumulative survival probabilities for all-cause mortality and cardiovascular mortality, Cox regression analyses, and hazard ratio (HR) and 95% confidence interval (CI) were calculated. Over a median follow-up of 11.76 years, lower Cr/CysC ratio was associated with lower risk of all-cause mortality (per 0.1 increase, HR:0.81, 95% CI: 0.77-0.85, P < 0.001) and cardiovascular mortality (per 0.1 increase, HR:0.80, 95% CI: 0.72-0.89, P < 0.001). Compared with patients with normal muscle mass, all-cause mortality, and cardiovascular mortality HR for patients with LMM diagnosed by Cr/CysC ratio were 1.57 (95% CI: 1.36-1.82, P < 0.001) and 1.64 (95% CI: 1.12-2.42, P = 0.012), respectively. CONCLUSION: We found that low muscle mass shown by lower Cr/CysC ratio was an independent risk factor for poor prognosis in hypertensive patients. We recommend routine screening of Cr/CysC ratio in hypertensive patients and early intervention for low muscle mass or sarcopenia.

Bidirectional Association Between Cardiovascular Disease and Lung Cancer in a Prospective Cohort Study.

INTRODUCTION: The study aimed to prospectively investigate the bidirectional association between cardiovascular disease (CVD) and lung cancer, and whether this association differs across genetic risk levels. METHODS: This study prospectively followed 455,804 participants from the United Kingdom Biobank cohort who were free of lung cancer at baseline. Cox proportional hazard models were used to estimate the hazard ratio (HR) for incident lung cancer according to CVD status. In parallel, similar approaches were used to assess the risk of incident CVD according to lung cancer status among 478,756 participants free of CVD at baseline. The bidirectional causal relations between these conditions were assessed using Mendelian randomization analysis. Besides, polygenic risk scores were estimated by integrating genome-wide association studies identified risk variants. RESULTS: During 4,007,477 person-years of follow-up, 2006 incident lung cancer cases were documented. Compared with participants without CVD, those with CVD had HRs (95% confidence interval [CI]) of 1.49 (1.30-1.71) for NSCLC, 1.80 (1.39-2.34) for lung squamous cell carcinoma (LUSC), and 1.25 (1.01-1.56) for lung adenocarcinoma (LUAD). After stratification by smoking status, significant associations of CVD with lung cancer risk were observed in former smokers (HR = 1.44, 95% CI: 1.20-1.74) and current smokers (HR = 1.38, 95% CI: 1.13-1.69), but not in never-smokers (HR = 0.98, 95% CI: 0.60-1.61). In addition, CVD was associated with lung cancer risk across each genetic risk level (pheterogeneity = 0.336). In the second analysis, 32,974 incident CVD cases were recorded. Compared with those without lung cancer, the HRs (95% CI) for CVD were 2.33 (1.29-4.21) in NSCLC, 3.66 (1.65-8.14) in LUAD, and 1.98 (0.64-6.14) in LUSC. In particular, participants with lung cancer had a high risk of incident CVD at a high genetic risk level (HR = 3.79, 95% CI: 1.57-9.13). No causal relations between these conditions were observed in Mendelian randomization analysis. CONCLUSIONS: CVD is associated with an increased risk of NSCLC including LUSC and LUAD. NSCLC, particularly LUAD, is associated with a higher CVD risk. Awareness of this bidirectional association may improve prevention and treatment strategies for both diseases. Future clinical demands will require a greater focus on cardiac oncology.

A smartphone-based electrochemical POCT for CEA based on signal amplification of Zr6MOFs.

Carcinoembryonic antigen (CEA) is a biomarker of high expression in cancer cells. Highly sensitive and selective detection of CEA holds significant clinical value in the diagnosis, monitoring and efficacy evaluation of malignant tumors. In this work, a smartphone-based electrochemical point-of-care testing (POCT) platform for the detection of CEA was developed based on a Zr6MOF signal amplification strategy. Ferrocene labeled DNA strands (Fc-DNA) were immobilized on Zr6MOFs to form a Fc-DNA/Zr6MOF signal probe. Double-stranded DNA (dsDNA) formed by complementary DNA (cDNA) and CEA aptamer was assembled on a screen-printed electrode via an Au-S bond. When CEA was added, the aptamer specifically bound with CEA, resulting in the exposure of cDNA. Then, Fc-DNA/Zr6MOF signal probes were introduced on the electrode surface through hybridization between Fc-DNA and cDNA. The detection of CEA was realized by measuring the electrochemical response of Fc. The POCT device was made by connecting a modified electrode with a smartphone through a Sensit Smart USB flash disk. Due to the signal amplification of Zr6MOFs, this POCT platform exhibited high sensitivity, wide linear range, and low detection limit for CEA detection. The developed POCT platform has been used for the detection of CEA in actual human serum samples with satisfactory results.

Tungsten-based polyoxometalate nanoclusters with remarkable reactive oxygen species-scavenging activity efficiently quenched luminol-based electrochemiluminescence for sensitive detection of Her-2.

This study aimed to develop a quenching-type electrochemiluminescence (ECL) immunosensor for human epidermal growth factor receptor (Her-2) detection. Firstly, Pd/NiFeOx nanoflowers decorated by in situ formation of gold nanoparticles (Au NPs) and 2D Ti3C2 MXene nanosheets were synthesized (AuPd/NiFeOx/Ti3C2) as carriers to load luminol and primary antibodies. Impressively, AuPd/NiFeOx/Ti3C2 with excellent peroxidase-like activity could accelerate the decomposition of the coreactant H2O2 generating more reactive oxygen species (ROSs) under the working potential from 0 to 0.8 V, resulting in highly efficient ECL emission at 435-nm wavelengths. The introduction of tungsten-based polyoxometalate nanoclusters (W-POM NCs) which exhibit remarkable ROSs-scavenging activity as secondary antibody labels could improve the sensitivity of immunosensors. The ZnO nanoflowers were employed to encapsulate minute-sized W-POM NCs, and polydopamine was self-polymerized on the surface of Zn(W-POM)O to anchor secondary antibodies. The mechanism of the quenching strategy was explored and it was found that W-POM NCs could consume ROSs by the redox reaction of W5+ resulting in W6+. The proposed ECL immunosensor displayed a wide linear response range of 0.1 pg·mL-1 to 50 ng·mL-1, and a low detection limit of 0.036 pg mL-1 (S/N = 3). The recoveries ranged from 93.9 to 99.4%, and the relative standard deviation (RSD) was lower than 10%. This finding is promising for the design of detecting new protein biomarkers.

Copper-Catalyzed Fluoroalkylphosphorothiolation of Alkynes for the Synthesis of (E)-ß-Fluoroalkyl Vinyl Phosphorothioates.

A convenient copper-catalyzed three-component radical-based fluoroalkylphosphorothiolation of terminal alkynes with (iPrO)2P(O)SH and fluoroalkylation reagent for the synthesis of a variety of (E)-ß-fluoroalkyl vinyl phosphorothioates with excellent regioselectivity and stereoselectivity has been developed. All the starting materials used in this reaction are highly stable and readily available. Thus, this process features with mild reaction conditions, simple operation and good functional group tolerance (>40 examples). Furthermore, this modular reaction system allows the late-stage functionalization of bioactive molecules.

Extracellular vesicles derived from different tissues attenuate cardiac dysfunction in murine MI models.

BACKGROUND: Extracellular vesicles (EVs) derived from various cell sources exert cardioprotective effects during cardiac ischemic injury. Our previous study confirmed that EVs derived from ischemic-reperfusion injured heart tissue aggravated cardiac inflammation and dysfunction. However, the role of EVs derived from normal cardiac tissue in myocardial ischemic injury remains elusive. RESULTS: In the present study, normal heart-derived EVs (cEVs) and kidney-derived EVs (nEVs) were isolated and intramyocardially injected into mice after myocardial infarction (MI). We demonstrated that administration of both cEVs and nEVs significantly improved cardiac function, reduced the scar size, and alleviated inflammatory infiltration into the heart. In addition, cardiomyocyte apoptosis was inhibited, whereas angiogenesis was enhanced in the hearts receiving cEVs or nEVs treatment. Moreover, intramyocardial injection of cEVs displayed much better cardiac protective efficacy than nEVs in murine MI models. RNA-seq and protein-protein interaction (PPI) network analysis revealed the protective mRNA clusters in both cEVs and nEVs. These mRNAs were involved in multiple signaling pathways, which may synergistically orchestrate to prevent the heart from further damage post MI. CONCLUSIONS: Collectively, our results indicated that EVs derived from normal heart tissue may represent a promising strategy for cardiac protection in ischemic heart diseases.

In Situ Construction of High-Thermal-Conductivity and Negative-Permittivity Epoxy/Carbon Fiber@Carbon Composites with a 3D Network by High-Temperature Chemical Vapor Deposition.

Modern highly integrated microelectronic devices are unable to dissipate heat over time, which greatly affects the operating efficiency and service life of electronic equipment. Constructing high-thermal-conductivity composites with 3D network structures is a hot research topic. In this article, carbon fiber felt (CFF) was prepared by airflow netting forming technology and needle punching combined with stepped heat treatment. Then, carbon-coated carbon fiber felt (C@CFF) with a three-dimensional network structure was constructed in situ by high-temperature chemical vapor deposition (CVD). Finally, high-temperature treatment was used to improve the degree of crystallinity of C@CFF and further enhance its graphitization. The epoxy (EP) composites were prepared by simple vacuum infiltration-molding curing. The test results showed that the in-plane thermal conductivity (K∥) and through-plane thermal conductivity (K⊥) of EP/C@CFF-2300 °C could reach up to 13.08 and 2.78 W/mK, respectively, where the deposited carbon content was 11.76 vol %. The in-plane thermal conductivity enhancement (TCE) of EP/C@CFF-2300 °C was improved by 6440 and 808% compared to those of pure EP and EP/CFF, respectively. The high-temperature treatment greatly provides an improvement in thermal conductivity for the in-plane and the through-plane. Infrared imaging showed excellent thermal management properties of the prepared epoxy composites. EP/C@CFF-2300 °C owned an in-plane AC conductivity of up to 0.035 S/cm at 10 kHz, and Lorentz-Drude-type negative permittivity behaviors were observed at the tested frequency region. The CFF thermally conductive composites prepared by the above method have a broad application prospect in the field of advanced thermal management and electromagnetics.

Polysaccharide from walnut green husk alleviates liver inflammation and gluconeogenesis dysfunction by altering gut microbiota in ochratoxin A-induced mice.

Walnut green husk polysaccharides (WGP) are isolated from the walnut green husk with a mean molecular weight of 12.77 kDa. The structural characterization revealed by methylation and NMR analysis indicated that WGP might consist of →4-α-D-Galp-(1→, α-D-Galp (1→, and →2)-α-L-Rhap-(1→. Previous studies have been demonstrated that WGP effectively prevented liver injury and modulated gut microbiota in high fructose-treated mice and high fat diet-treated rats. In this study, we found for the first time that WGP presenting outstanding protective effects on liver inflammation and gluconeogenesis dysfunction induced by ochratoxin A (OTA) in mice. Firstly, WGP decreased oxidative stress, down-regulated the expression of inflammatory factors and inhibited the TLR4/p65/IκBα pathway in the liver. Then, WGP reversed OTA-induced lower phosphoenolpyruvate carboxyl kinase (PEPCK), and glucose 6-phosphatase (G6PC) activities in the liver. Furthermore, WGP increased the diversity of gut microbiota and the abundance of beneficial bacteria, especially Lactobacillus and Akkermansia. Importantly, the results of fecal microbiota transplantation (FMT) experiment further confirmed that gut microbiota involved in the protective effects of WGP on liver damage induced by OTA. Our results indicated that the protective effect of WGP on liver inflammation and gluconeogenesis dysfunction caused by OTA may be due to the regulation of gut microbiota.

Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts.

BACKGROUND: The associations of vitamin C intake with colorectal cancer (CRC) survival according to tumour KRAS or BRAF mutation status remain unclear. METHODS: We used the inverse probability weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality, and spline analysis to evaluate the dose-response relationship in the Nurses' Health Study and Health Professionals Follow-up Study. We also assessed SLC2A1 mRNA expression according to KRAS or BRAF mutation in the TCGA database. RESULTS: During an average of 12.0 years of follow-up, we documented 2,096 CRC cases, of which 703 cases had KRAS and BRAF mutation data. The association between total vitamin C intake and CRC-specific mortality suggestively differed according to KRAS or BRAF mutation status (Pinteraction = 0.04), with the multivariable HR (95% CI) per 400 mg/day increase in vitamin C intake for CRC-specific mortality of 1.07 (0.87-1.32, Ptrend = 0.52) in cases with both wild type and 0.74 (0.55-1.00, Ptrend < 0.05) in cases with either KRAS or BRAF mutant type. TCGA analysis showed a higher mRNA SLC2A1 expression in KRAS or BRAF-mutated tumours than in wild-type tumours (P = 0.02). CONCLUSION: Our findings support the laboratory evidence for a potential benefit of vitamin C for CRC patients with KRAS or BRAF mutated tumours.

Inhibitory role of bone marrow mesenchymal stem cells-derived exosome in non-small-cell lung cancer: microRNA-30b-5p, EZH2 and PI3K/AKT pathway.

Exosomal microRNA (miRNA) exerts potential roles in non-small-cell lung cancer (NSCLC). The current study elucidated the role of miR-30b-5p shuttled by bone marrow mesenchymal stem cells (BMSCs)-derived exosomes in treating NSCLC. Bioinformatics analysis was performed with NSCLC-related miRNA microarray GSE169587 and mRNA data GSE74706 obtained for collection of the differentially expressed miRNAs and mRNAs. The relationship between miR-30b-5p and EZH2 was predicted and confirmed. Exosomes were isolated from BMSCs and identified. BMSCs-derived exosomes overexpressing miR-30b-5p were used to establish subcutaneous tumorigenesis models to study the effects of miR-30b-5p, EZH2 and PI3K/AKT signalling pathway on tumour growth. A total of 86 BMSC-exo-miRNAs were differentially expressed in NSCLC. Bioinfomatics analysis found that BMSC-exo-miR-30b-5p could regulate NSCLC progression by targeting EZH2, which was verified by in vitro cell experiments. Besides, the target genes of miR-30b-5p were enriched in PI3K/AKT signalling pathway. Animal experiments validated that BMSC-exo-miR-30b-5p promoted NSCLC cell apoptosis and prevented tumorigenesis in nude mice via EZH2/PI3K/AKT axis. Collectively, the inhibitory role of BMSC-derived exosomes-loaded miR-30b-5p in NSCLC was achieved through blocking the EZH2/PI3K/AKT axis.