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EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85–90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFRL858R/T790M and more than 76-fold selectivity for EGFRWT. Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 μΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFRL858R/T790M by cell migration assay and apoptosis assay. [ABSTRACT FROM AUTHOR]

Aim: Risk assessment models for deep vein thrombosis (DVT) used worldwide are based on multidisciplinary data from Western countries. We aimed to establish a DVT risk assessment model that is applicable to Chinese patients with gynaecological conditions. Design: A risk assessment tool for DVT in gynaecology using the Delphi method. Methods: A three‐round Delphi study was conducted among experts who were asked to rate the importance of each risk factor in the Caprini scale. The consensus for each item was defined as a mean rating of >3 and a coefficient of variation (CV) of <0.5 in the first round, as CV <0.3 in the second round. Results: Eleven experts participated in the Delphi method, with a response rate of 100%. Kendall's coefficients of concordance (W) were 0.264 and 0.322 in the first and second rounds, respectively (p < 0.001). The DVT risk assessment scale includes 8 dimensions and 34 items. [ABSTRACT FROM AUTHOR]

This paper deals with blow-up and quenching solutions of degenerate parabolic problem involving m-Laplacian operator and nonlinear boundary flux. The blow-up and quenching criteria are classified under the conditions on the initial data but with less conditions on the relationship among the exponents, respectively. Moreover, asymptotic properties including singular rates, set and time estimates are determined for the blow-up solutions and the quenching solutions, respectively. [ABSTRACT FROM AUTHOR]

Background/Aims: The role of two polymorphisms rs1800591 and rs3816873 of the microsomal triglyceride transfer protein (MTTP) gene in the development of nonalcoholic fatty liver disease (NAFLD) remains controversial. A meta-analysis was conducted to determine the correlation between these MTTP polymorphisms and NAFLD. Materials and Methods: A systematic search was carried out using PubMed, Embase, and Cochrane Library to retrieve English studies that reported the relationship between MTTP polymorphisms (rs1800591 and rs3816873) and NAFLD published before February 18, 2020. Odds ratio (OR) and 95% confidence interval (CI) were used to appraise the risk of MTTP polymorphism in NAFLD. Results: A total of 10 case-control studies, including 1388 cases and 1690 healthy subjects, were included. No significant correlation between the rs1800591 (G vs. T: OR = 1.08, 95% CI = 0.68–1.70, P = 0.76) and rs3816873 (CT + CC vs. TT: OR = 1.23, 95% CI = 0.76–2.01, P = 0.398) polymorphisms of MTTP and NAFLD was found in any of the models. However, when NASH patients confirmed by liver biopsy were extracted alone for rs1800591 polymorphism analysis, it was found that the G allele significantly increased the risk of NASH under the heterozygote model (GT vs. TT: OR = 3.16, 95% CI = 1.13–8.83, P = 0.028) and dominant model (GT + GG vs. TT: OR = 3.03, 95% CI = 1.13–8.09, P = 0.027). Conclusion: The present meta-analysis revealed that the rs1800591 and rs3816873 polymorphisms of the MTTP gene are uncommon in NAFLD. However, the G allele of rs1800591 was more likely to be correlated to NASH susceptibility. [ABSTRACT FROM AUTHOR]

The 2019 novel coronavirus disease, SARS-CoV-2, is now spreading globally and is characterized by person-to-person transmission. However, it has recently been found that individuals infected with SARS-CoV-2 can be asymptomatic, and simultaneously a source of infection in others. The viral load detected in nasopharyngeal swabs of asymptomatic carriers is relatively high, with a great potential for transmission. More attention should be paid to the insidious spread of disease and harm contributed by asymptomatic SARS-CoV-2 carriers. To provide a theoretical basis for the accurate and early clinical identification of asymptomatic patients, this review objectively summarizes the epidemic status, transmission characteristics and clinical features of asymptomatic patients with SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

In this paper, we study extinction and blow-up properties of weak solutions for the doubly nonlinear parabolic problem involving p(x, t)-Laplacian operator, subject to homogeneous Dirichlet boundary conditions. We first prove the existence and uniqueness of weak solutions in some anisotropic Orlicz-Sobolev spaces and also establish suitable regularity of weak solutions with respect to the introduced control functional. Second, we use the energy estimate and the comparison principle of the ordinary differential equation to study the extinction or non-extinction of solutions. Third, we combine some new energy functions with the embedding inequalities to show blow-up criteria of solutions. Moreover, the singular rates of weak solutions are determined. It is interesting that blow-up or extinction phenomena depend sensitively on the sign of the precise relationship among the different anisotropic variable exponents, which discovers a key clue to the different effects of diffusion and reaction of the equations on the singularities of weak solutions. [ABSTRACT FROM AUTHOR]

Early detection and timely intervention are essential to prevent liver fibrosis from progressing to cirrhosis or hepatocellular carcinoma. Herein, utilizing the enhanced ferritin‐manganese interaction by nanoplatinum growth, a novel ferritin‐platinum‐manganese magnetic resonance nanoplatform with RGD grafting and metformin loading (FNMMR) is developed. RGD can enhance the targeting ability of the nanoplatform toward integrin αVβ3 on activated hepatic stellate cells (aHSCs) in liver fibrosis. Systemic delivery of FNMMR shows clear degree‐dependent magnetic resonance contrast enhancement in liver fibrosis. 3D reconstruction techniques and histogram‐based features are achieved to qualitatively and quantitatively analyze the inhomogeneous liver fibrosis areas. FNMMR with catalase‐like activity can catalyze the generation of O2 to alleviate the liver fibrosis hypoxia and inhibit the expression of HIF‐1α, blocking the TGF‐β1/Smad signaling pathway. In addition, metformin shows synergy with HIF‐1α reduction in blocking the TGF‐β1/Smad pathway, effectively inhibiting the activation of HSCs and reducing collagen formation. Furthermore, FNMMR can achieve real‐time anti‐fibrotic therapy monitoring by magnetic resonance imaging. Importantly, no obvious side effects can be observed in both histological and hematology examinations. Therefore, this work presents a novel nanoplatform for accurate liver fibrosis diagnosis and synergistic anti‐fibrotic therapy with real‐time monitoring. [ABSTRACT FROM AUTHOR]

Nanoplatforms with high Mn 2+ coordination can display efficient T 1 magnetic resonance imaging (MRI) contrast enhancement. Herein, an earth gravity-like method for enhanced interaction between Ferritin (Fn) and Mn 2+ by the growth of platinum nanoparticles (PNs) in Fn's cage structure via a biomineralization method is first proposed. Fn has good biocompatibility and can provide a suitable growth site for PNs. PNs with negative charge have certain attraction to Mn 2+ with positive charge, improving Fn's loading capacity of Mn 2+ by attraction force; and thus, achieving efficient MRI contrast enhancement. In addition, PNs can be applied for efficient photothermal therapy (PTT) under near infrared ray (NIR) irradiation. Systemic delivery of this nanoplatform shows obvious MRI contrast enhancement and tumor progression inhibition after NIR irradiation, as well as no obvious side effects. Therefore, this nanoplatform has the potential to contribute to nanotheranostic for clinical transformation., (© 2024 Wiley‐VCH GmbH.)

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC 50 value of 13 nM for kinase inhibitory activity against EGFR L858R/T790M and more than 76-fold selectivity for EGFR WT . Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC 50 value of 0.087 μΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFR L858R/T790M by cell migration assay and apoptosis assay.

Tumor metastasis is one of the most significant biological characteristics of malignant tumors. Advances in nanotechnology provide a new direction for tackling malignant tumors. Unlike previous studies that focused on the use of nanomaterials to eliminate tumors and avoid metastasis, this work focuses on summarizing the mechanisms by which some nanomaterials promote tumor metastasis in some cases. In this Review, we summarized recent research about various nanomaterials promoting tumor metastasis. The mechanisms of nanomaterials in this process have been highlighted, including the induction of epithelial-mesenchymal transition in tumor cells by nanomaterials, the interaction of nanomaterials with the vasculature, and the induction of inflammation by nanomaterials. Elucidating the mechanism of nanomaterials promoting tumor metastasis is beneficial to guide the development and application of safe and efficient nanomaterials, which can effectively reduce the incidence of tumor metastasis in the future., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Co-published by Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, and American Chemical Society.)

DNA damage-regulated autophagy modulator 1 (DRAM1) could play important roles in inflammation and hepatic apoptosis, while its roles in alcohol-related liver disease (ALD), which is characterized by hepatic inflammation and apoptosis, are still unclear. In this study, we explored the expression, role, and mechanism of DRAM1 in ALD. Firstly, our results showed that DRAM1 was significantly increased in liver tissues of mice at the early stage of alcohol treatment. In addition, DRAM1 knockout reduced, and liver-specific overexpression of DRAM1 aggravated, alcohol-induced hepatic steatosis, injury, and expressions of M1 macrophage markers in mice. Furthermore, ethanol-induced DRAM1 of hepatic cells increased pyruvate kinase M2 (PKM2)-enriched extracellular vesicles (EVs), and ectosomes derived from hepatic cells with DRAM1 overexpression promoted macrophage activation. Mechanistic investigations showed that DRAM1 interacted with PKM2 and increased the PKM2 level in plasma membrane. At last, DRAM1 was significantly increased in liver tissues of ALD patients, and it was positively correlated with M1 macrophage markers. Taken together, this study revealed that ethanol-induced DRAM1 of hepatic cells could increase the PKM2-enriched EVs, promote macrophage activation, and aggravate the disease progression of ALD. These findings suggested that DRAM1 might be a potentially promising target for the therapy of ALD., Competing Interests: All authors declare no conflicts of interest., (© 2021 The Authors.)

Diagnostic markers for non-alcoholic fatty liver disease (NAFLD) are still needed for screening individuals at risk. In recent years, the machine learning method was used to search for the diagnostic markers of multiple diseases. In this study, we developed and validated a machine learning model to diagnose NAFLD using laboratory indicators. NAFLD patients and non-NAFLD controls were recruited in the training and validation cohorts. The laboratory indicators of the participants in the training cohort were collected, and six indicators including alanine aminotransferase/aspartate aminotransferase (ALT/AST), white blood cells (WBC), alpha-L-fucosidase (AFU), hemoglobin (Hb), triglycerides (TG) and gamma-glutamyl transpeptidase (GGT) were screened out with higher weights by an integrate machine learning method. The areas under the receiver operating characteristic curves (AUROCs) for the selected indicators using logistic regression (LR), random forest (RF) and support vector machine (SVM) were 0.814, 0.837 and 0.810, respectively. Then the binary logistic regression was used to construct the predictive model. What's more, the AUROC of the predicted model was 0.732 in the validation cohort of patients with NAFLD. And the combined AUROC of the six parameters was 0.716 in the mouse model fed with high-fat diet (HFD). In summary, we created a predictive model with six laboratory indicators for the diagnosis of NAFLD based on the machine learning method, which has the potential value for the diagnosis of the NAFLD., Competing Interests: None., (AJTR Copyright © 2021.)

The biogenesis and diagnostic value of exosomes in nonalcoholic fatty liver disease (NAFLD) are unclear. In this study, we revealed that the plasma exosome level was higher in patients with NAFLD than that in healthy controls. Damage-regulated autophagy modulator (DRAM) was identified as one of the genes related to exosome secretion in patients with NAFLD. Then, loss or knockdown of DRAM down-regulated exosome secretion from hepatic cells using a knockout mouse model and a knockdown cell model. DRAM knockout reversed high-fat diet–induced increase of secreted exosomes. Furthermore, DRAM knockdown inhibited fatty acid (FA)–induced lysosomal membrane permeabilization and lysosome inhibitor reversed the down-regulation of exosome release in DRAM knockout mice. Last, FA-induced DRAM interacted with stomatin and promoted its lysosomal localization to enhance exosome secretion from hepatic cells. We revealed a DRAM-mediated mechanism for exosome secretion and provided the foundation for plasma exosomes as a potential biomarker for NAFLD.

MicroRNAs (miRNAs) are non-coding RNAs 21-23 nucleotides in length that regulate gene expression, and thereby modulate signaling pathways and protein synthesis in both physiological and pathogenic processes. miR-30b inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transformation in multiple types of cancer. In addition to its role in several types of neoplasias, miR-30b has been shown to exhibit essential roles in cardiovascular and metabolic diseases. In the present review, an overview of the biological functions of miR-30b and its role in the pathogenesis of neoplastic, cardiovascular and metabolic diseases is provided. miR-30b is a potential candidate for clinical development as a diagnostic and prognostic biomarker, therapeutic agent and drug target. However, further research is required to elucidate its role in health and disease and to harness its potential clinical utility., (Copyright: © Zhang et al.)