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The Help tells the story of racial segregation in Jackson, Mississippi, in the early 1960s. In the novel, animals symbolize the marginalized existence of white and black women under male and racial oppression. White women are demeaned in marriage and the workplace, while black women face silence regarding bodily and linguistic rights. This paper, from a feminist and postcolonial perspective, integrates animal criticism to examine the portrayal of animals like cockroaches, bears, and dogs, illustrating the existential dilemma of these women and exploring ways to overcome these challenges. It argues that Stockett depicts both groups’ discourses as ineffective under patriarchy and racism but also highlights the positive aspects of inter-female assistance across racial lines and the inevitable breakdown of racial segregation.

Background Lung cancer is a malignant tumour, and early diagnosis has been shown to improve the survival rate of lung cancer patients. In this study, we assessed the use of plasma metabolites as biomarkers for lung cancer diagnosis. In this work, we used a novel interdisciplinary mechanism, applied for the first time to lung cancer, to detect biomarkers for early lung cancer diagnosis by combining metabolomics and machine learning approaches. Results In total, 478 lung cancer patients and 370 subjects with benign lung nodules were enrolled from a hospital in Dalian, Liaoning Province. We selected 47 serum amino acid and carnitine indicators from targeted metabolomics studies using LC‒MS/MS and age and sex demographic indicators of the subjects. After screening by a stepwise regression algorithm, 16 metrics were included. The XGBoost model in the machine learning algorithm showed superior predictive power (AUC = 0.81, accuracy = 75.29%, sensitivity = 74%), with the metabolic biomarkers ornithine and palmitoylcarnitine being potential biomarkers to screen for lung cancer. The machine learning model XGBoost is proposed as an tool for early lung cancer prediction. This study provides strong support for the feasibility of blood-based screening for metabolites and provide a safer, faster and more accurate tool for early diagnosis of lung cancer. Conclusions This study proposes an interdisciplinary approach combining metabolomics with a machine learning model (XGBoost) to predict early the occurrence of lung cancer. The metabolic biomarkers ornithine and palmitoylcarnitine showed significant power for early lung cancer diagnosis.

N 6 -Methyladenosine (m 6 A) is the most prevalent mRNA modification in mammalian cells that is mainly catalyzed by the methyltransferase complex of methyltransferase-like 3 and methyltransferase-like 14 (METTL3-METTL14). Many lines of evidence suggest that METTL3 plays important roles in several diseases such as cancers and viral infection. In the present study, 1,042 natural products from commercially available sources were chosen to establish a screening library, and docking-based high-throughput screening was performed to discover potential METTL3 inhibitors. The selected compounds were then further validated by an in vitro methyltransferase inhibition assay in which m 6 A content was determined by LC-MS/MS. A cellular assay of the inhibition of m 6 A methylation was performed to determine the METTL3 inhibitory activity of the selected compound. CCK-8 assay was applied to evaluate the effects of the selected compound on tumor cell viability. Additionally, binding mode analysis, molecular dynamics (MD) simulation, and binding free energy analysis were performed to study the process and characteristics of inhibitor binding. Finally, quercetin was identified as a METTL3 inhibitor with an IC 50 value of 2.73 μM. The cellular assay of m 6 A methylation inhibition showed that quercetin decreased m 6 A level in a dose-dependent manner in MIA PaCa-2 pancreatic cancer cells. CCK-8 assay showed quercetin efficiently inhibited the proliferation of MIA PaCa-2 and Huh7 tumor cells, with IC 50 values 73.51 ± 11.22 μM and 99.97 ± 7.03 μM, respectively. Molecular docking studies revealed that quercetin filled the pocket of the adenosine moiety of SAM but not the pocket of the SAM methionine in the METTL3 protein, and hydrogen bonds, hydrophobic interactions, and pi-stacking were formed. The values of the root mean square deviation (RMSD), the root mean square fluctuations (RMSF), and binding free energy suggested that quercetin can efficiently bind to the pocket of the METTL3 protein and form a stable protein-ligand complex. The present study is the first to identify METTL3 inhibitors from natural products, thus providing a basis for subsequent research and facilitating the development of METTL3-targeting drugs for diseases.

Background RNA 5-methylcytosine (m 5 C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m 5 C modification in tumor drug resistance remain unclear. Methods The correlation between RNA m 5 C methylation, m 5 C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo . RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m 5 C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays. Results RNA m 5 C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo . Integrated RNA-seq and m 5 C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m 5 C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m 5 C reader Y-box binding protein 1 (YBX1). Conclusions Our study reveals a critical function of aberrant RNA m 5 C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC.

Background Receptor-interacting protein kinase 2 (RIPK2, also known as RIP2) was reported to be associated with bacterial infections as well as inflammatory responses. However, the role of RIPK2 in prognosis and immunotherapy response is yet to be elucidated in human pan-cancer. Methods In this study, we investigated the expression, gene alteration landscape and prognostic value of RIPK2 in 33 cancers through various databases including Ualcan, cBioportal and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Then, the correlation between RIPK2 and immune infiltration, immune score, stromal score, and ESTIMATE score was investigated in the Cancer Genome Atlas (TCGA) and tumor immune estimation resource (TIMER) databases. Independent cohorts were utilized to explore the role of RIPK2 in tumor immunotherapy response. Furthermore, Gene set enrichment analysis (GSEA) was conducted to explore the mechanisms by which RIPK2 regulates immune therapy resistance. Single-cell RNA-seq datasets were used to analyze the expression level of RIPK2 on different immune cells. Moreover, CellMiner database was used to explore the relationship between RIPK2 expression with drug response. Result Compared with normal tissue, tumor tissue had a higher expression level of RIPK2 in various cancers. Survival analysis showed that high expression of RIPK2 associated with poor prognosis in numerous cancers. RIPK2 was found to promote a series of immune cell infiltration and B cells, macrophages, and neutrophils were significantly positively correlated with the expression of RIPK2. Moreover, RIPK2 affected immune score, stromal score and ESTIMATE score for a wide range of cancers. In the vast majority of 33 cancers, gene co-expression analysis showed that RIPK2 was positively correlated with the expression of immune checkpoint markers, such as PDCD1 (PD-1), CD274 (PD-L1), CTLA4 and TIGIT. RIPK2 aggravated cytotoxic T lymphocyte (CTL) dysfunction and related to the poor efficacy of immune checkpoint blockade in skin cutaneous melanoma (SKCM) and kidney renal clear cell carcinoma (KIRC). High expression of RIPK2 promoted innate immunotherapy resistance and adaptive immunotherapy resistance through IL-6/JAK/STAT3 signaling, interferon-gamma response, and interferon-alpha response pathway. Conclusions These results confirmed that RIPK2 could serve as a prognostic biomarker and promoted immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction.

Cirrhosis is the most common subclass of liver disease worldwide and correlated to immune infiltration. However, the immune-related molecular mechanism underlying cirrhosis remains obscure. Two gene expression profiles GSE89377 and GSE139602 were investigated to identify differentially expressed genes (DEGs) related to cirrhosis. Enrichment analysis for DEGs was conducted. Next, the immune infiltration of DEGs was evaluated using CIBERSORT algorithm. The hub DEGs with tight connectivity were identified using the String and Cytoscape databases, and the expression difference of these hub genes between normal liver and cirrhosis samples was determined. Moreover, in order to evaluate the discriminatory ability of hub genes and obtained the area under the receiver operating characteristic curve values in the GSE89377 and GSE139602 datasets. Finally, the association between hub DEGs and immune cell infiltration was explored by Spearman method. Among the 299 DEGs attained, 136 were up-regulated and 163 were down-regulated. Then the enrichment function analysis of DEGs and CIBERSORT algorithm showed significant enrichment in immune and inflammatory responses. And four hub DEGs ( ACTB, TAGLN, VIM, SOX9 ) were identified, which also showed a diagnostic value in the GSE89377 and GSE 139,602 datasets. Finally, the immune infiltration analysis indicated that, these hub DEGs were highly related to immune cells. This study revealed key DEGs involved in inflammatory immune responses of cirrhosis, which could be used as biomarkers for diagnosis or therapeutic targets of cirrhosis.

A long non-coding RNA (lncRNA), named myocardial infarction associated transcript (MIAT), has been documented to confer risk of myocardial infarction (MI). The aim of this study is to elucidate the pathophysiological role of MIAT in regulation of cardiac fibrosis. In a mouse model of MI, we found that MIAT was remarkably up-regulated, which was accompanied by cardiac interstitial fibrosis. MIAT up-regulation in MI was accompanied by deregulation of some fibrosis-related regulators: down-regulation of miR-24 and up-regulation of Furin and TGF-β1. Most notably, knockdown of endogenous MIAT by its siRNA reduced cardiac fibrosis and improved cardiac function and restored the deregulated expression of the fibrosis-related regulators. In cardiac fibroblasts treated with serum or angiotensin II, similar up-regulation of MIAT and down-regulation of miR-24 were consistently observed. These changes promoted fibroblasts proliferation and collagen accumulation, whereas knockdown of MIAT by siRNA or overexpression of miR-24 with its mimic abrogated the fibrogenesis. Our study therefore has identified MIAT as the first pro-fibrotic lncRNA in heart and unraveled the role of MIAT in the pathogenesis of MI. These findings also promise that normalization of MIAT level may prove to be a therapeutic option for the treatment of MI-induced cardiac fibrosis and the associated cardiac dysfunction.

China National Health Commission issued an implementation plan for budget performance management in health projects in April 2021, which emphasizes all health projects must be evaluated in advance prior to implementation. The study aims to develop an ex-ante performance evaluation framework for health projects and formulate a self-assessment report template. The study also attempts to gain insights into the ex-ante performance of health projects in China, identify issues and explore the factors that influence the ex-ante performance of health projects and make suggestions about improvement strategies. The framework was established by using a framework development methodology. To develop the framework, the findings from existing research were pooled and organized to create indicators and key points. The preliminary ex-ante performance evaluation framework was refined, validated and tested by the experts. Weight analysis was conducted by using the Analytic Hierarchy Process. Then the indicator system has been transformed into a project ex-ante performance self-assessment report template. Samples of 698 municipal health projects in China from 2021 to 2022 were analyzed. We invited experts to complete the scoring task by using our ex-ante performance evaluation framework. The ex-ante performance evaluation framework primarily examines five aspects, the necessity of the project, economy of input, rationality of performance indicators, feasibility of implementation plans, and compliance of financing. The overall ex-ante performance evaluation score for the sample projects was (91.19 ± 8.02). The sub-scores for necessity of project were (14.74 ± 1.85), economy of input was (34.45 ± 2.43), reasonableness of performance indicators was (8.27 ± 2.28), feasibility of implementation plan was (23.99 ± 3.84), and compliance of financing was (9.75 ± 1.47). Factors such as whether it was an epidemic prevention and control project, the project budget, project content, project objective, and project implementation organization were all influencing the ex-ante performance of health projects ( P  < 0.05). We have developed a ex-ante performance evaluation framework for health projects and established a project ex-ante performance self-assessment report template. They can offer a sufficient reference for project process management. Project implementation organization should elevate the awareness and proficiency of project managers regarding budget performance management. Government should improve the ability of ex-ante performance evaluation, and eliminate ineffective projects through ex-ante performance evaluation.

To alleviate the contradiction in healthcare resources, the Chinese government formally established the framework of a hierarchical medical system in 2015, which contains the following brief generalities: \" separate treatment of emergencies and slows, first-contact care at the primary, two-way referral, and upper and lower linkage, \". This study systematically summarizes and models the connotations of China's hierarchical medical system and a sample of 11,200 chronic disease patients in Tianjin, the largest port city in northern China, was selected for the empirical study to investigate the relationship between chronic disease patients' policy perceptions of the hierarchical medical system and their preference for healthcare. We found that under the strategy of separate treatment, improving the healthcare accessibility, drug supply, and lowering the cost of medical care would have a positive impact on increasing the preference of patients with chronic diseases to go to the primary hospitals. Under the two-way triage strategy, improving the level of physician services, referral convenience and treatment Standards have a positive impact on chronic disease patients' preference for primary care; The impact of the hierarchical medical system on the preference for healthcare differed between groups, focusing on differences in health literacy level, age and household type; The role of \" upper and lower linkage \" is crucial in the hierarchical medical system and it plays a part in mediating the influence of the \" separate treatment of emergencies and slows\" design and the \"two-way referral \" order on the treatment preferences of chronic disease patients. The results of the study provide a reference for the further development of a scientific and rational hierarchical medical system in the future.

Background Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide ( TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy. Results We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice. Conclusion The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma. Graphical Abstract