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Introduction: The escalating global surge in Rifampicin-resistant strains poses a formidable challenge to the worldwide campaign against tuberculosis (TB), particularly in developing countries. The frequent reports of suboptimal treatment outcomes, complications, and the absence of definitive treatment guidelines for Rifampicin-resistant spinal TB (DSTB) contribute significantly to the obstacles in its effective management. Consequently, there is an urgent need for innovative and efficacious drugs to address Rifampicin-resistant spinal tuberculosis, minimizing the duration of therapy sessions. This study aims to investigate potential targets for DSTB through comprehensive proteomic and pharmaco-transcriptomic analyses.Methods: Mass spectrometry-based proteomics analysis was employed to validate potential DSTB-related targets. PPI analysis confirmed by Immunohistochemistry (IHC) and Western blot analysis.Results: The proteomics analysis revealed 373 differentially expressed proteins (DEPs), with 137 upregulated and 236 downregulated proteins. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses delved into the DSTB-related pathways associated with these DEPs. In the context of network pharmacology analysis, five key targets—human leukocyte antigen A chain (HLAA), human leukocyte antigen C chain (HLA-C), HLA Class II Histocompatibility Antigen, DRB1 Beta Chain (HLA-DRB1), metalloproteinase 9 (MMP9), and Phospholipase C-like 1 (PLCL1)—were identified as pivotal players in pathways such as “Antigen processing and presentation” and “Phagosome,” which are crucially enriched in DSTB. Moreover, pharmaco-transcriptomic analysis can confirm that 58 drug compounds can regulate the expression of the key targets.Discussion: This research confirms the presence of protein alterations during the Rifampicin-resistant process in DSTB patients, offering novel insights into the molecular mechanisms underpinning DSTB. The findings suggest a promising avenue for the development of targeted drugs to enhance the management of Rifampicin-resistant spinal tuberculosis.

Resistiveness to care (RTC) is a common abnormal behavioral symptom in dementia patients during the care process, which seriously negatively impacts the patients and their caregivers. The research on assessment tools for RTC started earlier in foreign countries, and has explored relevant aspects more deeply and comprehensively. Since the Resistiveness to Care Scale for Dementia of the Alzheimer's Type (RTC-DAT) came out in 1999, overseas researchers have made several revisions to its content and methods, and have expanded it to include different scales for assessing RTC in different care settings. In this paper, we present a review of the tools developed overseas to assess RTC in patients with dementia, focusing on the differences in contents and methods of the tools, and the characteristics, strengths and weaknesses of each tool, which may offer insights into China's development of such a tool or introduction of a foreign tool applicable to China. The evaluation method of the assessment tools currently used in foreign research on RTC in patients with dementia is mostly based on the researcher-observed method used in the initial RTC-DAT, which faces many limitations in its practical application. The Refusal of Care Informant Scale (RoCIS) developed in 2022 attempts to use the method of evaluation by consulting caregivers, which is commonly used in other fields, providing a new way for China's introduction or development of a RTC assessment tool applicable to Chinese dementia patients. Considering various types of these tools, we recommend that the tool should be selected according to its applicability assessed comprehensively.

Resistance to care (RTC) is a common abnormal behavioral manifestation of behavioral and psychological symptoms of dementia. Although RTC is strongly associated with agitation or aggressive behavior, it is a specific behavioral response of dementia patients to caregivers, and may result in a negative feedback mechanism as it often directly, negatively impacts caregivers. Currently, there are rare studies on RTC in dementia patients or measuring RTC in these patients using relevant tools in China, which may be because domestic researchers easily confuse RTC with other behavioral concepts. While the concept of RTC was introduced earlier in foreign studies, and has been systematically explored and studied. In this paper, we reviewed available relevant studies, and gave a detailed description of the concept, impact, assessment tools, and interventions regarding RTC, with a view to providing ideas and strategies for the study of RTC in patients with dementia in China.

Abstract Background Endothelial-mesenchymal transition (EndoMT) is an emerging adaptive process that modulates lymphatic endothelial function to drive aberrant lymphatic vascularization in the tumour microenvironment (TME); however, the molecular determinants that govern the functional role of EndoMT remain unclear. Here, we show that cancer-associated fibroblast (CAF)-derived PAI-1 promoted the EndoMT of lymphatic endothelial cells (LECs) in cervical squamous cell carcinoma (CSCC). Methods Immunofluorescent staining of α-SMA, LYVE-1 and DAPI were examined in primary tumour samples obtained from 57 CSCC patients. Assessment of cytokines secreted by CAFs and normal fibroblasts (NFs) was performed using human cytokine antibody arrays. The phenotype of EndoMT in lymphatic endothelial cells (LECs), gene expression levels, protein secretion and activity of signaling pathways were measured by real-time RT-PCR, ELISA or western blotting. The function of lymphatic endothelial monolayers was examined by transwell, tube formation assay, transendothelial migration assay in vitro. Lymphatic metastasis was measured using popliteal lymph node metastasis model. Furthermore, association between PAI-1 expression and EndoMT in CSCC was analyzed by immunohistochemistry. The Cancer Genome Atlas (TCGA) databases was used to assess the association of PAI-1 with survival rate in CSCC. Results CAF-derived PAI-1 promoted the EndoMT of LECs in CSCC. LECs undergoing EndoMT could initiate tumour neolymphangiogenesis that facilitated cancer cell intravasation/extravasation, which in turn promoted lymphatic metastasis in CSCC. Mechanistically, PAI-1 activated the AKT/ERK1/2 pathways by directly interacting with low-density lipoprotein receptor-related protein (LRP1), thereby leading to elevated EndoMT activity in LECs. Blockade of PAI-1 or inhibition of LRP1/AKT/ERK1/2 abrogated EndoMT and consequently attenuated CAF-induced tumour neolymphangiogenesis. Furthermore, clinical data revealed that increased PAI-1 levels positively correlated with EndoMT activity and poor prognosis in CSCC patients. Conclusion Our data indicate that CAF-derived PAI-1 acts as an important neolymphangiogenesis-initiating molecular during CSCC progression through modulating the EndoMT of LECs, resulting in promotion of metastasis ability in primary site. PAI-1 could serve as an effective prognostic biomarker and therapeutic target for CSCC metastasis.

AimTo identify functional lung adenocarcinoma (LUAD) risk SNPs.Materials & methodsEighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression.ResultsForty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD.ConclusionIntegration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.