Juan Wang

Rationale: Carbapenem-resistant gram-negative bacterial infections remain a challenge. Colistin is an important treatment option but exhibits substantial pharmacokinetic variability and nephrotoxicity, particularly in critically ill patients with altered renal function. Patient concerns: Five critically ill patients (aged from 25 to 94) with infections in the setting of heterogeneous underlying conditions, including hematologic malignancy, acute respiratory failure, severe trauma, chronic obstructive pulmonary disease, and acute cerebral infarction. Their renal function varied markedly, ranging from augmented renal clearance to severe renal impairment. Diagnoses: Carbapenem-resistant Klebsiella pneumoniae , carbapenem-resistant Acinetobacter baumannii , or both were identified during hospitalization. The patients exhibited different renal function profiles. Acute kidney injury was observed in cases 2 to 5, and cases 3 to 5 required continuous renal replacement therapy. Interventions: All patients received intravenous colistin sulfomethate sodium, with plasma colistin concentrations quantified by liquid chromatography–triple quadrupole mass spectrometry; dosing was adjusted according to clinical course and renal function. Outcomes: Colistin plasma concentrations varied considerably among patients and were not simply inversely related to renal function. All patients achieved the ratio of the unbound area under the concentration–time curve to the minimum inhibitory concentration target for systemic infection, and 3 additionally achieved the higher target for pulmonary infection; however, a favorable clinical outcome was observed in only 2 of the 5 cases. Lessons: Colistin exposure cannot be predicted only from renal function; therapeutic drug monitoring may assist in individualized colistin sulfomethate sodium dosing, particularly in patients with augmented renal clearance or markedly altered renal function. Moreover, the target of unbound area under the concentration–time curve to the minimum inhibitory concentration attainment does not necessarily translate into clinical success, indicating that clinical efficacy is also influenced by disease severity and patient-specific factors.

Triptolide (TP), a potent bioactive compound from the Chinese herb Tripterygium wilfordii, demonstrates strong anti-inflammatory and immunosuppressive effects. Evidence indicates that TP modulates macrophage polarization and regulates inflammatory responses through multiple signaling pathways, exerting significant immunomodulatory effects in various diseases. This review summarizes the immunomodulatory mechanisms of TP on macrophage function, with a focus on its therapeutic potential in diverse diseases. We also explore strategies to mitigate TP's toxicity, including formulation enhancements, targeted delivery, ligand conjugation, and structural modifications. Finally, we highlight the therapeutic utility and clinical progress of TP derivatives, offering insights into their broad clinical applications. TP modulates macrophage migration, polarization, phagocytosis, and the production of cytokines and chemokines, thereby alleviating various macrophage-centric diseases. Strategies to reduce TP's toxicity not only mitigate systemic adverse effects but also enhance therapeutic efficacy through macrophage-targeted delivery. The clinical progress of TP derivatives demonstrates their broad therapeutic potential. TP's macrophage-targeted immunomodulation shows promising therapeutic potential for macrophage-centric diseases. However, its limited clinical use due to poor water solubility and significant toxicity highlights the need for further research to develop effective toxicity-reduction strategies.

Background: Elongation Factor Tu GTP Binding Domain Containing 2 (EFTUD2), a conserved spliceosomal GTPase, is involved in craniofacial development and various cancers, but its role in lung adenocarcinoma (LUAD) remains unclear.Methods: EFTUD2 expression in LUAD tissues was analyzed using data from TCGA and GEO, and validated by immunohistochemistry, RT-qPCR, and Western blotting. The relationship between EFTUD2 expression and clinical features was examined using Fisher’s exact test. Diagnostic and prognostic analyses were performed in R. Hub genes related to EFTUD2 were identified through topological algorithms, and immune infiltration was assessed using CIBERSORT. The cGAS-STING pathway and m6A modification were also analyzed in the TCGA LUAD cohort. Functional assays were conducted to assess EFTUD2’s impact on LUAD cell proliferation, cell cycle, invasion, and metastasis, while glycolytic enzyme levels were measured by Western blotting.Results: EFTUD2 was upregulated in LUAD tissues and cells, correlating with N classification, visceral pleural invasion, intravascular tumor embolism, and cytokeratin-19 fragment antigen 21-1. Sixteen EFTUD2-related hub genes were identified. Higher EFTUD2 expression was linked to altered immune cell infiltration, with increased TumorPurity scores and decreased StromalScore, ImmuneScore, and ESTIMATEScore values. Gene enrichment analyses highlighted EFTUD2’s involvement in cell adhesion, immune response. EFTUD2 was strongly associated with the cGAS-STING pathway and m6A modification. EFTUD2 knockdown inhibited LUAD cell proliferation, migration, and tumorigenicity, causing G0/G1 phase cell cycle arrest, and altered glycolytic enzyme expression. These findings may suggest that EFTUD2 positively regulates the progression of LUAD and modulates the glycolytic activity of tumor cells, making it valuable for LUAD treatment and prognosis.Conclusions: EFTUD2 is a potential diagnostic and prognostic marker for LUAD, associated with immune infiltration, the tumor microenvironment, the cGAS-STING pathway, m6A modification, and glycolysis.

The formation of mature mRNA is inseparable from the processing of RNA precursors and splicing by the spliceosome. The spliceosome is a multi‑protein complex composed of five small nuclear ribonucleoproteins. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a component of spliceosome complex that is involved in the reorganization of the spliceosome complex, thereby promoting the removal of introns from precursor mRNA. Therefore, EFTUD2 can regulate embryonic development and innate immunity by modulating the splicing of various mRNAs. The mutations in EFTUD2 itself also lead to developmental defects and clinical manifestations in mandibulofacial dysostosis, the nervous system, the circulatory system, the digestive system and the reproductive system. Furthermore, the overexpression of EFTUD2 promotes the progression of hepatocellular carcinoma, breast cancer and colorectal cancer. The present review discussed the molecular mechanisms by which EFTUD2 exerts its physiological functions, focusing on EFTUD2 mutations and their corresponding clinical manifestations. It aimed to provide insight for the diagnosis and treatment of EFTUD2‑related diseases.

Background: Non‐small‐cell lung cancer (NSCLC) often presents at later stages, typically associated with poor prognosis. Autophagy genes play a role in the progression of tumors. This study investigated the clinical relevance, prognostic value, and biological significance of RBBP4 in NSCLC.Methods: We assessed RBBP4 expression using the GSE30219 and TCGA NSCLC datasets and NSCLC cells, exploring its links with clinical outcomes, tumor immunity, and autophagy genes through bioinformatics analysis after transcriptome sequencing of RBBP4‐knockdown and control PC9 cells. We identified differentially expressed genes (DEGs) and conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein–protein interaction network analyses. The significance of autophagy‐related DEGs was evaluated for diagnosis and prognosis using the GSE30219 dataset. Experiments both in vivo and in vitro explored the biological mechanisms behind RBBP4‐mediated autophagic cell death in NSCLC.Results: RBBP4 overexpression in NSCLC correlates with a poorer prognosis. Eighteen types of immune cell were significantly enriched in cultures that had low RBBP4 expression compared high expression. DEGs associated with RBBP4 are enriched in autophagy pathways. Transcriptomic profiling of the PC9 cell line identified autophagy‐related DEGs associated with RBBP4 that exhibited differential expression in NSCLC, suggesting prognostic applications. In vitro experiments demonstrated that RBBP4 knockdown induced autophagy and apoptosis in PC9 cells, promoting cell death, which was inhibited by 3‐MA. In vivo, targeted siRNA against RBBP4 significantly reduced tumor development in PC9 cell‐injected nude mice, elevating autophagy‐related protein levels and inducing apoptosis and necrosis in tumor tissues.Conclusion: In NSCLC, RBBP4 upregulation correlates with poor prognosis and altered immunity. Its knockdown induces autophagic cell death in NSCLC cells. These results indicate RBBP4 as a potential NSCLC diagnostic marker and its autophagy modulation as a prospective therapeutic target.

Histone chaperones serve a pivotal role in maintaining human physiological processes. They interact with histones in a stable manner, ensuring the accurate and efficient execution of DNA replication, repair and transcription. Retinoblastoma binding protein (RBBP)4 and RBBP7 represent a crucial pair of histone chaperones, which not only govern the molecular behavior of histones H3 and H4, but also participate in the functions of several protein complexes, such as polycomb repressive complex 2 and nucleosome remodeling and deacetylase, thereby regulating the cell cycle, histone modifications, DNA damage and cell fate. A strong association has been indicated between RBBP4/7 and some major human diseases, such as cancer, age‑related memory loss and infectious diseases. The present review assesses the molecular mechanisms of RBBP4/7 in regulating cellular biological processes, and focuses on the variations in RBBP4/7 expression and their potential mechanisms in various human diseases, thus providing new insights for their diagnosis and treatment.

Non-small cell lung cancer (NSCLC) is a malignant tumor with high incidence worldwide. Triptolide (TP), extracted from Tripterygium wilfordii Hook F, exhibits potent broad-spectrum antitumor activity. Although some mechanisms through which TP inhibits NSCLC are well understood, those that involve ribosomal proteins remain yet to be understood. In this study, the transcriptome and proteome were integrated and analyzed. Our data indicated ribosomal protein L4 (RPL4) to be a core hub protein in the protein-protein interaction network. RPL4 is overexpressed in NSCLC tissues and cells. Transfection with siRPL4 or TP treatment alone arrested the cell cycle in the G1 phase, induced cell apoptosis, and repressed cell invasion. Compared to treating cells with TP alone or siRPL4, treating them with siRPL4–TP enhanced the inhibition of NSCLC cells. Reduced RPL4 expression reinforced the inhibitory effects of TP on NSCLC cells by disrupting the MDM2-P53 pathway and by altering the expression of PARP1/Snail/cyclin D1. In vivo assays verified that TP induced cell apoptosis and reduced RPL4 expression in xenografts. These findings provide clues to facilitate the development of effective TP-based therapeutic strategies to kill NSCLC cells.

Background and Objective. Long noncoding RNAs (lncRNAs) have attracted increasing attention as novel biomarkers facilitating early diagnosis, prognostic predictions, and treatment of colorectal cancer (CRC). LINC01314 is aberrantly expressed in many cancers, suggesting its role in tumor development. However, its expression and underlying molecular mechanism in CRC remain to be clarified. The aim of this study was to evaluate the expression levels of LINC01314 and its potentially interacting microRNA (miRNA) miR-96 in CRC patients, as well as clinical values. Methods. A tissue microarray (TMA) containing 76 individual colorectal tumor samples and 28 adjacent normal samples was constructed, and the expression levels of LINC01314 and miR-96 were detected by fluorescence in situ hybridization. Results. The expression levels of both LINC01314 and miR-96 were upregulated in CRC tissues and were associated with vascular metastasis ( ). A significantly positive correlation was observed between LINC01314 and miR-96 expression in tumor tissues ( , ). Dominant expression of LINC01314 was a risk factor for both blood vessel invasion ( ) and poor 5-year survival ( , hazard ). The Kaplan–Meier analysis indicated that patients with LINC01314-dominant expression exhibited worse 5-year survival rates than those with miR-96-dominant expression ( ). Conclusion. The expression patterns of both LINC01314 and miR-96 may be diagnostic of, and prognostic for, CRC. These findings will facilitate further exploration of the molecular mechanism of lncRNAs in CRC.

The epidermal growth factor receptor‑tyrosine kinase inhibitor (EGFR‑TKI), gefitinib, is used widely to treat non‑small cell lung cancer (NSCLC) with EGFR‑activating mutations. Unfortunately, the acquired drug resistance promoted by epithelial‑mesenchymal transition (EMT) markedly limits the clinical effects and remains a major barrier to a cure. Our previous isobaric tags for relative and absolute quantitation‑based proteomics analysis revealed that the E‑cadherin protein level was markedly upregulated by triptolide (TP). The present study aimed to determine whether TP reverses the gefitinib resistance of human lung cancer cells by regulating EMT. It was revealed that TP combined with gefitinib synergistically inhibited the migration and invasion of lung adenocarcinoma cell line A549; the combination treatment had a significantly better outcome than that of TP and gefitinib alone. Moreover, TP effectively increased the sensitivity of drug resistant A549 cells to gefitinib by upregulating E‑cadherin protein expression and downregulating the MMP9, SNAIL, and vimentin expression levels. The dysregulated E‑cadherin expression of gefitinib‑sensitive cells induced gefitinib resistance, which could be overcome by TP. Finally, TP combined with gefitinib significantly inhibited the growth of xenograft tumors induced using gefitinib‑resistant A549 cells, which was associated with EMT reversal and E‑cadherin signaling activation in vivo. The present results indicated that the combination of TP and TKIs may be a promising therapeutic strategy to treat patients with NSCLCs harboring EGFR mutations.

Persistence of human immunodeficiency virus 1 (HIV-1) latency and residual immune activation remain major barriers to treatment in patients receiving highly active antiretroviral therapy (HAART). In the present study, we investigated the molecular mechanisms of persistent HIV infection and residual immune activation in HAART-treated patients. We showed that the expression level of B-cell CLL/lymphoma 11B (BCL11B) was significantly increased in CD4⁺T cells from HIV-infected patients undergoing HAART, and this was accompanied by increased expression of BCL11B-associated chromatin modifiers and inflammatory factors in comparison to healthy controls and untreated patients with HIV. In vitro assays showed that BCL11B significantly inhibited HIV-1 long terminal repeat (LTR)-mediated transcription. Knockdown of BCL11B resulted in the activation of HIV latent cells, and dissociation of BCL11B and its related chromatin remodeling factors from the HIV LTR. Our findings suggested that increased expression of BCL11B and its related chromatin modifiers contribute to HIV-1 transcriptional silencing, and alteration of BCL11B levels might lead to abnormal transcription and inflammation.