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Chinese Medical Journal, Beijing (2025)

21/05/2025

FABP4 expression in neutrophils as a predictor of sepsis and SI-ARDS based on BALF transcriptome and peripheral blood validation

Background:
The objective of this study is to delineate the differential gene expression patterns of neutrophils in bronchoalveolar lavage fluid (BALF) from patients with sepsis and those experiencing progression to sepsis-induced acute respiratory distress syndrome (SI-ARDS). Additionally, we aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens.

Methods:
Patients with confirmed sepsis ( n = 14) or SI-ARDS ( n = 11) were recruited. Besides, a control group consisting of patients with unrelated diseases ( n = 7) who required bronchoscopy was also included (cohort 1). We collected the neutrophils in BALF from participants in cohort 1. To validate the identified differentially expressed genes (DEGs) and evaluate neutrophil apoptosis, an additional cohort (cohort 2) was recruited, consisting of 5 healthy controls, 10 patients with sepsis, and 10 patients with SI-ARDS. Peripheral blood neutrophils were collected from participants in cohort 2 for further analysis. DEGs between SI-ARDS patients and controls, sepsis patients and controls, as well as SI-ARDS patients and sepsis patients were identified. And, publicly available datasets were downloaded to compare with local results. Additionally, the DEGs were also identified between patients infected with drug-resistant Klebsiella pneumoniae and those infected with other bacterial pathogens. Furthermore, a third cohort (cohort 3) consisting of 57 sepsis patients and 46 SI-ARDS patients was recruited for investigating the prognostic significance of neutrophils in SI-ARDS.

Results:
In cohort 1, 8/14 of the septic patients and 6/11 of the SI-ARDS patients were affected by drug-resistant Klebsiella pneumonia. There were 9921 DEGs between sepsis patients and controls, 10,252 DEGs between SI-ARDS patients and controls, and 24 DEGs between SI-ARDS and sepsis patients in neutrophils from BALF. Notably, fatty acid-binding protein 4 (FABP4) exhibited significant downregulation in SI-ARDS patients. In cohort 2, peripheral blood analysis confirmed consistent trends, demonstrating that FABP4 expression was decreased, which contributed to the attenuation of neutrophil apoptosis. And FABP4 inhibitor-induced apoptosis resistance was reversed by a phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) inhibitor. Furthermore, survival analysis revealed that SI-ARDS patients with low levels of neutrophil FABP4 expression exhibited poor survival. Additionally, 520 overlapping DEGs were identified between the sepsis and control group comparisons and the SI-ARDS and sepsis group comparisons. Among these overlapping DEGs, 85% were downregulated, predominantly targeting immune-related pathways, whereas a smaller subset was upregulated, mainly associated with metabolism. DEGs in neutrophils in BALF of SI-ARDS and controls notably overlapped with those in neutrophils in peripheral blood. Importantly, DEGs in sepsis/SI-ARDS caused by drug-resistant Klebsiella pneumoniae differed from DEGs in sepsis/SI-ARDS caused by other bacteria. Additionally, FABP4 expression consistently decreased, attenuating neutrophil apoptosis.

Conclusions:
The downregulation of FABP4 in neutrophils was found to inhibit apoptosis through the activation of the PI3K/AKT signaling pathway. Importantly, the expression level of FABP4 in neutrophil emerged as a prognostic indicator for sepsis and SI-ARDS patients, suggesting its potential utility in clinical decision-making to address the challenges posed by this condition.

aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens. Methods: Patients with confirmed sepsis (n = 14) or SI-ARDS (n = 11) were recruited. Besides, a control gro...

21/05/2025

Epigenetically elevated RAD51AP1 regulates the RAD51–UAF1 complex contributing to temozolomide resistance in EGFRvIII glioblastoma

Background:
Epidermal growth factor receptor variant III ( EGFRvIII ) mutation is the most prevalent genetic change in glioblastoma. Abnormal DNA damage repair caused by EGFRvIII, which leads to temozolomide (TMZ) resistance, is a major cause of reduced postoperative survival in glioblastoma patients. This study aims to uncover the molecular mechanism of TMZ resistance in EGFRvIII -mutant glioblastoma.

Methods:
We constructed a CRISPR/Cas9 library to identify synthetic lethal genes for EGFRvIII -bearing cells. Abnormal epigenetic regulation of the RAD51-associated protein 1 ( RAD51AP1 ) promoter was assessed via chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation polymerase chain reaction (ChIP-PCR) analyses. In vitro and in vivo experiments were carried out to investigate the role of the RAD51AP1 gene in TMZ resistance in EGFRvIII -bearing glioblastoma.

Results:
The CRISPR/Cas9 library identified RAD51AP1 , a synthetic lethal gene for EGFRvIII -bearing cells exposed to TMZ. ChIP-seq and ChIP-PCR analyses revealed that acetylated histone H3 lysine 27 (H3K27ac) and SRY-box transcription factor 9 ( SOX9 ) together induced RAD51AP1 transcription in EGFRvIII cells. High expression levels of RAD51AP1 , promoted formation of the RAD51–UAF1 complex to activate homologous recombination and inhibit TMZ-induced DNA damage.

Conclusion:
The results of this study suggest that aberrant RAD51AP1 expression is a crucial mechanism by which EGFRvIII -mutant glioblastoma resists TMZ chemotherapy, laying the groundwork for future personalized medicine.

ients. This study aims to uncover the molecular mechanism of TMZ resistance in EGFRvIII-mutant glioblastoma. Methods: We constructed a CRISPR/Cas9 library to identify synthetic lethal genes for EGFRvIII-bearing cells. Abnormal epigenetic regulation of the RAD51-associated protein 1 (RAD51AP1) promot...

21/05/2025

FLT3 ligand regulates expansion of regulatory T-cells induced by regulatory dendritic cells isolated from gut-associated lymphoid tissues through the Notch pathway

Background:
Regulatory dendritic cell (DCreg) subset exhibits a unique capacity for inducing immune tolerance among the variety subsets of dendritic cells (DCs) within gut-associated lymphoid tissues (GALTs). Fms-like tyrosine kinase 3 ligand (FLT3L) is involved in the differentiation of DCregs and the subsequent expansion of regulatory T-cells (Tregs) mediated by DCregs, though the precise mechanism remains poorly understood. This study aimed to explore the expansion mechanism of Treg induced by DCreg and the role of FLT3L in this process.

Methods:
DCregs were distinguished from other DC subsets isolated from GALTs of BALB/c mice through a mixed lymphocyte reaction assay. The functions and mechanisms by which FLT3L promoted Treg expansion via DCregs were investigated in vitro through co-culture experiments involving DCregs and either CD4 + CD25 − T-cells or CD4 + CD25 + T-cells. Additionally, an in vivo experiment was conducted using a dextran sulfate sodium (DSS)-induced colitis model in mice.

Results:
CD103 + CD11b + DC exhibited DCreg-like functionality and was identified as DCreg for subsequent investigation. Analysis of Foxp3 + Treg percentages within a co-culture system of CD4 + CD25 − T-cells and DCregs, with or without FLT3L, demonstrated the involvement of the FLT3/FLT3L axis in driving the differentiation of precursor T-cells into Foxp3 + Tregs induced by DCregs. Cell migration and co-culture assays revealed that the FLT3/FLT3L axis enhanced DCreg migration toward Tregs via the Rho pathway. Additionally, it was observed that DCregs could promote Treg proliferation through the Notch pathway, as inhibition of Notch signaling by DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) suppressed Treg expansion within the co-culture system of DCregs and CD4 + T-cells or CD4 + CD25 + T-cells. Furthermore, the FLT3/FLT3L axis influenced JAG1 expression in DCregs, indirectly modulating Treg expansion. In vivo experiments further established that FLT3L promoted DCreg expansion and restored Treg balance in DSS-induced colitis models, thereby ameliorating colitis symptoms in mice.

Conclusion:
The FLT3/FLT3L axis is integral to the maintenance of DCreg function in Treg expansion.

s and the subsequent expansion of regulatory T-cells (Tregs) mediated by DCregs, though the precise mechanism remains poorly understood. This study aimed to explore the expansion mechanism of Treg induced by DCreg and the role of FLT3L in this process. Methods: DCregs were distinguished from other D...

21/05/2025

Life’s Essential 8 scores, socioeconomic deprivation, genetic susceptibility, and new-onset chronic kidney diseases

Background:
The American Heart Association recently released a new cardiovascular health (CVH) metric, Life’s Essential 8 (LE8), for health promotion. However, the association between LE8 scores and the risk of chronic kidney disease (CKD) remains uncertain. We aimed to explore the association of LE8 scores with new-onset CKD and examine whether socioeconomic deprivation and genetic risk modify this association.

Methods:
A total of 286,908 participants from UK Biobank and without prior CKD were included between 2006 and 2010. CVH was categorized using LE8 scores: low (LE8 scores

of LE8 scores with new-onset CKD and examine whether socioeconomic deprivation and genetic risk modify this association. Methods: A total of 286,908 participants from UK Biobank and without prior CKD were included between 2006 and 2010. CVH was categorized using LE8 scores: low (LE8 scores

21/05/2025

Clinical practice guidelines for perioperative multimodality treatment of non-small cell lung cancer

Background:
Lung cancer is currently the most prevalent malignancy and the leading cause of cancer deaths worldwide. Although the early stage non-small cell lung cancer (NSCLC) presents a relatively good prognosis, a considerable number of lung cancer cases are still detected and diagnosed at locally advanced or late stages. Surgical treatment combined with perioperative multimodality treatment is the mainstay of treatment for locally advanced NSCLC and has been shown to improve patient survival. Following the standard methods of neoadjuvant therapy, perioperative management, postoperative adjuvant therapy, and other therapeutic strategies are important for improving patients’ prognosis and quality of life. However, controversies remain over the perioperative management of NSCLC and presently consensus and standardized guidelines are lacking for addressing critical clinical issues in multimodality treatment.

Methods:
The working group consisted of 91 multidisciplinary experts from thoracic surgery, medical oncology, radiotherapy, epidemiology, and psychology. This guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The clinical questions were collected and selected based on preliminary open-ended questionnaires and subsequent discussions during the Guideline Working Group meetings. PubMed, Web of Science, Cochrane Library, Scopus, and China National Knowledge Infrastructure (CNKI) were searched for available evidence. The GRADE system was used to evaluate the quality of evidence and grade the strengths of recommendations. Finally, the recommendations were developed through a structured consensus-building process.

Results:
The Guideline Development Group initially collected a total of 62 important clinical questions. After a series of consensus-building conferences, 24 clinical questions were identified and corresponding recommendation were ultimately developed, focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assement, and follow-up protocols for NSCLC.

Conclusions:
This guideline puts forward reasonable recommendations focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assessment, and follow-up protocol of NSCLC. It standardizes perioperative multimodality treatment and provides guidance for clinical practice among thoracic surgeons, medical oncologists, and radiotherapists, aiming to reduce postoperative recurrence, improve patient survival, accelerate recovery, and minimize postoperative complications such as atelectasis.

locally advanced or late stages. Surgical treatment combined with perioperative multimodality treatment is the mainstay of treatment for locally advanced NSCLC and has been shown to improve patient survival. Following the standard methods of neoadjuvant therapy, perioperative management, postoperati...

21/05/2025

LGR5 interacts with HSP90AB1 to mediate enzalutamide resistance by activating the WNT/β-catenin/AR axis in prostate cancer

Background:
Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer.

Methods:
LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes.

Results:
LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide.

Conclusions:
LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.

ne-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. Methods: LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The....

21/05/2025

Global burden of metabolic-associated fatty liver disease: A systematic analysis of Global Burden of Disease Study 2021

Background:
Metabolic-associated fatty liver disease (MAFLD) is a common liver disease and may become the leading cause of severe liver disease in the future. The Global Burden of Disease (GBD) study assesses MAFLD’s impact in countries and regions worldwide, providing insights into its prevalence.

Methods:
Prevalence data for MAFLD from 1990 to 2021 by country and region in all s*x and age groups were collected from the Global Health Data Exchange. The categorization of countries and geographic areas by development was performed using the Sociodemographic Index (SDI).

Results:
Between 1990 and 2021, the global crude prevalence rate of MAFLD increased from 10.6% to 16.1% (beta-coefficient: 0.2%, 95% confidence interval [CI]: 0.2–0.2%, P

ence. Methods: Prevalence data for MAFLD from 1990 to 2021 by country and region in all s*x and age groups were collected from the Global Health Data Exchange. The categorization of countries and geographic areas by development was performed using the Sociodemographic Index (SDI). Results: Between 1...

21/05/2025

SAMSN1 causes sepsis immunosuppression by inducing macrophages to express coinhibitory molecules that cause T-cell exhaustion via KEAP1–NRF2 signaling

Background:
Immunosuppression is closely related to the pathogenesis of sepsis, but the underlying mechanisms have not yet been fully elucidated. In this study, we aimed to examine the role of the Sterile Alpha Motif, Src Homology 3 domain and nuclear localization signal 1 (SAMSN1) in sepsis and elucidate its potential molecular mechanism in sepsis induced immunosuppression.

Methods:
RNA sequencing databases were used to validate SAMSN1 expression in sepsis. The impact of SAMSN1 on sepsis was verified using gene knockout mice. Flow cytometry was employed to delineate how SAMSN1 affects immunity in sepsis, focusing on immune cell types and T cell functions. Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated gene editing in RAW264.7 macrophages enabled interrogation of SAMSN1 ’s regulatory effects on essential macrophage functions, including cell proliferation and phagocytic capacity. The mechanism of SAMSN1 in the interaction between macrophages and T cells was investigated using the RAW264.7 cell line and primary cell lines.

Results:
SAMSN1 expression was significantly increased in patients with sepsis and was positively correlated with sepsis mortality. Genetic deletion of Samsn1 in murine sepsis model improved T cell survival, elevated T cell cytolytic activity, and activated T cell signaling transduction. Concurrently, Samsn1 knockout augmented macrophage proliferation capacity and phagocytic efficiency. In macrophage, SAMSN1 binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), causing nuclear factor erythroid 2-related factor 2 (NRF2) to dissociate from the KEAP1–NRF2 complex and translocate into the nucleus. This promotes the transcription of the coinhibitory molecules CD48/CD86/carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), which bind to their corresponding receptors natural killer cell receptor 2B4 (2B4)/CD152/T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on the surface of T cells, inducing T-cell exhaustion.

Conclusions:
SAMSN1 deletion augmented adaptive T cell immunity and macrophage phagocytic-proliferative dual function. Furthermore, it mediates the KEAP1–NRF2 axis, which affects the expression of coinhibitory molecules on macrophages, leading to T-cell exhaustion. This novel immunosuppression mechanism potentially provides a candidate molecular target for sepsis immunotherapy.

nd elucidate its potential molecular mechanism in sepsis induced immunosuppression. Methods: RNA sequencing databases were used to validate SAMSN1 expression in sepsis. The impact of SAMSN1 on sepsis was verified using gene knockout mice. Flow cytometry was employed to delineate how SAMSN1 affects i...

21/05/2025

Intestinal metabolites in colitis-associated carcinogenesis: Building a bridge between host and microbiome

Microbial-derived metabolites are important mediators of host–microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.

odification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyami...

21/05/2025

The interval of rescue treatment does not affect the efficacy and safety of Helicobacter pylori eradication: A prospective multicenter observational study

Background:
The effect of the interval between previous Helicobacter pylori (H. pylori) eradication and rescue treatment on therapeutic outcomes remains unknown. The aim of this study was to investigate the association between eradication rates and treatment interval durations in H. pylori infections.

Methods:
This prospective observational study was conducted from December 2021 to February 2023 at six tertiary hospitals in Shandong, China. We recruited patients who were positive for H. pylori infection and required rescue treatment. Demographic information, previous times of eradication therapy, last eradication therapy date, and history of antibiotic use data were collected. The patients were divided into four groups based on the rescue treatment interval length: Group A, ≥4 weeks and ≤3 months; Group B, >3 and ≤6 months; Group C, >6 and ≤12 months; and Group D, >12 months. The primary outcome was the eradication rate of H. pylori . Drug compliance and adverse events (AEs) were also assessed. Pearson’s χ 2 test or Fisher’s exact test was used to compare eradication rates between groups.

Results:
A total of 670 patients were enrolled in this study. The intention-to-treat (ITT) eradication rates were 88.3% in Group A, 89.6% in Group B, 89.1% in Group C, and 87.7% in Group D. The per-protocol (PP) eradication rates were 92.9% in Group A, 94.5% in Group B, 94.5% in Group C, and 93.6% in Group D. There was no statistical difference in the eradication rates between groups in either the ITT ( P = 0.949) or PP analysis ( P = 0.921). No significant differences were observed in the incidence of AEs ( P = 0.934) or drug compliance ( P = 0.849) between groups.

Conclusion:
The interval duration of rescue treatment had no significant effect on H. pylori eradication rates or the incidence of AEs.

ections. Methods: This prospective observational study was conducted from December 2021 to February 2023 at six tertiary hospitals in Shandong, China. We recruited patients who were positive for H. pylori infection and required rescue treatment. Demographic information, previous times of eradication...

21/05/2025

Tofacitinib vs. glucocorticoids in mild-to-moderate systemic lupus erythematosus: A real-world study of the CSTAR cohort

An abstract is unavailable.

21/05/2025

Gut microbiota Lactobacillus johnsonii alleviates hyperuricemia by modulating intestinal urate and gut microbiota-derived butyrate

Background:
Gut microbiota are important for uric acid (UA) metabolism within hyperuricemia (HUA); however, the underlying mechanisms of how the gut microbiota regulate intestinal UA metabolism remain unclear. This study aimed to explore the function of the intestine in HUA and to further reveal the possible mechanism.

Methods:
We conducted gut microbiota depletion to validate the role of gut microbiota in UA metabolism. A mouse model of HUA was established, and the gut microbiota and microbiome-derived metabolites were analyzed via 16S RNA gene sequencing and metabolomics analysis. The mechanism of the gut microbiota in HUA was elucidated by in vivo and in vitro experiments.

Results:
Antibiotic treatment elevated serum UA, disturbed purine metabolism, and decreased the relative abundance of Lactobacillus. HUA mice had a lower relative abundance of Lactobacillus johnsonii (L. johnsonii) and decreased gut butyrate concentration. Supplementation of L. johnsonii significantly reduces serum UA in hyperuricemia mice by preventing UA synthesis and promoting the excretion of gut purine metabolites. In addition, L. johnsonii enhanced intestinal UA excretion by heightening the urate transporter ABCG2 (adenosine triphosphate-binding cassette transporter, subfamily G, member 2) expression, and increasing the levels of butyrate, which upregulated ABCG2 expression via the Wnt5a/b/β-catenin signaling pathway.

Conclusion:
Our results suggest that gut microbiota and microbiota-derived metabolites directly regulate gut UA metabolism, highlighting potential applications in the treatment of diet-induced HUA by targeting gut microbiota and its metabolites.

al the possible mechanism. Methods: We conducted gut microbiota depletion to validate the role of gut microbiota in UA metabolism. A mouse model of HUA was established, and the gut microbiota and microbiome-derived metabolites were analyzed via 16S RNA gene sequencing and metabolomics analysis. The....

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