Current Medical Science最新文献

mRNA vaccines have emerged as a transformative platform in oncology, offering significant advantages in rapid development, flexibility, and safety over traditional modalities. However, their clinical translation faces challenges such as mRNA instability, inefficient in vivo delivery, and the immunosuppressive tumor microenvironment (TME). This review comprehensively outlines recent advancements in overcoming these hurdles. We discuss the molecular design of mRNA vaccines, including non-replicating and self-amplifying RNAs, and highlight breakthroughs in delivery strategies, particularly lipid nanoparticles (LNPs), that enhance stability and immunogenicity. Furthermore, we explore various administration routes and their impact on eliciting robust antitumor immunity. The review also covers the classification of antigens-viral, tumor-associated, and neoantigens-and the innovative use of mRNA to encode immunomodulators to reprogram the TME. Finally, we address key considerations for clinical translation, including manufacturing, stability, safety, and combination strategies with immunotherapies. By synthesizing these developments, this review underscores the potential of mRNA vaccines to realize personalized cancer immunotherapy and outlines future directions for the field.

Sepsis-associated encephalopathy (SAE) is a critical consequence of sepsis, marked by elevated morbidity and fatality rates. An unbalanced inflammatory response is a significant pathogenic mechanism. The blood-brain barrier (BBB) is an essential element of the central nervous system (CNS). Sepsis can impact the BBB and neural networks in multiple ways, especially via microglia, astrocytes, and neurons. Long non-coding RNAs (lncRNAs) can participate in the development of various diseases by modulating inflammatory responses, cellular metabolism, and immune cell functions. They not only impact the BBB but also directly influence neurons, affecting the development and prognosis of SAE. This review summarizes the current research status of lncRNAs in SAE, highlights the latest research advances of lncRNAs in sepsis and related diseases, and aims to explore their new application prospects in SAE, offering new targets and methodologies for its diagnosis and therapy.

Objective: Brown and beige adipocytes dissipate energy through thermogenesis, and the impaired thermogenic function of these adipocytes is a key driver of obesity and related metabolic disorders. However, the molecular mechanisms governing adipocyte thermogenesis are not fully understood. This study investigated the role of inorganic pyrophosphatase 1 (PPA1) in regulating adipocyte thermogenesis and assessed its potential as a therapeutic target for obesity and metabolic disorders.

Methods: To investigate the function of PPA1 in adipose tissue thermogenesis, we generated adipose-specific heterozygous PPA1 knockout mice via the Cre-loxP system and established cold exposure models. PPA1 deletion effects were assessed by hematoxylin and eosin (H&E) staining, immunofluorescence, quantitative polymerase chain reaction (qPCR), and immunoblotting. Mitochondrial changes during browning were further characterized via transmission electron microscopy (TEM), mitochondrial DNA (mtDNA) quantification, qPCR, and Western blotting. The molecular mechanisms involved were subsequently dissected via mass spectrometry, coimmunoprecipitation (Co-IP), and immunofluorescence colocalization.

Results: Adi-PPA1^fl/+ mice presented impaired adipose tissue thermogenesis upon cold exposure. Mechanistically, PPA1 deficiency impaired adipose browning in an enzyme activity-independent manner. PPA1 knockdown promoted the aberrant translocation and accumulation of fused in sarcoma (FUS) to mitochondria, which triggered mitochondrial dysfunction and suppressed browning. Crucially, silencing FUS effectively rescued the mitochondrial defects caused by PPA1 depletion.

Conclusion: PPA1 functions as a nonenzymatic positive regulator of adipocyte thermogenesis by interacting with FUS to prevent its mitochondrial mislocalization, thereby maintaining mitochondrial function and promoting adipose browning. These findings highlight PPA1 as a potential therapeutic avenue for obesity and metabolic disorders.

Objective: Long non-coding RNAs (lncRNAs) are critical in the pathogenesis of hematological malignancies, including acute myeloid leukemia (AML). However, the specific role and underlying mechanisms of the lncRNA chromosome 9 open reading frame 139 (C9orf139) in AML remain unclear. This study aimed to investigate the role and molecular mechanism of C9orf139 in AML development.

Methods: AML-related sequencing and microarray data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Significant lncRNAs and mRNAs influencing AML progression were identified and analyzed. A competing endogenous RNA network involving lncRNA-microRNA (miRNA)3-mRNA interactions was subsequently constructed. The expression levels of C9orf139, miR-24-3p, and human TAO kinase 1 (TAOK1) were assessed via real-time fluorescent quantitative polymerase chain reaction (PCR). Cell proliferation was evaluated via the Cell Counting Kit-8 (CCK8) assay, whereas Transwell assays were used to assess cell invasion and migration. Apoptosis was measured by Annexin V Fluorescein Isothiocyanate (FITC) double staining. Tumor formation in nude mice was assessed to examine the effect of C9orf139 on in vivo tumor growth. The C9orf139-miR-24-3p-TAOK1 regulatory axis was validated via dual luciferase reporter assays and RNA-binding protein immunoprecipitation (RIP). Western blot assays were used to assess the expression and phosphorylation of key proteins in the mitogen-activated protein kinase (MAPK) signaling pathway.

Results: Bioinformatics analysis identified C9orf139 and TAOK1 as differentially expressed genes that play key roles in AML pathogenesis. The C9orf139-miR-24-3p-TAOK1 axis was tightly linked to AML development, as confirmed by clinical sample analysis. In vitro, C9orf139 downregulation resulted in reduced proliferation, invasion, and migration and enhanced the apoptosis of AML cells. In vivo, the inhibition of C9orf139 significantly impaired tumor growth in nude mice. The regulatory axis was further validated. C9orf139 knockdown reduced the phosphorylation levels of the key MAPK pathway proteins, including Raf, mitogen-activated protein kinase kinase (MEK), and extracellular regulated protein kinase (ERK).

Conclusion: C9orf139 regulates AML progression by activating the MAPK signaling pathway through the C9orf139-miR-24-3p-TAOK1 axis.

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are characterized by an uncertain malignant potential and exhibit prominent sex cord-like differentiation. The purpose of this study was to comprehensively review the clinicopathological characteristics of UTROSCTs and analyze eight cases of UTROSCTs treated at our hospital. We conducted an extensive review of the relevant literature and gathered pertinent data. In addition, we identified eight patients with UTROSCTs and analyzed their clinical and pathological features, diagnosis, treatment, and prognosis. Patients presented with symptoms such as abnormal vaginal bleeding or uterine mass detection. Surgical interventions varied, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy, with adjuvant therapy given to one patient. All eight patients are currently disease-free, with the longest follow-up period being nearly 10 years. Our systematic review of UTROSCTs summarized the clinical and pathological features and revealed several novel markers, including ESR1-NCOA2-3, GREB1-NCOA1-3, GREB1-CTNNB1, and GREB1-NR4A3. UTROSCTs are rare mesenchymal tumors with unclear histogenesis and uncertain malignant potential. Although our understanding of UTROSCTs remains incomplete, the promising findings and increasing availability of clinical data will contribute to the further understanding and development of this rare neoplasm.

Objective: IgA nephropathy (IgAN) is the most prevalent form of primary glomerular disease. However, its diagnosis is contingent on kidney biopsy. Therefore, noninvasive biomarkers are urgently needed for diagnosis. This study aims to identify novel urinary biomarkers that differentiate IgAN from other common primary glomerular diseases, specifically membranous nephropathy (MN) and minimal change disease (MCD).

Methods: The peripheral blood mononuclear cell (PBMC) transcriptome dataset GSE73953 was obtained from the GEO database. Differential gene expression, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene Ontology (GO) enrichment, and immune infiltration analyses were performed. Protein-protein interaction (PPI) analysis and lysosome-related genes were used to identify hub genes. The expression of the hub gene ATP6V1D in urine and kidney tissues from individuals with IgAN, healthy controls, MCD and MN patients was assessed using enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunostaining techniques. Spearman's correlation analysis was employed to investigate the relationships between the concentration of ATP6V1D in urine, the concentration of galactose-deficient IgA1 (GD-IgA1), and the clinical data of patients. The receiver operating characteristic (ROC) curve was used to assess the role of urine ATP6V1D levels in distinguishing IgAN from MN and MCD.

Results: ATPase was identified as the principal intracellular structure associated with differentially expressed genes (DEGs) between IgAN patients and healthy controls in PBMCs. ATP6V1D was identified as a hub gene at the intersection of lysosome-related and differential genes. ATP6V1D levels were lower in PBMCs, urine, and kidney samples from IgAN patients than in those from healthy individuals, MCD and MN patients. The decreased urinary ATP6V1D levels and increased GD-IgA1 levels in IgAN patients were further validated. These changes were positively correlated with 24-h urine protein levels. Notably, a negative correlation was observed between ATP6V1D and GD-IgA1 levels. ROC curve analysis demonstrated that urinary ATP6V1D (AUC = 0.972) and GD-IgA1 (AUC = 0.952) had significant discriminative power in distinguishing IgAN patients from MCD and MN patients, with no significant difference in predictive performance between the two biomarkers (P > 0.05).

Conclusions: The findings underscore the potential utility of the urine ATP6V1D concentration as a biomarker to distinguish IgAN from MN and MCD.

Objective: To develop a novel prognostic scoring system for severe cytokine release syndrome (CRS) in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 chimeric antigen receptor (CAR)-T-cell therapy, aiming to optimize risk mitigation strategies and improve clinical management.

Methods: This single-center retrospective cohort study included 125 B-ALL patients who received anti-CD19 CAR-T-cell therapy from January 2017 to October 2023. These cases were selected from a cohort of over 500 treated patients on the basis of the availability of comprehensive baseline data, documented CRS grading, and at least 3 months of follow-up. Data on patient demographics, treatment history, laboratory parameters, CAR-T-cell characteristics, safety, and efficacy endpoints were collected. CRS severity was graded according to the 2019 ASTCT consensus criteria. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with CRS severity, and a prognostic model was constructed.

Results: The overall incidence of CRS was 67.2%, with 13.6% having grade ≥ 3 (severe) CRS. Higher baseline and post-lymphodepletion minimal residual disease (MRD) levels and neutropenia on day 7 post-infusion were significantly associated with severe CRS. Inflammatory markers (CRP, ferritin, and IL-6) and coagulation dysfunction (APTT) on day 7 post-infusion were also predictive of CRS severity. The prognostic model incorporating these factors demonstrated robust discriminatory ability, with an area under the ROC curve of 0.875.

Conclusion: This study developed a novel prognostic scoring system for severe CRS in Chinese B-ALL patients receiving anti-CD19 CAR-T-cell therapy. The model integrates clinical and laboratory parameters to facilitate early identification and management of severe CRS. Further validation in larger, prospective cohorts is warranted.

Background: Konjac oligosaccharide (KOS), which is produced through the degradation of konjac glucomannan via enzymatic, chemical, or physical treatments, has been found to have laxative effects. The current study aimed to elucidate the mechanisms underlying the laxative effect of KOS.

Methods: KOS was administered by gavage to wild-type and 5-hydroxytryptamine 4 receptor (5-HT4R)-knockout C57BL/6 mice subjected to loperamide-induced constipation for four weeks. Following treatment, feces, blood, small intestine, colonic tissue, and intestinal contents were collected. Constipation-related parameters, gastrointestinal hormones, and Ca²⁺ concentrations were evaluated. Histopathological changes were examined via hematoxylin and eosin staining. Immunofluorescence staining, Western blotting, and immunohistochemical staining were performed to detect the 5-HT4R/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. Isolated smooth muscle cells (SMCs) were treated with KOS and GR113808 (a 5-HT4R antagonist), morphologically observed under an inverted microscope, and identified by α-SMA immunofluorescence staining. Cell viability was assessed via CCK-8 assays. 5-HT4R/cAMP/PKA/p-CREB pathway activity in SMCs was detected via Western blotting.

Results: KOS alleviated loperamide-induced constipation in mice. KOS activated the 5-HT4R/cAMP/PKA/p-CREB pathway in loperamide-induced constipated mice. The protective effect of KOS was significantly diminished in 5-HT4R^-/- mice. KOS promoted the proliferation of SMCs by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.

Conclusion: KOS improves loperamide-induced constipation by activating the 5-HT4R/cAMP/PKA/p-CREB signaling pathway.

Objective: Acute myeloid leukemia (AML) is a highly heterogeneous disease, and molecular events such as DNMT3A gene mutations are associated with poor prognosis in AML patients. Consequently, there is an urgent need for a novel therapeutic approach for AML.

Methods: DNMT3A mRNA and protein expression were confirmed in DNMT3A-mutant AML cells via RT-qPCR and Western blotting. Cell proliferation and apoptosis were assessed via CCK-8 and Annexin V/PI staining, respectively. Flow cytometry was used to analyze surface antigens and CD44v6 CAR-T-cell transfection efficiency. CD44v6-directed CAR plasmids were constructed, and lentiviruses were packaged. Methylation-specific PCR was used to evaluate differences in promoter methylation, whereas ELISA was used to measure cytokine secretion.

Results: In this study, we found that the DNMT3A-mutant group presented significantly increased expression of CD44v6 on the cell surface. Methylation of the CD44 promoter region was lower in the mutant group than in the control group. CD44v6 CAR-T cells exhibited specific cytotoxicity against DNMT3A-mutant AML cells. Furthermore, pretreatment with low concentrations of decitabine significantly enhanced the killing effect of CD44v6 CAR-T cells on DNMT3A-mutant AML cells (P < 0.05). Additionally, decitabine treatment upregulated the expression of CD44v6 on the surface of DNMT3A-mutant AML cells (P < 0.05).

Conclusion: CD44v6 is a promising CAR-T-cell therapy target in AML patients with DNMT3A mutations. Notably, treatment with decitabine resulted in increased CD44v6 expression on the cell surface of DNMT3A-mutant AML cells. This increase in CD44v6 expression facilitates improved recognition and targeting by CD44v6 CAR-T cells.

Objective: To investigate the differential expression of microRNA-144-3p in endometrial cells exposed to copper ions in vitro. The specific mechanism by which microRNA-144-3p is involved in Cu²⁺-induced damage to the human endometrial epithelial cells (HEECs) was explored.

Methods: HEECs were cultured in copper-containing culture medium to simulate changes in the endometrium after copper intrauterine device (Cu-IUD) implantation. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the differential expression of miR-144-3p in HEECs after Cu²⁺ treatment. MiRNAs, siRNAs and related inhibitors were used to treat HEECs. The expression levels of related downstream genes were then analyzed by RT-qPCR, Western blotting and immunofluorescence to explore the specific mechanism involved.

Results: MiR-144-3p was significantly upregulated in the Cu²⁺-treated HEECs. The expression of P-NF-κB, MMP9, TGF-β3 and P-SMAD3 was significantly decreased in HEECs treated with 10 μg/mL Cu²⁺. MiR-144-3p regulated the expression of metallothionein 1A (MT1A) and thrombospondin-1 (THBS-1) in Cu²⁺-treated HEECs. The expression of P-NF-κB can be regulated by MT1A, and an inhibitor of P-NF-κB can significantly reduce the expression of MMP9 in Cu²⁺-treated HEECs. The expression of TGF-β3 can be regulated by THBS-1, and a TGF-β3 inhibitor can significantly reduce the expression of SMAD3 in Cu²⁺-treated HEECs. The proliferative capacity of HEECs treated with MMP9 or SMAD3 inhibitors was significantly reduced.

Conclusions: The increased Cu²⁺ concentration led to the upregulation of miR-144-3p, further reducing the expression levels of its target genes (MT1A and THBS-1), which in turn downregulated the expression of NF-κB, MMP9, TGF-β3 and SMAD3, ultimately leading to increased endometrial cell damage and decreased cell proliferation.