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The emergence of immunotherapy has revolutionized the treatment landscape for various types of cancer. Nevertheless, lung cancer remains one of the leading causes of cancer-related mortality worldwide due to the development of resistance in most patients. As one of the most abundant groups of immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play crucial and complex roles in the development of lung cancer, including the regulation of immunosuppressive TME remodeling, metabolic reprogramming, neoangiogenesis, metastasis, and promotion of tumoral neurogenesis. Hence, relevant strategies for lung cancer therapy, such as inhibition of macrophage recruitment, TAM reprograming, depletion of TAMs, and engineering of TAMs for drug delivery, have been developed. Based on the satisfactory treatment effect of TAM-targeted therapy, recent studies also investigated its synergistic effect with current therapies for lung cancer, including immunotherapy, radiotherapy, chemotherapy, anti-epidermal growth factor receptor (anti-EGFR) treatment, or photodynamic therapy. Thus, in this article, we summarized the key mechanisms of TAMs contributing to lung cancer progression and elaborated on the novel therapeutic strategies against TAMs. We also discussed the therapeutic potential of TAM targeting as adjuvant therapy in the current treatment of lung cancer, particularly highlighting the TAM-centered strategies for improving the efficacy of anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) treatment.

Triple-negative breast cancer (TNBC) is known for its aggressive nature, lack of effective diagnostic tools and treatments, and generally poor prognosis. The objective of this study was to investigate metabolic changes in TNBC using metabolomics approaches and explore the underlying mechanisms through integrated analysis with transcriptomics. In this study, serum untargeted metabolic profiles were first examined between 18 TNBC patients and 21 healthy control (HC) subjects using liquid chromatography-mass spectrometry (LC-MS), identifying a total of 22 significantly differential metabolites (DMs). Subsequently, receiver operating characteristic analysis revealed that 7-methylguanine could serve as a potential biomarker for TNBC in both the discovery and validation sets. Additionally, transcriptomic datasets were retrieved from the GEO database to identify differentially expressed genes (DEGs) between TNBC and normal tissues. An integrative analysis of the DMs and DEGs was conducted, uncovering potential molecular mechanisms underlying TNBC. Notably, three pathways—tyrosine metabolism, phenylalanine metabolism, and glycolysis/gluconeogenesis—were enriched, providing insight into the energy metabolism disorders in TNBC. Within these pathways, two DMs (4-hydroxyphenylacetaldehyde and oxaloacetic acid) and six DEGs (MAOA, ADH1B, ADH1C, AOC3, TAT, and PCK1) were identified as key components. In summary, this study highlights metabolic biomarkers that could potentially be used for the diagnosis and screening of TNBC. The comprehensive analysis of metabolomics and transcriptomics data offers a validated and in-depth understanding of TNBC metabolism.

Background MicroRNAs (miRNAs) are involved in the prognosis of nasopharyngeal carcinoma (NPC). This study used clinical data and expression data of miRNAs to develop a prognostic survival signature for NPC patients to detect high-risk subject. Results We identified 160 differentially expressed miRNAs using RNA-Seq data from the GEO database. Cox regression model consisting of hsa-miR-26a, hsa-let-7e, hsa-miR-647, hsa-miR-30e, and hsa-miR-93 was constructed by the least absolute contraction and selection operator (LASSO) in the training set. All the patients were classified into high-risk or low-risk groups by the optimal cutoff value of the 5-miRNA signature risk score, and the two risk groups demonstrated significant different survival. The 5-miRNA signature showed high predictive and prognostic accuracies. The results were further confirmed in validation and external validation set. Results from multivariate Cox regression analysis validated 5-miRNA signature as an independent prognostic factor. A total of 13 target genes were predicted to be the target genes of miRNA target genes. Both PPI analysis and KEGG analysis networks were closely related to tumor signaling pathways. The prognostic model of mRNAs constructed using data from the dataset GSE102349 had higher AUCs of the target genes and higher immune infiltration scores of the low-risk groups. The mRNA prognostic model also performed well on the independent immunotherapy dataset Imvigor210. Conclusions This study constructed a novel 5-miRNA signature for prognostic prediction of the survival of NPC patients and may be useful for individualized treatment of NPC patients.

Purpose Cisplatin is a widely used and effective chemotherapeutic agent for most solid malignant tumors. However, cisplatin-induced ototoxicity is a common adverse effect that limits the therapeutic efficacy of tumors in the clinic. To date, the specific mechanism of ototoxicity has not been fully elucidated, and the management of cisplatin-induced ototoxicity is also an urgent challenge. Recently, some authors believed that miR34a and mitophagy played a role in age-related and drug-induced hearing loss. Our study aimed to explore the involvement of miR-34a/DRP-1-mediated mitophagy in cisplatin-induced ototoxicity. Methods In this study, C57BL/6 mice and HEI-OC1 cells were treated with cisplatin. MiR-34a and DRP-1 levels were analyzed by qRT‒PCR and western blotting, and mitochondrial function was assessed via oxidative stress, JC-1 and ATP content. Subsequently, we detected DRP-1 levels and observed mitochondrial function by modulating miR-34a expression in HEI-OC1 cells to determine the effect of miR-34a on DRP-1-mediated mitophagy. Results MiR-34a expression increased and DRP-1 levels decreased in C57BL/6 mice and HEI-OC1 cells treated with cisplatin, and mitochondrial dysfunction was involved in this process. Furthermore, the miR-34a mimic decreased DRP-1 expression, enhanced cisplatin-induced ototoxicity and aggravated mitochondrial dysfunction. We further verified that the miR-34a inhibitor increased DRP-1 expression, partially protected against cisplatin-induced ototoxicity and improved mitochondrial function. Conclusion MiR-34a/DRP-1-mediated mitophagy was related to cisplatin-induced ototoxicity and might be a novel target for investigating the treatment and protection of cisplatin-induced ototoxicity.

Osteoarthritis (OA) is the most common joint disease in the world, characterized by pain and loss of joint function, which has led to a serious reduction in the quality of patients’ lives. In this work, ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QToF/MS) in conjunction with multivariate pattern recognition methods and an univariate statistical analysis scheme were applied to explore the serum metabolic signatures within OA group ( n = 31), HC (healthy controls) group ( n = 57) and non-OA group ( n = 19) for early diagnosis and differential diagnosis of OA. Based on logistic regression analysis and receiver operating characteristic (ROC) curve analysis, seven metabolites, including phosphatidylcholine (18:0/22:6), p-cresol sulfate and so on, were identified as critical metabolites for the diagnosis of OA and HC and yielded an area under the curve (AUC) of 0.978. The other panel of unknown m/z 239.091, phosphatidylcholine (18:0/18:0) and phenylalanine were found to distinguish OA from non-OA and achieved an AUC of 0.888. These potential biomarkers are mainly involved in lipid metabolism, glucose metabolism and amino acid metabolism. It is expected to reveal new insight into OA pathogenesis from changed metabolic pathways.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep and is frequently accompanied by dyslipidemia. However, the molecular mechanisms linking lipid metabolism to OSA remain incompletely understood. This study aimed to investigate the association between blood lipid levels and OSA and explore potential underlying molecular pathways. Data from the National Health and Nutrition Examination Survey (NHANES) 2005-2008 and 2015-2018 were analyzed to evaluate the associations between OSA and blood lipid parameters using multivariable regression and sensitivity analyses. Additionally, OSA-related transcriptomic data (GSE135917) were obtained from the Gene Expression Omnibus (GEO), and lipid metabolism-related genes were retrieved from the Molecular Signatures Database (MSigDB). Differentially expressed lipid metabolism-related genes (DELMRGs) were identified through data integration. Machine learning approaches, protein-protein interaction network analysis, and receiver operating characteristic analysis were applied to identify key genes. Gene set enrichment analysis (GSEA) was performed to elucidate associated biological pathways, and transcription factor-gene and gene-microRNA regulatory networks were constructed using NetworkAnalyst and Cytoscape. Analysis of NHANES data showed that triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels were positively associated with OSA, whereas high-density lipoprotein cholesterol (HDL-C) levels was inversely associated (all p < 0.001). A nonlinear, inverted U-shaped association between TG levels and OSA risk was also observed (p for nonlinearity < 0.05). Transcriptomic analysis identified 34 DELMRGs, among which CYP3A4, CYP4A22, and MED18 emerged as key genes. GSEA revealed pathways potentially involved in lipid metabolism and OSA pathophysiology, while regulatory network analyses further supported the biological relevance of these genes. This study demonstrates that dyslipidemia characterized by elevated TG and LDL-C levels and reduced HDL-C levels is associated with an increased likelihood of OSA, and identifies three DELMRGs that may be involved in OSA pathophysiology. These findings provide exploratory mechanistic insights and offer a basis for future studies to further investigate the role of lipid metabolism in OSA.

Reliable prognostic biomarkers for lung adenocarcinoma (LUAD) remain limited because of inter-cohort heterogeneity across transcriptomic studies. This study aimed to identify survival-related gene signatures associated with immune characteristics in LUAD. Three independent Gene Expression Omnibus (GEO) datasets were analyzed separately to identify consistently dysregulated genes in LUAD. Functional enrichment, protein-protein interaction network, survival, receiver operating characteristic (ROC) curve analysis, principal component analysis (PCA), expression validation, and immune infiltration analyses were performed. A total of 68 overlapping differentially expressed genes were identified. Functional enrichment analysis showed that these genes were mainly involved in vascular-related biological processes. Network and survival analyses identified seven significantly downregulated genes, including AGER, CAV1, EDNRB, ROBO4, EMCN, TEK, and PTPRB, which were associated with overall survival in LUAD. ROC analysis showed favorable diagnostic performance across the three GEO datasets, with area under the curve (AUC) values ranging from 0.873 to 1.000. In the larger datasets, AUCs ranged from 0.932 to 0.952 in GSE19188 and from 0.873 to 0.949 in GSE30219, with corresponding 95% CI ranges of 0.870-1.000 and 0.710-1.000, respectively. PCA further supported separation between LUAD and normal samples. Immune infiltration analysis showed associations between the seven-gene signature, tumor purity, and multiple immune cell populations. A seven-gene vascular-related signature was associated with prognosis and immune infiltration patterns in LUAD. These findings may support future biomarker development and studies of tumor microenvironment remodeling in LUAD.

Recent progress in chimeric antigen receptor-modified T-cell（CAR-T cell） technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti-MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment（sc Fv） sequence specifically targeting the MUC1 antigen and co-expressing interleukin（IL） 12（named SM3-CAR）. The other CAR-T cell line carried the SM3 sc Fv sequence modified to improve its binding to MUC1 antigen（named p SM3-CAR） but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1＋ seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR-T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that p SM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors.

Human serine palmitoyltransferase (SPT) complex catalyzes the initial and rate-limiting step in the de novo biosynthesis of all sphingolipids. ORMDLs regulate SPT function, with human ORMDL3 being related to asthma. Here we report three high-resolution cryo-EM structures: the human SPT complex, composed of SPTLC1, SPTLC2 and SPTssa; the SPT–ORMDL3 complex; and the SPT–ORMDL3 complex bound to two substrates, PLP- l -serine (PLS) and a non-reactive palmitoyl-CoA analogue. SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core. SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity. ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly. Our structural and biochemical analyses provide a molecular basis for the assembly and substrate selectivity of the SPT and SPT–ORMDL3 complexes, and lay a foundation for mechanistic understanding of sphingolipid homeostasis and for related therapeutic drug development. Cryo-EM structures of serine palmitoyltransferase complexes mediating a key reaction of sphingolipid biosynthesis elucidate principles of its multimeric assembly, regulation and substrate selectivity

Background Reactive nodular fibrous pseudotumor is a rare benign fibroinflammatory lesion of the gastrointestinal tract and mesentery that can closely mimic malignant disease on clinical examination and imaging. Most reported cases are associated with prior abdominal surgery, trauma, or inflammation. Omental involvement is particularly uncommon, and preoperative diagnosis remains difficult because of its rarity and the limited description of multimodality imaging findings. We report a rare case of omental reactive nodular fibrous pseudotumor in a young man without any history of abdominal surgery, trauma, or abdominal discomfort, highlighting its unusual presentation and diagnostic features. Case presentation A 31-year-old man presented with a palpable abdominal mass that had been present for more than 1 month. He had no previous abdominal surgery, trauma, or gastrointestinal symptoms. Contrast-enhanced computed tomography revealed multiple well-defined solid masses in the greater omentum with scattered calcifications. The lesions were similar in attenuation to skeletal muscle on unenhanced images and showed mild progressive enhancement after contrast administration. Magnetic resonance imaging demonstrated low signal intensity on both T1-weighted and T2-weighted images with a similar gradual enhancement pattern. Ultrasound and contrast-enhanced ultrasound showed hypoechoic lesions with limited enhancement. Because malignancy could not be excluded radiologically, surgical resection was performed. Histopathological examination demonstrated spindle cell proliferation within dense hyalinized collagenous stroma with focal chronic inflammatory infiltrates. Immunohistochemical findings supported the diagnosis of reactive nodular fibrous pseudotumor. The patient recovered well after surgery and remained recurrence-free during more than 4 years of follow-up. Conclusions This case indicates that reactive nodular fibrous pseudotumor should be included in the differential diagnosis of solid omental masses, even in patients without a history of abdominal surgery or inflammation. Multimodality imaging may provide important clues to its fibrous nature, but definitive diagnosis still depends on histopathological confirmation. Greater awareness of this rare entity may reduce misdiagnosis and help avoid unnecessary aggressive treatment.