Lung adenocarcinoma (LUAD) and chronic airway obstruction frequently coexist and are associated with poorer clinical outcomes. Although airway obstruction is recognized as a risk factor for adverse prognosis in LUAD, the molecular alterations associated with airway obstruction in LUAD remain incompletely understood. Most previous studies have been confounded by smoking-related molecular changes. To identify proteins associated with airway obstruction status in non-smoking patients with LUAD using a proteomics-based approach. Proteomic analysis was performed on paired tumor and adjacent normal tissues obtained from 12 non-smoking LUAD patients, including 6 patients with airway obstruction and 6 without airway obstruction. A four-group design combined with a three-step intersection strategy was used to identify candidate proteins associated with both airway obstruction status and tumor-related alterations. Functional enrichment, protein–protein interaction (PPI) network analysis, Western blot validation, correlation with pulmonary function, and transcriptomic validation using The Cancer Genome Atlas (TCGA) database were subsequently performed. A total of 2036 differentially expressed proteins were identified in tumor tissues between airway obstruction and non-obstruction groups. The three-step intersection strategy identified 15 candidate proteins. PPI network analysis and expression-direction consistency screening further identified four core proteins: Cystatin B (CSTB), Bone Morphogenetic Protein Receptor Type 1A (BMPR1A), Complement C4B (C4B), and Potassium Channel Tetramerization Domain Containing 10 (KCTD10). Western blot validation supported the differential expression patterns of these four core proteins in tumor tissues. Functional enrichment analysis indicated involvement in DNA damage repair, immune regulation, and cellular proliferation pathways. CSTB expression was positively correlated with FEV1

Background:Molecular testing has become an essential part of managing non-small cell lung cancer (NSCLC). The detection of EGFR, BRAF, and MNNG HOS transforming gene (MET) mutations, and the analysis of anaplastic lymphoma kinase (ALK), ROS1, RET, and NTRK rearrangements have been incorporated into NSCLC diagnostic standards, and inhibitors of these kinases are used routinely in clinical practice. Although targeted therapies, represented by ALK-tyrosine kinase inhibitor (ALK-TKI), have significantly improved the prognosis of ALK-positive NSCLC patients, acquired resistance (such as MET amplification) remains a core challenge faced by clinicians. Currently, there is no standardized treatment regimen established in Chinese and international clinical guidelines for patients with ALK-TKI resistance caused by MET amplification. Although clinical practice has attempted to combine targeted drugs for MET amplification, such as crizotinib, with first and second-generation ALK-TKIs and observed preliminary efficacy, there is no published research on the combination of third-generation ALK-TKI lorlatinib with new MET inhibitors such as vebreltinib. Case Description:This report describes a patient with advanced NSCLC with multiple systemic metastases and ALK gene fusion, in whom MET amplification emerged as a resistance mechanism following disease progression on targeted therapy. The first-line treatment was lorlatinib, a third-generation ALK inhibitor, but the disease progressed rapidly. The second biopsy showed that MET amplification is the main mechanism of resistance to ALK-targeted therapy in the patient. Specifically, MET amplification was not present at baseline but appeared after lorlatinib treatment, confirming it as an acquired rather than intrinsic resistance mechanism. Due to complications, such as elevated transaminase (an indication of hepatotoxicity), hyperlipidemia, and depression, that occurred during the patient's first-line treatment, combined ALK- and MET-TKI targeted therapy was not administered. Subsequent second-line treatment with single-agent vebreltinib failed to halt disease progression. After thorough systemic evaluation, a combination regimen of lorlatinib and vebreltinib was initiated, resulting in sustained partial remission (PR), excellent treatment tolerance, and notable improvement in quality of life. Conclusions:Our case report first successfully documented the use of third-generation ALK inhibitor (lorlatinib) in combination with novel MET inhibitor (vebreltinib) for the treatment of advanced NSCLC patients with ALK-TKI resistance due to MET amplification, enabling sustained clinical remission. This case highlights the importance of repeat biopsy to identify acquired resistance mechanisms arising from intratumoral heterogeneity in response to targeted therapy, which is critical for making clinical decisions and adjusting treatment plans for patients with NSCLC.

BackgroundMitochondrial dysfunction is a hallmark of diabetic kidney disease (DKD), yet its regulatory mechanisms remain poorly defined. Mitochondrial transcription factor A (TFAM), a central regulator of mitochondrial homeostasis, undergoes lysine 76 (K76) acetylation, but the functional significance of this modification in DKD has not been established.MethodsWe collected kidney tissues from DKD patients and DKD mice, and assessed TFAM acetylation in HK-2 cells and primary renal tubular cells under high-glucose conditions. In addition, to investigate the potential mechanism of TFAM acetylation in mitochondrial damage within the kidney, we explored relevant pathways using proteomics and utilized streptozotocin (STZ)-induced DKD mouse models with tubular-specific expression of TFAM wild-type and mutant forms to examine kidney injury. Moreover, we identified TFAM K76 acetylation-specific inhibitors through high-throughput virtual screening and thoroughly validated them in HK-2 cells, primary cells, and DKD mice, confirming the critical role of TFAM acetylation in DKD-related kidney injury.ResultsHere, we identify TFAM K76 acetylation as a critical mediator of mitochondrial injury in DKD. TFAM K76 acetylation was markedly elevated in kidney tissues from DKD patients and diabetic mouse models, correlating with mitochondrial damage, inflammation, and fibrosis under hyperglycemic conditions. In vivo, overexpression of acetylation-mimetic TFAM K76Q in renal tubular epithelial cells aggravated renal injury and ultrastructural damage, whereas its deacetylation attenuated these effects. Mechanistically, TFAM K76 acetylation impaired oxidative phosphorylation and excessively activated autophagy, further exacerbating mitochondrial damage. We identified sirtuin 3 (SIRT3) as an upstream deacetylase that regulates this modification. Importantly, through high-throughput virtual screening, we discovered a novel small-molecule inhibitor (C14) that selectively reduces TFAM K76 acetylation and effectively alleviates hyperglycemia-induced mitochondrial dysfunction, inflammation, and fibrosis in both in vitro and in vivo models.ConclusionsCollectively, our findings define TFAM K76 acetylation as a pathogenic driver of DKD and propose C14 as a promising therapeutic candidate targeting mitochondrial metabolism.

Microglia, as the resident innate immune cells of the central nervous system, play a pivotal role in both the onset and progression of Alzheimer's disease (AD). Emerging evidence has shown that metabolic reprogramming serves as a critical determinant of microglial functional states and exerts profound effects on AD pathogenesis. In this review, we systematically synthesize recent advances concerning microglial metabolic reprogramming in AD, with particular emphasis on the contributions and underlying mechanisms of glucose, lipid and amino acid metabolism. We further examine how key genetic risk factors including APOE and TREM2 genes drive metabolic perturbations and functional impairment in microglia. The therapeutic promise of targeting metabolic pathways, especially via metabolic modulators such as transient receptor potential vanilloid 1 (TRPV1) agonists, is also underscored. Moreover, we discuss prevailing challenges in the field, including limitations inherent in current disease models and the complexity arising from microglial heterogeneity. Finally, we propose that integrating multi-omics approaches with spatially resolved technologies may enable a more comprehensive dissection of metabolism-immune crosstalk in AD and open new avenues for designing combination therapeutic regimens.

Objective To compare whether genetically proxied perturbation of major glucose-lowering drug targets is associated with susceptibility to lower respiratory infections and sepsis, with the aim of identifying clinically relevant target-specific differences in people with diabetes. Research Design and Methods We performed a two-sample drug-target Mendelian randomization study using variants proxying insulin signaling, thiazolidinediones, sulfonylureas, metformin-related targets, sodium-glucose cotransporter 2 inhibition, and glucagon-like peptide 1 receptor agonism. Outcomes included bacterial pneumonia, viral pneumonia, respiratory tuberculosis, influenza pneumonia, severe COVID-19, and sepsis from FinnGen and the UK Biobank. Positive-control analyses against type 2 diabetes were used to assess instrument validity before clinical interpretation. Results PPARG/thiazolidinedione proxies showed the clearest adverse pattern, with higher risks of bacterial pneumonia, respiratory tuberculosis, and influenza pneumonia, although estimates were imprecise. In contrast, insulin signaling and selected metformin-related targets were associated with lower risks of bacterial or viral pneumonia. Sulfonylurea proxies showed heterogeneous associations, including higher bacterial pneumonia risk but lower severe COVID-19 susceptibility. Glucagon-like peptide 1 receptor agonist proxies were not associated with infection outcomes. Sodium-glucose cotransporter 2 instruments failed positive-control validation for type 2 diabetes; corresponding infection estimates were therefore considered exploratory. Conclusions Genetically proxied glucose-lowering drug targets showed heterogeneous associations with respiratory infection and sepsis phenotypes. The most consistent adverse signals involved PPARG-related pathways, whereas insulin signaling and selected metformin-related targets showed potentially protective associations for specific outcomes. These findings support a more target-aware view of infection risk in diabetes and provide a rationale for prioritizing infectious outcomes when evaluating glucose-lowering therapies.

BACKGROUND: Eosinophilic asthma, affecting more than 50% of adult asthma patients, demonstrates airway inflammation severity directly correlated with eosinophil infiltration levels. While transepithelial eosinophil migration constitutes a pivotal step in airway inflammation pathogenesis, the regulatory mechanisms remain undefined. We aim to investigate how desmoglein-2 (DSG2), which is a key desmosomal cadherin mediating epithelial intercellular adhesion, regulates eosinophil transmigration across the bronchial epithelial barrier. METHODS: DSG2 protein levels were measured by ELISA in asthma patients’ and healthy volunteers’ serum. In vitro, a lower level of DSG2 in bronchial cells weakened barrier integrity, boosting eosinophil migration. To further investigate the role of DSG2 in eosinophilic asthma, in vivo mouse studies were conducted. These studies employed an adeno-associated virus to modulate DSG2 expression (either downregulation or upregulation) or utilized exogenous supplementation with recombinant DSG2 protein, followed by assessment of their effects on ovalbumin (OVA)/house dust mite (HDM)-induced eosinophilic asthma. RESULTS: DSG2 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients compared to healthy individuals. The serum levels of DSG2 protein were significantly lower in asthmatic patients compared to healthy subjects. A negative correlation was observed between serum DSG2 protein levels and the count of peripheral blood eosinophils in asthma patients. Furthermore, Th2 cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13) downregulated the expression of DSG2 protein. In bronchial epithelial cells, DSG2 protein played a crucial role in maintaining epithelial barrier function and cell adhesion. A reduction in its expression led to enhanced transepithelial migration of eosinophils in vitro. Consistent with these findings, a murine model of eosinophilic asthma exhibited decreased DSG2 expression and increased eosinophil infiltration in the airways. Notably, this eosinophil infiltration was exacerbated by the downregulation of DSG2. Critically, in both in vivo and in vitro experiments, overexpression of DSG2 in bronchial epithelial cells or exogenous addition of recombinant DSG2 protein partially reversed asthma-associated epithelial barrier impairment and alleviated eosinophilic airway inflammation. CONCLUSION: We elucidated the crucial role of DSG2 in bronchial epithelial cells during eosinophilic asthma development, focusing on its maintenance of desmosome structure and facilitation of eosinophil migration across the airway epithelium.

Gouty arthritis (GA), triggered by monosodium urate (MSU) crystal deposition, is closely associated with oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome-mediated pyroptosis. This study combined network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation to elucidate the mechanism by which the iridoid glycoside ajugol alleviates GA. Network pharmacology analyses identified the PI3K/AKT/mTOR pathway as a key regulatory axis, and docking results revealed stable binding of ajugol to PI3K, AKT, and mTOR. In LPS/MSU-stimulated human chondrocytes, ajugol significantly restored cell viability, reduced LDH release, and preserved extracellular matrix integrity by increasing Collagen II and Aggrecan expression while decreasing MMP-3 levels. Ajugol markedly inhibited the expression of NLRP3, ASC, caspase-1, and GSDMD-N, reduced the secretion of IL-1β, IL-18, IL-6, and TNF-α, and decreased caspase-1 activity and membrane pore formation, indicating that ajugol suppresses pyroptosis through enhanced mitophagy. The mitophagy inhibitor cyclosporin A (CsA) significantly weakened ajugol-induced mitophagy activation and pyroptosis inhibition, confirming that mitophagy plays a pivotal role in its protective effects. Mechanistically, ajugol inhibited PI3K/AKT/mTOR phosphorylation, upregulated PINK1, Parkin, and LC3-II/LC3-I while reducing p62, thereby activating PINK1/Parkin-dependent mitophagy. PI3K agonist 740YP partially reversed ajugol's effects, whereas PI3K inhibitor LY294002 mimicked them, verifying pathway involvement. In MSU-induced GA mice, oral ajugol administration alleviated joint swelling, reduced inflammatory cytokines and NLRP3 expression, preserved cartilage integrity, and restored autophagy via PI3K/AKT/mTOR suppression. Collectively, ajugol alleviates inflammation and cartilage damage by suppressing the PI3K/AKT/mTOR pathway, activating mitophagy, and inhibiting pyroptosis, providing a promising mitochondrial-targeted therapeutic strategy for gouty arthritis.

Osteoporosis is characterized by reduced bone mass and impaired skeletal microarchitecture, with impaired osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs) serving as a key contributing factor in its development. Cellular repressor of E1A-stimulated genes 1 (CREG1), a lysosomal glycoprotein, has been implicated in the regulation of autophagy and osteogenic differentiation. However, the molecular mechanisms underlying CREG1-mediated bone homeostasis remain unclear. In this study, we identified RAB7, a small GTPase involved in endosomal trafficking and autophagy, as a downstream effector of CREG1. We found that RAB7 expression progressively increased during osteogenic differentiation of BMSCs. RAB7 knockdown impaired osteogenesis, whereas its overexpression enhanced the process. Functional assays demonstrated that modulation of RAB7 expression significantly influenced the effects of CREG1 on BMSCs. RAB7 knockdown inhibited CREG1-induced osteogenic differentiation and autophagy activation, whereas RAB7 overexpression restored the osteogenic potential suppressed by CREG1 knockdown. Our findings suggest that CREG1 facilitates osteogenic differentiation and bone homeostasis via RAB7-mediated regulation of autophagy.

Alanyl-tRNA Synthetase 1 (AARS1) is a bifunctional enzyme with emerging roles in lactate sensing and protein lactylation (Kla), both driving tumor progression. However, its clinical significance across diverse cancer types remains largely unexplored. Leveraging comprehensive bioinformatics analysis across multiple public repositories, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Tumor IMmune Estimation Resource (TIMER), The University of Alabama at Birmingham CANcer data analysis Portal (UALCAN), and Human Protein Atlas (HPA), we systematically evaluated AARS1 expression and its associations with TP53 mutations, DNA methylation, prognostic outcomes, and genetic alterations, as well as its correlation with the immune microenvironment. Functional enrichment analyses were further conducted to elucidate its molecular mechanisms. Moreover, immunohistochemistry (IHC) in renal and lung cancers, complemented by in vitro functional assays in renal cancer cells, validated its oncogenic role. Our results demonstrate that AARS1 is significantly upregulated in most malignancies and correlates with poor survival rates. Notably, AARS1 exhibited high diagnostic efficacy (AUC > 0.85) and was inversely associated with antitumor immune infiltration. Functional downregulation of AARS1 significantly inhibited the proliferation, migration, and invasion abilities of these cells, whereas overexpression of the enzymatically inactive mutant failed to rescue these inhibitory effects, further confirming that its pro-tumorigenic role is dependent on its lactyltransferase activity. This inaugural pan-cancer study highlights AARS1 as a robust diagnostic and prognostic biomarker, immunological indicator, and promising therapeutic target across multiple cancers.

Clear cell renal cell carcinoma (ccRCC) is characterized by mitochondrial dysfunction and the Warburg effect, which refers to enhanced aerobic glycolysis. Mitochondrial ribosomal protein 12 (MRPL12) plays a pivotal role in mitochondrial biogenesis by promoting mitochondrial transcription through its interaction with POLRMT. Our previous studies have demonstrated that MRPL12 is involved in the progression of diabetic kidney disease (DKD) and acute kidney injury (AKI). However, its specific role in ccRCC remains unclear. Therefore, this study aims to elucidate the function of MRPL12 in the metabolic reprogramming of ccRCC. Online databases and tissue microarray analysis were utilized to explore the role of MRPL12 in ccRCC. Quantitative real-time PCR (qRT-PCR) was performed to quantify mRNA expression levels, while Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to evaluate protein expression of the relevant genes. In vitro functional assays were conducted to determine the biological effects of MRPL12, and aerobic glycolysis was assessed using Seahorse XF Analyzers to measure cellular metabolic activity. Mass spectrometry analysis, combined with Gene Ontology (GO) analysis and integrated with Ingenuity Pathway Analysis (IPA), was carried out to identify potential pathway interconnections. To investigate the regulatory mechanism, chromatin immunoprecipitation (ChIP) assays were performed to examine the binding interaction between HIF-1α and the MRPL12 promoter. Finally, an in vivo mouse model was established to further elucidate the functional role of MRPL12 in ccRCC progression. MRPL12 is significantly downregulated in ccRCC tissues, and its reduced expression is associated with poor prognosis. MRPL12 inhibits ccRCC cell proliferation, migration, and invasion by modulating mitochondrial metabolism. Overexpression of MRPL12 enhances oxidative phosphorylation (OXPHOS) and suppresses aerobic glycolysis, while MRPL12 knockdown produces the opposite effects. Potential interconnections between the MRPL12, ILK, ISGylation, and SUMO pathways have been identified. Additionally, HIF-1α was found to act as a transcriptional repressor of MRPL12. Our study reveals that MRPL12 regulates mitochondrial metabolism to inhibit ccRCC cell proliferation, migration, and invasion, suggesting that targeting MRPL12 may represent a promising therapeutic strategy for ccRCC.

Background:Kluyvera intermedia is a rare Gram-negative bacillus that predominantly functions as an opportunistic pathogen. Commonly found in environmental sources such as freshwater and soil, it has been infrequently reported in human infections, often leading to underrecognition in clinical practice. Because it can resemble more prevalent pathogens, accurate identification is crucial for effective management of infections. Case report:We report a case of pneumonia caused by Kluyvera intermedia in a 55-year-old male with a 10-year history of well-controlled hypertension. The patient initially presented with classic pneumonia symptoms, including fever, cough, and right-sided chest pain. Although he received empirical treatment with Cefotaxime Sodium and Levofloxacin at the local hospital, follow-up CT scans revealed further enlargement of the pulmonary lesions. To investigate the underlying etiology, the patient underwent MRI-guided lung biopsy at our hospital, and culture of the aspirated fluid identified Kluyvera intermedia as the causative pathogen. He was subsequently treated with Ceftizoxime sodium and Levonidazole Sodium Chloride Injection, resulting in significant clinical improvement. The patient was discharged after 22 days of hospitalization. Conclusion:Further accumulation and reporting of cases will enhance the recognition of the clinical characteristics of Kluyvera intermedia. These studies will not only expand our understanding of this rare pathogen but also provide a foundation for improved response strategies, thereby ensuring better management of similar infections in future clinical practice.

Renal cell carcinoma (RCC) is a common urological tumor, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Metabolic reprogramming plays a critical role in ccRCC progression, making it a promising target for therapeutic intervention, though effective treatments remain unavailable. Our previous studies have shown that mitochondrial ribosomal protein L12 (MRPL12) contributes to various metabolic diseases, including diabetic kidney disease and HCC, by regulating mitochondrial biosynthesis. In this study, we demonstrated that MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, a key modification that influences its regulatory effect on mitochondrial metabolism. Mechanistically, we clarified that acetylation at the K163 site enhances mitochondrial biosynthesis by promoting MRPL12’s binding to POLRMT, which subsequently increases mitochondrial metabolism and suppresses cellular glycolysis. Additionally, we found that MRPL12 K163 acetylation levels were significantly downregulated in ccRCC and that restoring this acetylation inhibited ccRCC progression in both in vitro and in vivo models. Furthermore, we demonstrated that the acetyltransferase TIP60 and the deacetylase SIRT5 bind to MRPL12 and regulate its acetylation. These findings highlight K163 acetylation as a critical site for MRPL12-mediated regulation of mitochondrial metabolism and reveal that this modification inhibits renal cancer development by promoting mitochondrial biosynthesis, reducing glycolysis, and driving metabolic reprogramming. This study suggests a potential therapeutic strategy for targeting MRPL12 acetylation in ccRCC.

BACKGROUND:Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism. MATERIALS AND METHODS:The cytotoxicity of H2O2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot. RESULTS:Our results indicated that H2O2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H2O2. Western blot and immunofluorescence analyses showed that DAS decreased the H2O2-induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H2O2-induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13. CONCLUSION:Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H2O2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.

BackgroundRecent studies have highlighted the essential role of the zinc finger gene family, whose encoded proteins play a pivotal role in all stages of tumor initiation and development. Zinc Finger Protein 514 (ZNF514) is a member of the ZNF family, and its abnormal expression and prognostic value in human pan-cancer have not yet been described. The purpose of this study is to investigate the prognostic and immunological roles of ZNF514 in pan-cancer and to confirm its cancer-promoting effect in renal clear cell carcinoma.MethodsIn our study, we utilized the Human Protein Atlas (HPA) database to determine the expression of ZNF514 in human normal and tumor tissues. We also used the Tumor Immune Estimation Resource 2.0 (TIMER 2.0) database to investigate the association between ZNF514 expression and immune checkpoint genes and immune infiltration. To detect the expression and prognostic value of ZNF514 in pan-cancers, we utilized The Cancer Genome Atlas (TCGA) or the Genotype-Tissue Expression (GTEx) databases and analyzed the data using the Kaplan-Meier plotter, GEPIA2, cBioPortal, or Xiantao software. Additionally, we obtained the protein-protein interaction network of ZNF514 from the STRING database. To validate our findings, we performed immunohistochemistry on clinical samples. Furthermore, we conducted cellular functional experiments to examine the effects of ZNF514 overexpression or knockdown on renal clear cell carcinoma cell proliferation, migration, and invasion.ResultsOur study found that ZNF514 expression was elevated in tumor tissues than in normal tissues in most tumor types. Furthermore, high expression of ZNF514 was associated with poor overall survival (OS) and disease-free survival (DFS) in certain tumor types. Further analysis of ZNF514 gene mutation data revealed that ZNF514 protein is infrequently mutated in human cancers. Moreover, ZNF514 affected prognosis and was associated with the expression of multiple immune checkpoint genes and the abundance of tumor-infiltrating immune cells across multiple types of cancer. Finally, our molecular biology experiments confirmed the oncogenic effect of ZNF514 in renal clear cell carcinoma.ConclusionOur study revealed that ZNF514 may serve as an immunological and prognostic biomarker in multiple human cancers, especially in KIRC, LIHC, LUSC, and COAD.

The pathological process of osteoporosis involves accelerated bone resorption and a decline in bone formation, among which the disruption of the balance between adipogenic and osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs) is a crucial part. Cellular repressor of E1A-stimulated genes 1 (CREG1), a small glycoprotein, is mainly localized to the endosomal-lysosomal compartment and is associated with the regulation of mitophagy and cell differentiation. However, its roles in BMSCs osteogenic differentiation and skeletal degenerative disorders, including osteoporosis, are poorly understood. We previously identified CREG1 as being highly expressed in the bone marrow through database analysis and found that its expression increased in the process of BMSCs osteogenic differentiation. In the present study, we demonstrated that the expression of CREG1 was reduced in osteoporosis patients and animal models, and the overexpression of CREG1 contributed to higher bone mass compared with ovariectomy (OVX)-induced bone loss models. Further research revealed that the knockdown of CREG1 inhibited the osteogenic differentiation of BMSCs, while CREG1 overexpression promoted this process. Additionally, we found that CREG1 overexpression was accompanied by an increase in mitophagy levels, and the osteogenic differentiation induced by this overexpression was blocked when mitophagy was inhibited, indicating that CREG1 promoted osteogenic differentiation through inducing mitophagy. Therefore, our findings demonstrated that CREG1 is involved in regulating the osteogenic differentiation of BMSCs, thereby providing new therapeutic targets and pathways for the treatment of osteoporosis.

The positive effect of the capsular closure in maintaining the integrity of the joint capsule has been demonstrated, but most capsular closure techniques are primarily for interportal capsulotomy, with few techniques described for longitudinal capsulotomy. In our clinical practice, the incomplete closure of the proximal capsule in longitudinal capsulotomy may result in weakness or nonunion of the proximal capsule. Thus, we propose a technique of anatomic repair of the joint capsule with the indirect head of the rectus femoris as proximal augmentation in cases of longitudinal capsulotomy. This technique could provide a plausible and feasible solution for complete capsular closure of the longitudinal capsulotomy, which could decrease the risk of weakness or nonunion of the proximal capsule.