BACKGROUND: The study aimed to investigate the influence of extremely low-frequency electromagnetic fields (ELF-EMF) on clear cell renal cell carcinoma (ccRCC) by assessing alterations in gene expression and the secretion of cytokines and chemokines.
METHODS: Three ccRCC cell lines (786-O, 769-P, and CAKI-1) and a healthy HEK293 cell line were subjected to ELF-EMF exposure (frequency 50 Hz, magnetic field strength 4.5 mT) for 30 min daily for 5 days. The study examined the expression of ADAM28, NCAM1, and VEGFC genes, along with the secretion of 30 cytokines and chemokines.
RESULTS: Notably, primary tumor-derived cell lines, but not those from metastatic sites, exhibited ADAM28 gene expression, which increased following ELF-EMF exposure. A statistically significant reduction in VEGFC gene expression was observed in 769-P cells after ELF-EMF exposure. Additionally, NCAM1 gene expression was upregulated in HEK293, 769-P, and 786-O cells, representing normal embryonic kidney cells and primary tumor cells, but not in CAKI-1 cells, which model metastatic sites. After EMF exposure, there was a statistically significant decrease in transforming growth factor β1 (TGF-β1) concentration in the cell culture supernatants of HEK293 and CAKI-1 cell lines, with no other significant changes in the secretion of tested cytokines.
CONCLUSIONS: Given the study\'s findings and available research, caution is warranted when drawing conclusions about the potential inhibitory effect of ELF-EMF on ccRCC progression. Standardization of experimental models is imperative when assessing the effects of EMF in a human context. Med Pr Work Health Saf. 2024;75(2):133-141.

BACKGROUND: Bladder cancer (BLCA) is a prevalent and deadly form of urinary cancer, and there is a need for effective therapies, particularly for muscle-invasive bladder cancer (MIBC). Cell cycle inhibitors show promise in restoring control of the cell cycle in BLCA cells, but their clinical prognosis evaluation is limited.
METHODS: Transcriptome and scRNA-seq data were collected from the Cancer Genome Atlas Program (TCGA)-BLCA and GSE190888 cohort, respectively. R software and the Seurat package were used for data analysis, including cell quality control, dimensionality reduction, and identification of differentially expressed genes. Genes related to the cell cycle were obtained from the genecards website, and a protein-protein interaction network analysis was performed using cytoscape software. Functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular docking were conducted using various tools and packages. BLCA cell lines were cultured and transfected for in vitro experimental assays, including RT-qPCR analysis, and CCK-8 cell viability assays.
RESULTS: We identified 32 genes as independent risk or protective factors for BLCA prediction. Functional enrichment analysis revealed their involvement in cell cycle regulation, apoptosis, and various signaling pathways. Using these genes, we developed a nomogram for predicting BLCA survival, which displayed high prognosis stratification efficacy in BLCA patients. Four cell cycle associated key genes identified, including NCAM1, HBB, CKD6, and CTLA4. We also identified the main cell types in BLCA patients and investigated the functional differences between epithelial cells based on their expression levels of key genes. Furthermore, we observed a high positive correlative relationship between the infiltration of cancer-associated fibroblasts and the risk score value. Finally, we conducted in vitro experiments to demonstrate the suppressive role of NCAM1 in BLCA cell proliferation.
CONCLUSIONS: These findings suggest that cell cycle associated genes could serve as potential biomarkers for predicting BLCA prognosis and may represent therapeutic targets for the development of more effective therapies. Hopefully, these findings provide valuable insights into the molecular mechanisms and potential therapeutic targets in BLCA from the perspective of cell cycle. Moreover, NCAM1 was a novel cell proliferation suppressor in the BLCA carcinogenesis.

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former\'s function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, \"atypical\" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).

BACKGROUND: The expression of major histocompatibility complex I (MHC-I) in neurons has recently been shown to regulate neurite outgrowth and synaptic plasticity. However, its contribution to neurodegenerative diseases such as Alzheimer\'s disease (AD) remains largely unknown.
METHODS: In this study, we investigated the relationship between impaired MHC-I-β2M complex and AD in vitro and human AD samples. Interaction between protein was identified by liquid chromatography-tandem mass spectrometry and confirmed by immunoprecipitation. Single-chain trimer of MHC-I-β2M was generated to study the effect of stabilization of MHC-I-β2M complex on NCAM1 signaling.
RESULTS: MHC-I is destabilized in the brains of AD patients and neuronal cells treated with oligomeric β-amyloid (Aβ). Specifically, Aβ oligomers disassemble the MHC-I-β2-microglobulin (β2M) complex, leading to reduced interactions with neural cell adhesion molecule 1 (NCAM1), a novel interactor of neuronal MHC-I, and decreased signaling. Inhibition of MHC-I-β2M complex destabilization by non-dissociable MHC-I-β2M-peptide complex restored MHC-I-NCAM1 signaling in neuronal cells.
CONCLUSIONS: The current study demonstrated that disruption of MHC-1-NCAM1 signaling by Aβ induced disassembly of MHC-I-β2M complex is involved in the pathophysiology of AD. Moreover, our findings suggest modulation of MHC-I stability may be a potential therapeutic target for restoring synaptic function in AD.

Resistance to chemotherapeutic drugs limits the efficacy of chemotherapy in non-small cell lung cancer (NSCLC). Autophagy is an essential mechanism which involves in drug resistance. Our previous research has revealed that miR-152-3p represses NSCLC progression. However, the mechanism of miR-152-3p in autophagy-mediated chemoresistance in NSCLC remains unclear. Cisplatin-resistant cell lines (A549/DDP and H446/DDP) were transfected with related vectors and subjected to cisplatin, autophagy inhibitor, activator, or extracellular signal-regulated kinase (ERK) activator. Flow cytometry, CCK8 and colony formation assays were performed for testing apoptosis and cell viability. The related RNAs or proteins were detected by qRT-PCR or Western blot. Chromatin immunoprecipitation, luciferase reporter assay or RNA immunoprecipitation were used for validating the interaction between miR-152-3p and ELF1 or NCAM1. Co-IP verified the binding between NCAM1 and ERK. The role of miR-152-3p in cisplatin resistance of NSCLC was also validated in vivo. The results showed that miR-152-3p and ELF1 were decreased in NSCLC tissues. miR-152-3p reversed cisplatin resistance by inhibiting autophagy through NCAM1. NCAM1 promoted autophagy through the ERK pathway and facilitated cisplatin resistance. ELF1 positively regulated miR-152-3p level by directly interacting with miR-152-3p promoter. miR-152-3p targeted NCAM1 to regulate NCAM1 level and then affected the binding of NCAM1 to ERK1/2. ELF1 inhibited autophagy and reversed cisplatin resistance through miR-152-3p/NCAM1. miR-152-3p inhibited autophagy and cisplatin resistance of xenograft tumor in mice. In conclusion, our study revealed that ELF1 inhibited autophagy to attenuate cisplatin resistance through the miR-152-3p/NCAM1/ERK pathway in H446/DDP and A549/DDP cells, suggesting a potential novel treatment strategy for NSCLC.

Perinatal mood and anxiety disorders encompass a range of mental health disorders that occur during pregnancy and up to 1 year postpartum, affecting approximately 20% of women. Traditional risk factors, such as a history of depression and pregnancy complications including preeclampsia, are known. Their predictive utility, however, is not specific or sensitive enough to inform clinical decision-making or prevention strategies for perinatal mood and anxiety disorders. Better diagnostic and prognostic models are needed for early identification and referral to treatment.
This study aimed to determine if a panel of novel third-trimester plasma protein biomarkers in pregnant women can be used to identify those who have a high predisposed risk for perinatal mood and anxiety disorders within 3 months postpartum.
We studied 52 women (n=34 with a risk for perinatal mood and anxiety disorders and n=18 controls) among whom mental health screening was conducted at 2 time points, namely in the third trimester and again at 3 months postdelivery. An elevated perinatal mood and anxiety disorder risk was identified by screening individuals with above-validated cutoffs for depression (Edinburgh Postnatal Depression Scale ≥12), anxiety (Overall Anxiety Severity and Impairment Scale ≥7), and/or posttraumatic stress disorder (Impact of Events Scale >26) at both time points. Plasma samples collected in the third trimester were screened using the aptamer-based SomaLogic SomaScan proteomic assay technology to evaluate perinatal mood and anxiety disorder-associated changes in the expression of 1305 protein analytes. Ingenuity Pathway Analysis was conducted to highlight pathophysiological relationships between perinatal mood and anxiety disorder-specific proteins found to be significantly up- or down-regulated in all subjects with perinatal mood and anxiety disorder and in those with perinatal mood and anxiety disorders and no preeclampsia.
From a panel of 53 significant perinatal mood and anxiety disorder-associated proteins, a unique 20-protein signature differentiated perinatal mood and anxiety disorder cases from controls in a principal component analysis (P<.05). This protein signature included NCAM1, NRCAM, and NTRK3 that converge around neuronal signaling pathways regulating axonal guidance, astrocyte differentiation, and maintenance of GABAergic neurons. Interestingly, when we restricted the analysis to subjects without preeclampsia, a 30-protein signature differentiated perinatal mood and anxiety disorder cases from all controls without overlap on the principal component analysis (P<.001). In the nonpreeclamptic perinatal mood and anxiety disorder group, we observed increased expression of proteins, such as CXCL11, CXCL6, MIC-B, and B2MG, which regulate leucocyte migration, inflammation, and immune function.
Participants with perinatal mood and anxiety disorders had a unique and distinct plasma protein signature that regulated a variety of neuronal signaling and proinflammatory pathways. Additional validation studies with larger sample sizes are needed to determine whether some of these molecules can be used in conjunction with traditional risk factors for the early detection of perinatal mood and anxiety disorders.

From genetic and etiological studies, autoimmune mechanisms underlying schizophrenia are suspected; however, the details remain unclear. In this study, we describe autoantibodies against neural cell adhesion molecule (NCAM1) in patients with schizophrenia (5.4%, cell-based assay; 6.7%, ELISA) in a Japanese cohort (n = 223). Anti-NCAM1 autoantibody disrupts both NCAM1-NCAM1 and NCAM1-glial cell line-derived neurotrophic factor (GDNF) interactions. Furthermore, the anti-NCAM1 antibody purified from patients with schizophrenia interrupts NCAM1-Fyn interaction and inhibits phosphorylation of FAK, MEK1, and ERK1 when introduced into the cerebrospinal fluid of mice and also reduces the number of spines and synapses in frontal cortex. In addition, it induces schizophrenia-related behavior in mice, including deficient pre-pulse inhibition and cognitive impairment. In conclusion, anti-NCAM1 autoantibodies in patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. These antibodies may be a potential therapeutic target and serve as a biomarker to distinguish a small but treatable subgroup in heterogeneous patients with schizophrenia.

Confirming the existence and composition of the shared genetic basis of Schizophrenia and cannabis and cigarette smoking has critical values for the clinical prevention and intervention of psychosis.
To achieve this goal, we leveraged Genome-Wide summary statistics of Schizophrenia (n = 99,934), cigarette smoking (n = 518,633) and cannabis usage (n = 162,082). We applied Causal Analysis Using Summary Effect Estimates (CAUSE) and genomic structural equation modeling (GenomicSEM) to quantify the contribution of a common genetic factor of cannabis and cigarette smoking and schizophrenia (referred to as SCZ_SMO), then identified genome-wide loci that made up SCZ_SMO.
We estimated that SCZ_SMO explained 8.6% of Schizophrenia heritability (Z score <-2.5 in CAUSE, p<10-20 in Genomic SEM). There were 20 independent loci showing association with SCZ_SMO at the genome-wide threshold of p<5 × 10-8. At the top locus on chromosome 11, fine-mapping identified rs7945073 (posterior inclusion probability =0.12, p = 2.24 × 10-32) as the top risk variants. Gene-level association and fine-mapping highlighted NCAM1, PHC2, and SEMA6D as risk genes of SCZ_SMO. Other risk genes were enriched in cortex, neuron, and dendritic spines (adjusted p<0.05). SCZ_SMO showed significant positive correlation (p<10-6) with the genetic risk of attention deficit hyperactivity disorder (r = 0.50), lifestyle problems (r = 0.83), social deprivation (r = 0.58) and all-cause pregnant loss (r = 0.60).
Our result provided new evidence on the shared genetic basis model for the association between Schizophrenia and smoking and provided genetic and biological insights into their shared mechanism.

Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS.
A comparative proteomics analysis was performed on the cerebrospinal fluid (CSF) from 10 patients with GBS and 10 patients with noninflammatory neurological disease (NND) using the tandem mass tags technique. The differentially expressed proteins were analyzed by bioinformatics, and then the candidate proteins were validated by the enzyme-linked immunosorbent assay method in another cohort containing 160 samples (paired CSF and plasma of 40 patients with GBS, CSF of 40 NND patients and plasma of 40 healthy individuals).
In all, 298 proteins were successfully identified in the CSF samples, of which 97 differentially expressed proteins were identified in the GBS and NND groups. Three key molecules were identified as candidate molecules for further validation. The CSF levels of TGOLN2 and NCAM1 decreased in GBS patients compared with NND patients, whereas the CSF levels of APOC3 increased. The enzyme-linked immunosorbent assay results were consistent with our proteomics analysis. Interestingly, in the validation cohort, serum APOC3 levels in the GBS group were consistent with those in the CSF samples and significantly higher than those in the healthy control group.
Our preliminary data suggest that the CSF protein expression profile of patients with GBS is different from that of patients with NND. Moreover, alterations of TGOLN2, NCAM1and APOC3 may be used as novel biomarkers for identifying patients with GBS.

BACKGROUND: Cholangiocarcinoma (CHOL) is one of the most fatal malignancies worldwide. PBRM1 is a tumor suppressor gene in diverse cancers. It regulates cell cycle, genomic stability, centromeric cohesion, and apoptosis. However, its relevance to remodel tumor cell immune response of PBRM1 in CHOL remains unclear.
METHODS: PBRM1 mutation and expression of CHOL patients were analyzed by the TCGA database using R packages and cBioPortal site. The correlation between PBRM1 and tumor cell immune infiltrates among CHOL patients was investigated by TIMER2.0. Correlation analysis between PBRM1 and gene markers of tumor-infiltrating immune cells in CHOL was analyzed by GEPIA. Pathway enrichment analysis and protein-protein interaction network of PBRM1 mutation and expression was investigated using STRING and Cytoscape.
RESULTS: Among CHOL patients, PBRM1 has a high mutation probability and significant differential expression. Mutations and differential expression of PBRM1 both have a significant effect on the infiltration of cancer associated fibroblasts (CAF) in CHOL patients. PBRM1 was highly correlated with MMP2 and FAK, which were reported as key regulators of CAF. Through protein-protein interaction network with hub gene analysis, we discovered that NCAM1 could play key roles in the potential mechanism of how PBRM1 affects immune infiltration and progress of CHOL.
CONCLUSIONS: PBRM1 may play an important role in immune cell infiltration, matrix formation, and tumor invasion of CHOL, by regulating the function and infiltrating of tumor stromal cells including cancer-associated fibroblasts through NCAM1. Therefore, PBRM1 might be a new therapeutic target in CHOL.