Potential Therapeutic Biomarkers Research Articles

Unraveling the tumor microenvironment of esophageal squamous cell carcinoma through single-cell sequencing: A comprehensive review.

Esophageal squamous cell carcinoma (ESCC) is a highly heterogeneous and aggressive malignancy. The progression, invasiveness, and metastatic potential of ESCC are shaped by a multitude of cells within the tumor microenvironment (TME), including tumor cells, immune cells, endothelial cells, as well as fibroblasts and other cell types. Recent advancements in single-cell sequencing technologies have significantly enhanced our comprehension of the diverse landscape of ESCC. Single-cell multi-omics technology, particularly single-cell transcriptome sequencing, have shed light on the expression profiles of individual cells and the molecular characteristics of distinct tumor cell populations. This review summarizes the latest literature on single-cell research in the field of ESCC, aiming to elucidate the heterogeneity of tumor cells, immune cells, and stromal cells at the single-cell level. Furthermore, it explores the impact of cellular interactions within the TME on the progression of ESCC. By compiling a comprehensive overview of single-cell omics research on ESCC, this article aims to enhance our understanding of ESCC diagnosis and treatment by elucidating the intricate interplay within the TME. It explores the cellular composition, spatial arrangement, and functional attributes of the ESCC TME, offering potential therapeutic targets and biomarkers for personalized treatment strategies.

Down-Regulated JDP2 Attenuated Trophoblast Invasion and Migration in Preeclampsia by Inhibiting Epithelial-Mesenchymal Transition through the Wnt/β-Catenin Pathway.

Preeclampsia (PE) is an immensely prevalent condition that poses a significant risk to both maternal and fetal health. It is recognized as a primary cause of perinatal morbidity and mortality. Despite extensive research efforts, the precise impact of JDP2 on trophoblast invasion and migration in the context of preeclampsia remains unclear. The present study aimed to investigate the differential expression of JDP2 between normal control and preeclampsia placentas through the use of quantitative polymerase chain reaction (qPCR), western blotting, and immunostaining techniques. Furthermore, the effects of JDP2 overexpression and silencing on the migration, invasion, and wound healing capabilities of HTR-8/SVneo cells were evaluated. In addition, this study also examined the impact of JDP2 on epithelial-mesenchymal transition (EMT)-associated biomarkers and the Wnt/β-catenin pathway. In the present investigation, it was ascertained that Jun dimerization protein 2 (JDP2) exhibited a substantial decrease in expression levels in placentae afflicted with preeclampsia in comparison to those of normal placentae. Impairment in migration and invasion was noted upon JDP2 down-regulation, whereas augmentation of migration and invasion was observed upon JDP2 overexpression in HTR-8/SVneo cells. Subsequently, western blot and immunofluorescence assays were conducted, revealing marked alterations in EMT-associated biomarkers, such as E-cadherin, N-cadherin, and β-catenin, thereby indicating that JDP2 can facilitate cell invasion by modulating the EMT process in HTR-8/SVneo cells. Finally, activation of Wnt/β-catenin signaling was observed as a result of JDP2. After that, IWR-1, a Wnt inhibitor, was used in the recovery study. IWR-1 could inhibit the role of JDP2 in promoting migration and invasion in HTR-8/SVneo cells. Our findings elucidated the impact of JDP2 on trophoblast invasion and migration in preeclampsia by suppressing the EMT through the Wnt/β-catenin signaling pathway, thereby offering a potential prognostic and therapeutic biomarker for this condition.

To describe the subsets of malignant epithelial cells in gastric cancer, their developmental trajectories and drug resistance characteristics

Gastric cancer is an aggressive malignancy characterized by significant clinical heterogeneity arising from complex genetic and environmental interactions. This study employed single-cell RNA sequencing, using the 10 × Genomics platform, to analyze 262,532 cells from gastric cancer samples, identifying 32 distinct clusters and 10 major cell types, including immune cells (e.g., T cells, monocytes) and epithelial subpopulations. Among 27 epithelial subgroups, five malignant subpopulations were identified, each defined by unique marker gene expressions and playing diverse roles in tumor progression. Developmental trajectory analysis revealed potential stem-like characteristics in certain clusters, suggesting their involvement in therapeutic resistance and disease recurrence. Cell–cell communication analysis uncovered a dynamic network of interactions within the tumor microenvironment, potentially influencing tumor growth and metastasis. Differential gene expression analysis identified key genes (LDHA, GPC3, MIF, CD44, and TFF3) that were used to construct a prognostic risk score model. This model demonstrated robust predictive power, achieving AUC values of 0.77, 0.77, and 0.76 for 1-, 3-, and 5-year overall survival in the TCGA training dataset, with validation across independent cohorts. These findings deepen our understanding of gastric cancer's cellular and molecular heterogeneity, offering insights into potential therapeutic targets and biomarkers. By facilitating the development of targeted therapies and personalized treatment strategies, these results hold promise for improving clinical outcomes in gastric cancer patients.

HOTAIR expression as a biomarker in glioblastoma multiforme: a comprehensive meta-analysis of current evidence.

Glioblastoma multiforme (GBM) is an aggressive brain tumor. This meta-analysis investigates the association between HOTAIR expression levels and GBM. We searched the literature for studies on HOTAIR expression in GBM patients. A meta-analysis of nine studies assessed standardized mean difference (SMD) and 95% confidence intervals (CIs) using a random-effects model. Subgroup analyses were performed based on sample source, country, and study design. Additionally, we conducted meta-regression and publication bias analyses. The meta-analysis found a significant positive association between elevated HOTAIR expression and GBM (SMD = 8.3, 95% CI 5.8-10.8, p = 0.00). Considerable heterogeneity was observed (Q-value: 1174.2, df = 9, I2 = 99.2%, p = 0.00). Subgroup analyses indicated significant associations in tissue samples and studies from the USA and China. Meta-regression revealed that study design and country contributed to the observed heterogeneity, with no significant publication bias detected. This analysis confirms the significant link between HOTAIR expression and GBM, highlighting HOTAIR as a potential therapeutic target and biomarker. Further research is necessary to clarify the biological mechanisms involved in this association.

Comprehensive Analysis Reveals Midnolin as a Potential Prognostic, Therapeutic, and Immunological Cancer Biomarker

Comprehensive Analysis Reveals Midnolin as a Potential Prognostic, Therapeutic, and Immunological Cancer Biomarker

Lipidomic Expression Analysis In Carotid Atherosclerotic Disease: A Systematic Review.

Lipids are key molecules for atherosclerosis, with tight regulation mechanisms, making them potential biomarkers for disease-specific diagnostics and therapeutics. Therefore, we aim to perform a systematic literature review on lipidomic analysis in serum/plasma and plaque samples of patients with carotid atherosclerosis. We performed a systematic review following the PRISMA guidelines on the lipidomic profile in serum/plasma and carotid artery plaques from patients with significant carotid disease by degree of stenosis in preoperative imaging and clinical presentation (symptomatic, asymptomatic, radiation-induced carotid disease). Main outcome was the differential lipidomic expression of serum/plasma, and plaque lipids of patients with carotid artery atherosclerosis. Studies were screened using the Newcastle-Ottawa Scale to determine the quality of the design and content of the selected manuscripts. We included fourteen studies, from which ten included plaque analysis. The lipidomic analysis revealed that sterols and hydroxycholesterols were consistently found in both blood and plaque across studies. Triacylglycerols were present in both sample types, with specific forms linked to radiation-induced carotid artery disease. Symptomatic patients exhibited esterified hydroxyeicosatetraenoic acids and arachidonic acid precursors exclusively in plaque with an inflammatory profile of the disease. In contrast, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were associated with plaque stability. Diabetics showed nonesterified fatty acids and specific phospholipids only in plaque, indicating localized lipid changes. Other pathways relevant to disease progression include the sphingolipids and ceramide pathways with inflammatory profiling. Lipidomic provides an innovative approach to stratify carotid atherosclerotic disease. Integrating lipidomic data with other -omics approaches may further enhance our understanding of disease mechanisms and aid in the development of precision medicine approaches, specifically in those patients at risk for early carotid atherosclerotic disease.

Overexpressed RPS6KA1 and its potential diagnostic value in head and neck squamous cell carcinoma

RPS6KA1 express disorder is associated with many cancers, but the role in head and neck squamous cell carcinoma (HNSCC) and the specific mechanism is still unclear. We used bioinformatics analysis to explore the role of Ribosomal Protein S6 Kinase A1(RPS6KA1) in HNSCC which were predicted to regulate certain pathway and immune microenvironment to increase the risk in HNSCC. Multiple bioinformatics tools based on the EBI, GEO, TCGA databases and clinical samples were used to analyze the expression of RPS6K1 in HNSCC. Western blot (WB) and PCR results confirmed the upregulation of RPS6KA1 in HNSCC tissues. Flow cytometry was used to validate the relationship between RPS6KA1 and immune cell infiltration in the tumor microenvironment. The correlation of RPS6KA1 with the immune environment was further analyzed, and flow cytometry validation was performed in HNSCC samples. Then, Gene Ontology(GO) and Gene Set Enrichment Analysis(GSEA) analysis were used to explore the pathway which could be regulated by RPS6KA1 in HNSCC. And drug sensitivity analysis was used to the access the relationships between RPS6KA1 and drugs therapeutic effects. EBI, TCGA and GEO databases were used to reveal that RPS6KA1 expression was significantly increased in HNSCC, especially in III + IV HNSCC. And it was related to many types of immune cells and immune adjustment factors and positively correlated with tumor immune score and B cells, but had no significant correlation with CD4+ and CD8+ T cells. Drug sensitivity analysis revealed that RPS6KA1 has certain predictive value. In this research, we indicated that RPS6KA1 is overexpressed and may serve as a potential diagnostic and therapeutic biomarker in HNSCC.

ATRX mutation modifies the DNA damage response in glioblastoma multiforme tumor cells and enhances patient prognosis.

The presence of specific genetic mutations in patients with glioblastoma multiforme (GBM) is associated with improved survival outcomes. Disruption of the DNA damage response (DDR) pathway in tumor cells enhances the effectiveness of radiotherapy drugs, while increased mutational burden following tumor cell damage also facilitates the efficacy of immunotherapy. The ATRX gene, located on chromosome X, plays a crucial role in DDR. The aim of this research is to elucidate the correlation between ATRX mutations and GBM. Dataset obtained from TCGA-GBM were conducted an analysis on the genomic features, biological characteristics, immunopathological markers, and clinical prognosis of patients carrying ATRX mutations. Our findings revealed a significantly elevated level of microsatellite instability in individuals with ATRX mutants, along with significant alterations in the receptor-tyrosine kinase (RTK)-ras pathway among patients exhibiting combined ATRX mutations. TCGA-GBM patients with concurrent ATRX mutations exhibited sensitivity to 26 chemotherapeutic and anticancer drugs, which exerted their effects by modulating the DDR of tumor cells through highly correlated mechanisms involving the RTK-ras pathway. Additionally, we observed an enrichment of ATRX mutations in specific pathways associated with DDR among TCGA-GBM patients. Our model also demonstrated prolonged overall survival in patients carrying ATRX mutations, particularly showing strong predictive value for 3- and 5-year survival rates. Furthermore, additional protective factors such as younger age, female gender, combined IDH mutations, and TP53 mutations were identified. The results underscore the protective role and prognostic significance of ATRX mutations in GBM as a potential therapeutic target and biomarker for patient survival.

Thymidine Phosphodiester Chemiluminescent Probe for Sensitive and Selective Detection of Ectonucleotide Pyrophosphatase 1.

ENPP-1 is a transmembrane enzyme involved in nucleotide metabolism, and its overexpression is associated with various cancers, making it a potential therapeutic target and biomarker for early tumor diagnosis. Current detection methods for ENPP-1 utilize a colorimetric probe, TMP-pNP, which has significant limitations in sensitivity. Here, we present probe CL-ENPP-1, the first nucleic acid-based chemiluminescent probe designed for rapid and highly sensitive detection of ENPP-1 activity. The design of probe CL-ENPP-1 features a phenoxy-adamantyl-1,2-dioxetane luminophore linked to thymidine via a phosphodiesteric bond. Upon cleavage of the enzymatic substrate by ENPP-1, the probe undergoes an efficient chemiexcitation process to emit a green photon. Probe CL-ENPP-1 demonstrates an exceptional signal-to-noise ratio of 15000 and a limit of detection value approximately 4500-fold lower than the widely used colorimetric probe TMP-pNP. A comparison of TMP-pNP activation by ENPP-1 versus alkaline phosphatase (ALP) reveals a complete lack of selectivity. Removal of the self-immolative spacer from probe CL-ENPP-1 resulted in a new chemiluminescent probe, CL-ENPP-2, with an 18.4-fold increase in selectivity for ENPP-1 over ALP. The ability of probe CL-ENPP-2 to detect ENPP-1 activity in mammalian cells was assessed using the human breast cancer cell line MDA-MB-231. This probe demonstrated a 19.5-fold improvement in the signal-to-noise ratio, highlighting its superior ability to detect ENPP-1 activity in a biological sample. As far as we know, to date, CL-ENPP-1 and CL-ENPP-2 are the most sensitive probes for the detection of ENPP-1 catalytic activity. We anticipate that our new chemiluminescent probes will be valuable for various applications requiring ENPP-1 detection, including enzyme inhibitor-based drug discovery assays. The insights gained from our probe design principles could advance the development of more selective probes for ENPP-1 and contribute to future innovations in chemiluminescence research.

Early-Stage Luminal B-like Breast Cancer Exhibits a More Immunosuppressive Tumor Microenvironment than Luminal A-like Breast Cancer.

Breast cancer is a heterogeneous malignant disease with a varying prognosis and is classified into four molecular subtypes. It remains one of the most prevalent cancers globally, with the tumor microenvironment playing a critical role in disease progression and patient outcomes. This study evaluated tumor samples from 40 female patients with luminal A and B breast cancer, utilizing flow cytometry to phenotypically characterize the immune cells and tumor cells present within the tumor tissue. The luminal B-like tumor samples exhibited increased infiltration of CD4+ cells, regulatory T cells (Tregs), and Th17 cells and decreased levels of NK cells, γδ T cells, Th1 cells, and follicular T cells, which is indicative of a more immunosuppressive tumor microenvironment. These findings suggest that luminal B-like tumors have a microenvironment that is less supportive of effective anti-tumor immune responses compared to luminal A tumors. This study enhances the understanding of the immunological differences between luminal subtypes of breast cancer and identifies potential new therapeutic targets and biomarkers that could drive advancements in precision medicine for breast cancer management.

Causal Association between Saturated Fatty Acid Foods and Osteoarthritis and Identification of Potential Targets

Background: Numerous studies suggest a link between the consumption of foods rich in saturated fatty acids and the development of osteoarthritis. However, the causal relationships are still unclear. Moreover, the complex pathogenesis poses challenges in developing targeted drugs and identifying biomarkers. Objective: To investigate the potential causal association between the consumption of foods in saturated fatty acids and osteoarthritis, as well as to identify potential therapeutic targets and biomarkers using colocalization analysis. Methods: A two-sample Mendelian randomization (MR) analysis based on publicly available genome-wide association studies was employed to infer the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method. Bayesian colocalization analysis was conducted to identify potential therapeutic targets and metabolic products. Results: Cheese intake per standard deviation increase causally reduced the risks of knee osteoarthritis (OR = 0.605; 95% CI, 0.479-0.764; p < 0.001), osteoarthritis of the hip or knee (OR = 0.676; 95% CI, 0.553-0.826; p < 0.001), and osteoarthritis self-reported (OR = 0.720; 95% CI, 0.521-0.995; p = 0.047). Cheesy biscuits intake per standard deviation increase causally reduced the risks of knee osteoarthritis (OR = 0.485; 95% CI, 0.239-0.987; p = 0.046), osteoarthritis of the hip or knee (OR = 0.535; 95% CI, 0.315-0.909; p = 0.021). Pork intake per standard deviation increase causally reduced the level of basophil (OR = 0.738; 95% CI,0.579-0.941; p = 0.014); each standard deviation increase in mutton intake reduced the level of CRP (OR = 0.763; 95% CI. 0.594-0.979; p = 0.034), each additional standard deviation of whole milk intake reduced the level of CRP (OR = 0.079; 95% CI, 0.008-0.737; p = 0.026), and each additional standard deviation of fried potato intake reduced the level of the neutrophil count (OR = 0.944; 95% CI, 0.892-0.999; p = 0.048). Three single nucleotide polymorphisms (SNPs), namely rs143384, rs66989638, and rs8053839, associated with knee or hip osteoarthritis, as well as one SNP (rs112635299) associated with osteoarthritis metabolism, were identified through colocalization analysis. Conclusions: This two sample MR analysis found a causal negative association between foods containing saturated fatty acids and both osteoarthritis and biomarkers. Colocalization analysis identified three potential drug targets and one metabolite that could serve as a diagnostic marker.

CYB561 a potential prognostic biomarker for liver hepatocellular carcinoma

Liver hepatocellular carcinoma (LIHC) is a malignancy characterized by a high rate of recurrence, metastasis, and poor prognosis. Cytochrome b561 (CYB561) has been previously reported to be associated with tumor progression, but it has not been revealed in LIHC. The aim of this study was to investigate the prognostic value and potential function of CYB561 in LICH. The expression level, clinical correlation, prognosis, and biological function of CYB561 in LIHC were analyzed using The Cancer Genome Atlas（TCGA), Gene Expression Omnibus (GEO), TIMER2, Kaplan–Meier Plotter, and GEPIA2 databases. The expression of CYB561 in LIHC tissue samples was analyzed by immunohistochemical staining. The effect of CYB561 on the proliferation and migration of LIHC cells was investigated by using CYB561 knockdown in vitro. GSE149614 dataset was used to analyze the expression distribution of CYB561 in LIHC on a single-cell dimension. This study showed that CYB561 mRNA and protein were highly expressed in LIHC. High expression of CYB561 suggests poor prognosis in LICH patients and is an independent risk factor for LIHC. Wound-healing experiment, transwell experiment, and clonal formation experiment confirmed that CYB561 knockdown could inhibit the proliferation and migration of LIHC cells. Functional enrichment analysis showed that CYB561 was related to biological processes such as cell adhesion and immune response. KEGG enrichment analysis showed that CYB561 interacts with tumor-related signaling pathways. Single-cell analysis showed that CYB561 was mainly expressed in hepatocytes. Cells with high CYB561 expression had a higher degree of malignancy. Our study found that abnormal expression of CYB561 in LIHC suggested poor prognosis of LIHC and was related to tumor migration and proliferation. CYB561 is a potential prognostic predictor or therapeutic biomarker.

Multi-omics and in-silico approach reveals AURKA, AURKB, and RSAD2 as therapeutic biomarkers in OSCC progression

Oral squamous cell carcinoma (OSCC), a prevalent form of head and neck cancer, poses a significant health challenge with limited improvements in patient outcomes over the years. Its development is influenced by a complex interplay of genetic alterations and environmental factors. While progress has been made in understanding the molecular mechanisms driving OSCC, pinpointing critical molecular markers and potential drug candidates has proven elusive. This study uniquely endeavors to conduct a meta-analysis to unveil therapeutic genes responsible for OSCC tumorigenesis. A multi-omics approach identified 951 differentially expressed genes (DEGs) associated with OSCC by analyzing microarray data from the NCBI GEO database. Weighted gene co-expression network analysis (WGCNA) detected a significant hub gene module comprising 805 genes, followed by the construction of protein-protein interaction network resulting in two small clusters of 7 gene-encoded proteins each. These clusters were filtered out based on top 10 significant pathways and gene ontology terms to identify six key target proteins with elevated expression levels, acting as potential therapeutic biomarkers for OSCC. Notably, RSAD2 emerged as a novel biomarker linked to OSCC progression. Furthermore, we identified potential inhibitors targeting AURKA, AURKB, and RSAD2 proteins and validated their interactions through molecular dynamics simulation studies. The simulations confirmed the stability of receptor-ligand complexes, suggesting ZINC03839281, ZINC04026167, and ZINC00718292 compounds hold promise as potential inhibitors for therapeutically targeting AURKA, AURKB, and RSAD2 as significant OSCC biomarkers. We recommend further comprehensive studies, including experimental and preclinical investigations, to validate the effectiveness of these lead compounds for OSCC treatment.

Role of eosinophil counts in mediating the association between asthma and colon cancer.

Epidemiological findings regarding the association between asthma and the risk of colon cancer (CC) are inconsistent. The causality and potential molecular mechanisms underlying asthma, eosinophil count, and CC remain unknown. We performed Mendelian randomization (MR) analysis to investigate the causality between asthma and CC and attempted to demonstrate that asthma indirectly affects CC mediated by eosinophil count through mediation analysis. Sensitivity analyses and multivariable MR were performed to test the robustness of our findings. Multiple bioinformatics tools were applied to further investigate the underlying mechanisms related to eosinophils that contribute to the pathogenesis of both asthma and CC. MR with mediation analyses suggested that eosinophil count may play a role in the mechanism through which asthma reduces the risk of CC. Our bioinformatic analyses identified PPP1R14A as a potential therapeutic target and an eosinophil-associated biomarker for CC patients. Higher expression of PPP1R14A may be associated with a poorer prognosis in CC patients. Additionally, the lysosome pathway emerges as a shared eosinophil-related pathway in both asthma and CC. Eosinophils may contribute to a lower risk of CC in patients with asthma. PPP1R14A is a potential therapeutic target and biomarker for CC.

Multi-targeted olink proteomics analyses of cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage

BackgroundThe complexity of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may require the simultaneous analysis of variant types of protein biomarkers to describe it more accurately. In this study, we analyzed for the first time the alterations of cerebrospinal fluid (CSF) proteins in patients with aSAH by multi-targeted Olink proteomics, aiming to reveal the pathophysiology of DCI and provide insights into the diagnosis and treatment of aSAH.MethodsSix aSAH patients and six control patients were selected, and CSF samples were analyzed by Olink Proteomics (including 96-neurology panel and 96-inflammation panel) based on Proximity Extension Assay (PEA). Differentially expressed proteins (DEPs) were acquired and bioinformatics analysis was performed.ResultsPCA analysis revealed better intra- and inter-group reproducibility of CSF samples in the control and aSAH groups. 23 neurology-related and 31 inflammation-relevant differential proteins were identified. In the neurology panel, compared to controls, the up-regulated proteins in the CSF of SAH patients predominantly included macrophage scavenger receptor 1 (MSR1), siglec-1, siglec-9, cathepsin C (CTSC), cathepsin S (CTSS), etc. Meanwhile, in the inflammation group, the incremental proteins mainly contained interleukin-6 (IL-6), MCP-1, CXCL10, CXCL-9, TRAIL, etc. Cluster analysis exhibited significant differences in differential proteins between the two groups. GO function enrichment analysis hinted that the differential proteins pertinent to neurology in the CSF of SAH patients were mainly involved in the regulation of defense response, vesicle-mediated transport and regulation of immune response; while the differential proteins related to inflammation were largely connected with the cellular response to chemokine, response to chemokine and chemokine-mediated signaling pathway. Additionally, in the neurology panel, KEGG enrichment analysis indicated that the differential proteins were significantly enriched in the phagosome, apoptosis and microRNAs in cancer pathway. And in the inflammation panel, the differential proteins were mainly enriched in the chemokine signaling pathway, viral protein interaction with cytokine and cytokine receptor and toll-like receptor signaling pathway.ConclusionsThese identified differential proteins reveal unique pathophysiological characteristics secondary to aSAH. Further characterization of these proteins and aberrant pathways in future research could enable their application as potential therapeutic targets and biomarkers for DCI after aSAH.

Neutrophil Extracellular Traps Drive Kidney Stone Formation

Introduction: This study aims to explore the contribution of neutrophil extracellular traps (NETs) to kidney stones. Methods: The microarray data from GSE73680 and bioinformatic analysis were applied to identify differentially expressed genes in patients with kidney stones. A rat model of kidney stones was established through ethylene glycol and ammonium chloride administration. The plasma was collected for examining cf-DNA, DNase I, MPO-DNA, H3Cit and NE. Superoxide dismutase, malondialdehyde, creatinine, blood urea nitrogen, and calcium were examined through biochemical analysis. MPO, H3Cit, and NE in kidney tissues were detected via immunofluorescence staining. Cell apoptosis was evaluated through TUNEL assays. HE, Periodic Acid-Schiff and Von Kossa staining were applied to determine histological structure, calcium deposits and stone formation in the kidneys. Neutrophil elastase inhibitor Sivelestat (SIVE) was administrated for NET suppression in rats. Results: A total of 403 differentially expressed genes including 270 upregulated and 133 downregulated genes were identified between renal papillary tissues with Randall’s plaque and normal tissues. Gene ontology enrichment, KEGG pathway and protein-protein interaction network analysis of these dysregulated genes were performed. Moreover, increased NET markers including cf-DNA, DNase I, MPO-DNA, H3Cit and NE and calcium deposits were observed in patients with kidney stones. Subsequently, we established a rat model of kidney stones. We found that NET formation was significantly elevated in kidney stone rats, and renal tubular injury and apoptotic cells were enhanced as kidney stones developed. Strikingly, we found that suppression of NETs via SIVE could significantly reduce calcium deposits and apoptotic cells and alleviate tubular injury, thus improving kidney function. Conclusion: NETs drive the formation of kidney stones, thus aggravating kidney injury. Our study identifies NETs as a potential diagnostic and therapeutic biomarker for nephrolithiasis.

Exploring SLC30A6 as a potential prognostic, immunomodulatory, and therapeutic biomarker in various cancers with a focus on pancreatic cancer: a pan-cancer analysis

BackgroundOur study investigates the multifaceted role of the gene SLC30A6 across 33 distinct cancer types. Understanding the function and impact of SLC30A6 in cancer biology is crucial, as previous studies have hinted at its aberrant expression and potential involvement in tumor progression. This research aims to elucidate the expression patterns, methylation variations, mutational signatures, and survival implications of SLC30A6, along with its engagement with the immune system in various cancers and specially in pancreatic cancer.MethodsWe conducted a comprehensive analysis of SLC30A6 using data from 33 different cancer types, and all data were analyzed in silico. The study involved examining expression levels, performing correlation analyses with clinical outcomes, assessing methylation variations, and identifying mutational signatures. Functional enrichment analyses were carried out to understand the gene's involvement in biological pathways. Additionally, we evaluated the relationship between SLC30A6 expression and immune cell infiltration levels to uncover its role in the tumor microenvironment.ResultsSLC30A6 was found to be significantly up-regulated in the majority of the 33 cancer types analyzed. High expression levels of SLC30A6 were consistently correlated with poor survival outcomes, indicating its potential role in cancer prognosis. Functional enrichment analyses revealed that SLC30A6 is involved in key pathways related to tumor progression, including cell proliferation and apoptosis. Moreover, SLC30A6 showed significant associations with diverse immune pathways, suggesting its involvement in immune regulation. Notably, our analysis demonstrated a significant correlation between SLC30A6 expression and the infiltration levels of key immune cells, highlighting its dual immunosuppressive and immunostimulatory roles in a pan-cancer context. Moreover, SLC30A6 is significantly overexpression in pancreatic cancer and have shown different clinical associations as above.ConclusionOur study provides comprehensive insights into the complex interplay between SLC30A6 and cancer development. These findings position SLC30A6 as a promising prognostic biomarker and therapeutic target across diverse cancer types, highlighting its importance in future cancer research and treatment strategies.

ATP6V1C1, associated with the tumor microenvironment and mTORC1 signaling pathway, is a potential diagnostic, prognostic, and therapeutic biomarker for hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a global health challenge with high mortality. ATP6V1C1, one of the subunit genes of vacuolar adenosine triphosphatase (V-ATPase), is a potential oncogene. However, its role in HCC remains unclear.Materials and methodsDifferential analysis of mRNA and microRNA (miRNA), combined with machine learning, identified ATP6V1C1 as a potential biomarker for HCC. The expression and prognostic role of ATP6V1C1 in HCC were evaluated. Additionally, we explored the distribution of ATP6V1C1 in HCC tumor microenvironment (TME) at single-cell and spatial transcriptome levels. Furthermore, the association between ATP6V1C1 and malignant biological features, TME characteristics, and therapy response in HCC was investigated. Finally, in vitro experiments validated the effects of ATP6V1C1 on the malignant phenotype of HCC.ResultsATP6V1C1 had higher expression in HCC tissues compared to paired normal tissues. Upregulated ATP6V1C1 was associated with poor HCC prognosis. ATP6V1C1 was primarily expressed in malignant cells and the tumor region in HCC TME. A positive correlation was observed between ATP6V1C1 expression and the activation of cancer-related pathways. The high ATP6V1C1 expression group exhibited increased pro-tumorigenic immune infiltration, inhibited anti-tumor immune activity, and high tumor proliferation rate. HCC patients of low ATP6V1C1 expression group had more clinical response to anti-tumor therapies. Knockdown of ATP6V1C1 impaired the proliferation, migration, and invasion of HCC cells by downregulating the mTORC1 signaling pathway.ConclusionATP6V1C1 multifacetedly contributes to the oncogenesis and progression of HCC and is a promising diagnostic and prognostic biomarker with predictive value on therapy response.

SITP: A single cell bioinformatics analysis flow captures proteasome markers in the development of breast cancer

Single cell sequencing and related databases have been widely used in the exploration of cancer occurrence and development, but there is still no in-depth explanation of specific and complicated cellular protein modification processes. Ubiquitin-Proteasome System (UPS), as a specific and precise protein modification and degradation process, plays an important role in the biological functions of cancer cell proliferation and apoptosis. Proteasomes, vital multi-catalytic proteinases in eukaryotic cells, play a crucial role in protein degradation and contribute to tumor regulation. The 26S proteasome, part of the ubiquitin–proteasome system. In this study, we have enrolled a common SITP process including analysis of single cell sequencing to elucidate a flow that can capture typical proteasome markers in the oncogenesis and progression of breast cancer. PSMD11, a key component of the 26S proteasome regulatory particle, has been identified as a critical survival factor in cancer cells. Results suggest that PSMD11’s rapid degradation is linked to acute apoptosis in cancer cells, making it a potential target for cancer treatment. Our study explored the potential mechanisms of PSMD11 in breast cancer development. The findings revealed the feasibility of disclosing ubiquitinating biomarkers from public database, as well as presented new evidence supporting PSMD11 as a potential therapeutic biomarker for breast cancer.

The circular RNA circNFIX regulates MEF2C expression in muscle satellite cells in spastic cerebral palsy

Cerebral palsy (CP) is a pediatric onset disorder with poorly understood molecular causes and progression, making early diagnosis difficult. Circular RNAs are regulatory RNAs that show promise as biomarkers in various diseases but the role of circular RNAs in CP is beginning to be understood. This study identified the role of circNFIX in regulating the expression of myocyte-specific enhancer factor 2C (MEF2C), an important transcription factor for sarcomere development. We found that circNFIX is downregulated in the muscle cells of individuals with CP, and its localization shifts toward the nucleus as visualized using single-molecule resolution imaging. The decreased expression of circNFIX, MEF2C, and MEF2C targets persisted throughout myoblasts to myotubes differentiation, and in the skeletal muscle tissue. Bioinformatic and experimental validation confirmed that circNFIX acts as a sponge for miR373-3p, a microRNA that represses MEF2C translation. In normal muscle, circNFIX derepresses MEF2C translation by sponging miR373-3p, allowing for normal sarcomere generation. In CP, reduced circNFIX expression results in loss of miRNA sponging, leading to lower MEF2C expression and downregulation of sarcomere genes, potentially causing shortened and dysfunctional muscle fibers. Knockdown (KD) of circNFIX reduced myogenic capacity of myoblasts to fuse and form myotubes similar to CP cells evident from the lower fusion index in CP and KD as compared to control myotubes. This is the first study reporting reduction of MEF2C in CP and single-molecule resolution imaging of circNFIX's subcellular distribution and its role in CP, suggesting circNFIX as a potential therapeutic target and biomarker for early CP diagnosis.