Potential Biomarker For Prognosis Research Articles

N6-methyladenosine modification of circMARK2 enhances cytoplasmic export and stabilizes LIN28B, contributing to the progression of Wilms tumor

BackgroundThe potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression.MethodsWe identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining.ResultsCircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates.ConclusionsOur study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.

Identifying key genes and functionally enriched pathways in acute myeloid leukemia by weighted gene co-expression network analysis.

Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of myeloid leukemia cells in the bone marrow and other hematopoietic tissues and is highly heterogeneous. While with the progress of sequencing technology, understanding of the AML-related biomarkers is still incomplete. The purpose of this study is to identify potential biomarkers for prognosis of AML. Based on WGCNA analysis of gene mutation expression, methylation level distribution, mRNA expression, and AML-related genes in public databases were employed for investigating potential biomarkers for the prognosis of AML. This study screened a total of 6153 genes by analyzing various changes in 103 acute myeloid leukemia (AML) samples, including gene mutation expression, methylation level distribution, mRNA expression, and AML-related genes in public databases. Moreover, seven AML-related co-expression modules were mined by WGCNA analysis, and twelve biomarkers associated with the AML prognosis were identified from each top 10 genes of the seven co-expression modules. The AML samples were then classified into two subgroups, the prognosis of which is significantly different, based on the expression of these twelve genes. The differentially expressed 7 genes of two subgroups (HOXB-AS3, HOXB3, SLC9C2, CPNE8, MEG8, S1PR5, MIR196B) are mainly involved in glucose metabolism, glutathione biosynthesis, small G protein-mediated signal transduction, and the Rap1 signaling pathway. With the utilization of WGCNA mining, seven gene co-expression modules were identified from the TCGA database, and there are unreported genes that may be potential driver genes of AML and may be the direction to identify the possible molecular signatures to predict survival of AML patients and help guide experiments for potential clinical drug targets.

Biomarkers in Cerebrospinal Fluid for the Diagnosis and Monitoring of Gliomas

Gliomas are the most common type of malignant brain tumor and are characterized by a plethora of heterogeneous molecular alterations. Current treatments require the emergence of reliable biomarkers that will aid personalized treatment decisions and increase life expectancy. Glioma tissues are not as easily accessible as other solid tumors; therefore, detecting prominent biomarkers in biological fluids is necessary. Cerebrospinal fluid (CSF) circulates adjacent to the cerebral parenchyma and holds promise for discovering useful prognostic, diagnostic, and predictive biomarkers. In this review, we summarize extensive research regarding the role of circulating DNA, tumor cells, proteins, microRNAs, metabolites, and extracellular vesicles as potential CSF biomarkers for glioma diagnosis, prognosis, and monitoring. Future studies should address discrepancies and issues of specificity regarding CSF biomarkers, as well as the validation of candidate biomarkers.

Biomarkers in Cerebrospinal Fluid for the Diagnosis and Monitoring of Gliomas

Gliomas are the most common type of malignant brain tumor and are characterized by a plethora of heterogeneous molecular alterations. Current treatments require the emergence of reliable biomarkers that will aid personalized treatment decisions and increase life expectancy. Glioma tissues are not as easily accessible as other solid tumors; therefore, detecting prominent biomarkers in biological fluids is necessary. Cerebrospinal fluid (CSF) circulates adjacent to the cerebral parenchyma and holds promise for discovering useful prognostic, diagnostic, and predictive biomarkers. In this review, we summarize extensive research regarding the role of circulating DNA, tumor cells, proteins, microRNAs, metabolites, and extracellular vesicles as potential CSF biomarkers for glioma diagnosis, prognosis, and monitoring. Future studies should address discrepancies and issues of specificity regarding CSF biomarkers, as well as the validation of candidate biomarkers.

PLA2G2D and CHIT1: Potential biomarkers for immune infiltration and prognosis in cervical squamous cell carcinoma

PLA2G2D and CHIT1: Potential biomarkers for immune infiltration and prognosis in cervical squamous cell carcinoma

Single-cell and bulk sequencing analysis to evaluate the oncogenic role of PDE3A in pan-cancer and validation in breast cancer.

e15128 Background: PDE3A is involved in critical physiological processes through the hydrolysis of cycle AMP (cAMP) and GMP (cGMP). Its role in the occurrence and progression of cancer has recently attracted attention, but carcinogenic mechanism in pan-cancer has not been fully elucidated. Methods: We explored the expression, prognostic and diagnostic value, mutation, methylation, immune infiltration, and signaling pathway enrichment analysis of PDE3A in pan-cancer by combining multiple bioinformatics databases and single-cell sequencing analysis. Furthermore, we verified the protein and mRNA expression levels of PDE3A and investigated its oncogenic role in the progression of breast cancer (BRCA). Results: PDE3A was expressed at lower levels than normal tissues in most cancers and showed a wonderful prognostic value. PDE3A was strongly correlated with immune cells, especially cancer-associated fibroblast (CAF), and was involved in various vital signaling pathways. Furthermore, PDE3A could facilitate BRCA progression by promoting cells invasion and migration, and it may be associated with the efficacy of endocrine therapy in ER+ BRCA. Conclusions: We provided new insights into the carcinogenic effect of PDE3A in pan-cancer. PDE3A may be a potential biomarker for cancer diagnosis and prognosis, and it is also a promising target for cancer immunotherapy.

Patient-reported symptom interference with activity- and mood-related functioning prior to start of an early-phase oncology combination trial including immune checkpoint blockade.

12084 Background: We examined symptom interference with activity- and mood-related functioning at baseline in early-stage trials of combination treatments that included at least one immune checkpoint inhibitor, and its association with quality of life (QOL)-, clinical-, and trial-related factors. Methods: Patients scheduled to begin an early-phase trial of a combination treatment with immune checkpoint blockade, and who had not received trial-related treatment were recruited into a prospective longitudinal study design (NCI R01CA242565), and completed the following validated patient-reported outcome (PRO) measures prior to trial start: MD Anderson Symptom Inventory- Immunotherapy (score range: 0-10, higher scores = worse symptom interference); NCI’s PRO Common Terminology Criteria for Adverse Events (0-4, higher = worse severity); EuroQoL-5 dimensions assessing health status (0-100, higher = better health) and problems with self-care, and the Sloan Global QOL scale (0-10, higher = better QOL). Statistical tests included Spearman’s correlation rho (r) and multivariable linear regression. Results: 977 baseline PRO measures were completed by 247 patients (median age = 59 y; 46% female). Worst symptom-related interference was with activity (3.0 on a 0-10 scale), work (2.9), and enjoyment of life (2.4). Composite score means were 2.8 for symptom interference with walking, activity, and work (WAW; activity-related functioning), and 2.1 for interference with relationships, enjoyment of life, and mood (REM; mood-related functioning). Symptoms most associated with worse WAW were fatigue (P<0.001) and appetite loss (P=0.001). Worse WAW was linked to worse REM (r=0.78, P<0.001). Diminished sexual interest/mood (DSI) was associated with worse WAW (r=0.35, P<0.001) and REM (r=0.33, P<0.001). Worse WAW was linked to shorter trial duration (P=0.003) and worse response (progression of disease/immune-related progression) on the clinical trial (P=0.05). Conclusions: This first, comprehensive and prospective examination of symptom interference with functioning at trial baseline found that worse symptom interference was linked to worse QOL, poorer clinical outcomes, and shorter trial duration. These findings suggest that baseline patient-reported symptom interference with functioning can serve as a potential biomarker of poor prognosis in investigational trials, and that trial patients may benefit from initiation of supportive care prior to trial start. [Table: see text]

Downregulation of DIP2B as a prognostic marker inhibited cancer proliferation and migration and was associated with immune infiltration in lung adenocarcinoma via CCND1 and MMP2

BackgroundDIP2B is related to cancer progression. This study investigated the roles and pathways of DIP2B in lung adenocarcinoma (LUAD). MethodsDIP2B expression and the relationship between survival time of cancer patients and DIP2B expression were analyzed. The relationship between DIP2B expression and survival time in LUAD patients was evaluated by a meta-analysis. Cox and survival analyses were used to evaluate the prognostic factors and construct a prognostic nomogram. The mechanisms and effects of DIP2B and the relationship between DIP2B expression and the immune microenvironment were investigated using bioinformatics, CCK-8, western blotting, and transwell experiments. ResultsDIP2B was overexpressed in LUAD tissues. DIP2B overexpression was associated with shorter prognosis and was an unfavorable risk factor for prognosis in LUAD patients. DIP2B co-expressed genes were involved in cell division, DNA repair, cell cycle, and others. Inhibition of DIP2B expression could downregulate the proliferation, migration, and invasion of LUAD A549 and H1299 cells, which was related to the decrease in CCND1 and MMP2 protein expression. BRCA1 overexpression was associated with short prognosis, and the nomogram formed by DIP2B and BRCA1 was associated with a poor prognosis in LUAD patients. DIP2B expression correlated with immune cells (such as CD8 T cells, Tcm, and iDCs) and cell markers. ConclusionDIP2B is a potential biomarker of poor prognosis and the immune microenvironment in LUAD. Inhibition of DIP2B expression downregulated cancer cell proliferation, migration, and invasion, which might be related to the decrease in CCND1 and MMP2 protein expression. DIP2B-related nomograms might be useful tools for predicting the prognosis of LUAD patients.

#1339 The characteristic of memory B-cell subsets in patients with IgA-nephropathy

Abstract Background and Aims Impaired B-cell development has been postulated to play an important role in the maintaining of autoimmune inflammation what makes memory B-cells a perspective target for a new therapeutic strategy in IgA-nephropathy (IgAN). However, to date there are few and controversial data about the precise role of circulating memory B-cell subsets in clinical progression of IgAN. The aim was to estimate the immunological profile of memory B-cell subpopulations in the peripheral blood of IgAN patients. Method The peripheral blood was obtained from 20 IgAN patients (aged of 32.0 (27.0-36.0) y.o., male/female ratio as 13/7) and 15 donors (aged of 38.0 (30.0-46.0) y.o., male/female ratio as 10/5). The diagnosis was confirmed by morphological examination of the biopsy material. The phenotype of B-cells subsets was determined by a panel of CD38-PE/CD19-ECD/CD27-PC5/IgD-APC antibodies; γδT-lymphocytes—by a panel of TCRγδ-FITC/TCRαβ-PE/HLA-DR-ECD/TCRVδ1-PC7/CD3-APC-A750/TCRVδ2-PB/ CD45-KRO antibodies using flow cytometry method (Cytoflex, Beckman Coulter, USA). The concentration of B-cell activating factor (BAFF) was measured using enzyme-linked immunosorbent assay. Statistical data processing was done in Statistica 10.0 program. Results Based on cell surface markers expression the following B-cells subsets were identified in the peripheral blood: naïve B-cells (CD19+CD27−IgD+), pre-switched B-cells (CD19+CD27+IgD+), switched B-cells (CD19+CD27+IgD−), plasmablasts (CD19+CD27+CD38+) and long-lived plasma cells (CD27hiCD38hi) (Fig. 1). The altered balance in B-cells maturation characterizing by a significant lower percent of pre-switched B-cells and plasmablasts (p < 0.05) as well as a higher trend (>55%) in the naive B-cells (p < 0.01) was established in IgAN patients as compared to healthy donors reflecting the exhaustion of peripheral blood plasmablasts due to constant generation of antibody-producing plasma cells. Moreover, the lower pre-switched B-cells percentage was detected in the blood, the more BAFF production was observed in serum of IgAN patients (R = 0.50; p < 0.05) and the higher proteinuria level was detected (R = 0.47; p < 0.05). The increased total number of γδТ-cells up to 9.42 (6.25-12.44)% in IgAN patients as compared to donors (p = 0.03) was correlated with total memory CD19+CD27+B-cells numbers (R = 0.54; p < 0.05) as well as pre-switched B-cells (R = 0.45; p < 0.05), plasmablasts (R = 0.57; p < 0.01) and long-lived plasma cells (R = 0.51; p < 0.05). A detailed subsets analysis revealed an elevated level of tissue-resident mucosa-associated cells (Vδ1+ and Vδ3+T-lymphocytes) as well as enhanced HLA-DR expression on them (p < 0.05) in combination with decreased normally circulating Vδ2+T-cells numbers (p < 0.01) as compared to healthy donors what characterized Vδ1+ and Vδ3+T-cells subsets as professional antigen presenting cells and indicated their possible role in the priming of antigen specific B-cells. Conclusion Suggesting that most peripheral B-lymphocytes are naïve, the obtained data may reflect a γδT-cells role in migration of pre-switched B-cells from the circulation to mucosa sites for possible further maturation and class-switching what allows us to consider these two parameters as potential useful biomarkers of IgAN disease prognosis in clinical practice.

Breast cancer clinical outcomes and tumor immune microenvironment: cross-dialogue of multiple epigenetic modification profiles.

The discovery of RNA methylation alterations associated with cancer holds promise for their utilization as potential biomarkers in cancer diagnosis, prognosis, and prediction. RNA methylation has been found to impact the immunological microenvironment of tumors, but the specific role of methylation-related genes (MRGs), particularly in breast cancer (BC), the most common cancer among women globally, within the tumor microenvironment remains unknown. In this study, we obtained data from TCGA and GEO databases to investigate the expression patterns of MRGs in both genomic and transcriptional domains in BC. By analyzing the data, we identified two distinct genetic groupings that were correlated with clinicopathological characteristics, prognosis, degree of TME cell infiltration, and other abnormalities in MRGs among patients. Subsequently, an MRG model was developed to predict overall survival (OS) and its accuracy was evaluated in BC patients. Additionally, a highly precise nomogram was created to enhance the practical usability of the MRG model. In low-risk groups, we observed lower TBM values and higher TIDE scores. We further explored how MRGs influence a patient's prognosis, clinically significant characteristics, response to therapy, and the TME. These risk signatures have the potential to improve treatment strategies for BC patients and could be applied in future clinical settings. Moreover, they may also be utilized to determine prognosis and biological features in these patients.

Biological functions and therapeutic potential of SRY related high mobility group box 5 in human cancer.

Cancer is a heavy human burden worldwide, with high morbidity and mortality. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Transcription factors, including SRY associated high mobility group box (SOX) proteins, are thought to be involved in the regulation of specific biological processes. There is growing evidence that SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumor microenvironment, and metastasis. SOX5 is a member of SOX Group D of Sox family. SOX5 is expressed in various tissues of human body and participates in various physiological and pathological processes and various cellular processes. However, the abnormal expression of SOX5 is associated with cancer of various systems, and the abnormal expression of SOX5 acts as a tumor promoter to promote cancer cell viability, proliferation, invasion, migration and EMT through multiple mechanisms. In addition, the expression pattern of SOX5 is closely related to cancer type, stage and adverse clinical outcome. Therefore, SOX5 is considered as a potential biomarker for cancer diagnosis and prognosis. In this review, the expression of SOX5 in various human cancers, the mechanism of action and potential clinical significance of SOX5 in tumor, and the therapeutic significance of Sox5 targeting in cancer were reviewed. In order to provide a new theoretical basis for cancer clinical molecular diagnosis, molecular targeted therapy and scientific research.

Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation

Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing ‘M1-like’ macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.

Exploring various carbon nanomaterials-based electrodes modified with polymelamine for the reagentless electrochemical immunosensing of Claudin18.2

Claudin18.2 (CLDN18.2) is a tight junction protein often overexpressed in various solid tumors, including gastrointestinal and esophageal cancers, serving as a promising target and potential biomarker for tumor diagnosis, treatment assessment, and prognosis. Despite its significance, no biosensor has been reported to date for the detection of CLDN18.2. Here, we present the inaugural immunosensor for CLDN18.2. In this study, an amine-rich conducting polymer of polymelamine (PM) was electrografted onto different carbon nanomaterial-based screen-printed electrodes (SPEs), including carbon (C), graphene (Gr), graphene oxide (GO), carbon nanotube (CNT), and carbon nanofiber (CNF) via cyclic voltammetry. A comparative study was performed to explore the best material for the preparation of the PM-modified electrodes to be used as in-situ redox substrate for the immunosensor fabrication. The surface chemistry and structural features of pristine and PM-deposited electrodes were analyzed using Raman and scanning electron microscopy (SEM) techniques. Our results showed that the PM deposited on Gr and CNT/SPEs exhibited the most significant and stable redox behavior in PBS buffer. The terminal amine moieties on the PM-modified electrode surfaces were utilized for immobilizing anti-CLDN18.2 monoclonal antibodies via N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide/N-hydroxysuccinimide chemistry to construct the electrochemical immunosensor platform. Differential pulse voltammetry-based immunosensing of CLDN18.2 protein on BSA/anti-CLDN18.2/PM-Gr/SPE and BSA/anti-CLDN18.2/PM-CNT/SPE exhibited excellent selectivity against other proteins such as CD1, PDCD1, and ErBb2. The limits of detection of these two immunosensor platforms were calculated to be 7.9 pg/mL and 0.104 ng/mL for the CNT and Gr immunosensors, respectively. This study demonstrated that the PM-modified Gr and CNT electrodes offer promising platforms not only for the reagentless signaling but also for covalent immobilization of biomolecules. Moreover, these platforms offer excellent sensitivity and selectivity for the detection of CLDN18.2 due to its enhanced stable redox activity. The immunosensor demonstrated promising results for the sensitive detection of CLDN18.2 in biological samples, addressing the critical need for early gastric cancer diagnosis.

Bioinformatics analysis and validation of mesenchymal stem cells related gene MT1G in osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor arising from mesenchymal cells. The standard clinical treatment for OS involves extensive tumor resection combined with neoadjuvant chemotherapy or radiotherapy. OS's invasiveness, lung metastasis, and drug resistance contribute to a low cure rate and poor prognosis with this treatment. Metallothionein 1G (MT1G), observed in various cancers, may serve as a potential therapeutic target for OS. OS samples in GSE33382 and TARGET datasets were selected as the test cohorts. As the external validation cohort, 13 OS tissues and 13 adjacent cancerous tissues from The Second Affiliated Hospital of Nanchang University were collected. Patients with OS were divided into high and low MT1G mRNA-expression groups; differentially expressed genes (DEGs) were identified as MT1G-related genes. The biological function of MT1G was annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and gene set enrichment analysis (GSEA). Gene expression correlation analysis and competing endogenous RNA (ceRNA) regulatory network construction were used to determine potential biological regulatory relationships of DEGs. Survival analysis assessed the prognostic value of MT1G. MT1G expression increased in OS samples and presented higher in metastatic OS compared with non-metastatic OS. Functional analyses indicated that MT1G was mainly associated with spliceosome. A ceRNA network with DEGs was constructed. MT1G is an effective biomarker predicting survival and correlated with increased recurrence rates and poorer survival. This research identified MT1G as a potential biomarker for OS prognosis, highlighting its potential as a therapy target.

Carbon nanotube-assisted detection of methylated cytosine: A DFT study for epigenetic biomarker analysis

DNA methylation plays a crucial role in cancer research, offering potential biomarkers for diagnosis and prognosis. We investigate the electronic and transport properties of carbon nanotubes (CNTs) as a device material to diagnose the tumor indicators, DNA 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), using density-functional theory (DFT). Our results reveal distinct electronic behaviors of 5mC and 5hmC compared to other nucleotides when interacting with CNT, suggesting its potential as diagnostic tool for tumor markers. Furthermore, electron transport and tunneling properties are examined using DFTB, demonstrating the ability to differentiate tumor indicators from other nucleotides based on current responses. Our findings highlight the ability of CNT-based biosensors for sensitive and efficient detection of DNA methylation patterns associated with cancer.

Label free quantitative proteomic profiling of serum samples of intellectually disabled young patients revealed dysregulation of complement coagulation and cholesterol cascade systems.

Intellectual disability is a heterogeneous disorder, diagnosed using intelligence quotient (IQ) score criteria. Currently, no specific clinical test is available to diagnose the disease and its subgroups due to inadequate understanding of the pathophysiology. Therefore, current study was designed to explore the molecular mechanisms involved in disease perturbation, and to identify potential biomarkers for disease diagnosis and prognosis. A total of 250 participants were enrolled in this study, including 200 intellectually disabled (ID) subjects from the subgroups (mild, moderate, and severe) with age and gender matched healthy controls (n = 50). Initially, IQ testing score and biochemical profile of each subject was generated, followed by label-free quantitative proteomics of subgroups of IQ and healthy control group through nano-LC/MS- mass spectrometry. A total of 310 proteins were identified, among them198 proteins were common among all groups. Statistical analysis (ANOVA) of the subgroups of ID showed 142 differentially expressed proteins, in comparison to healthy control group. From these, 120 proteins were found to be common among all subgroups. The remaining 22 proteins were categorized as exclusive proteins found only in disease subgroups. Furthermore, the hierarchical cluster analysis (HCL) of common significant proteins was also performed, followed by PANTHER protein classification and GO functional enrichment analysis. Results provides that the datasets of differentially expressed proteins, belong to the categories of immune / defense proteins, transfer carrier proteins, apolipoproteins, complement proteins, protease inhibitors, hemoglobin proteins etc., they are known to involvein immune system, and complement and coagulation pathway cascade and cholesterol metabolism pathway. Exclusively expressed 22 proteins were found to be disease stage specific and strong PPI network specifically those that have significant role in platelets activation and degranulation, such as Filamin A (FLNA). Furthermore, to validate the mass spectrometric findings, four highly significant proteins (APOA4, SAP, FLNA, and SERPING) were quantified by ELISA in all the study subjects. AUROC analysis showed a significant association of APOA4 (0.830), FLNA (0.958), SAP (0.754) and SERPING (0.600) with the disease. Apolipoprotein A4 (APOA4) has a significant role in cholesterol transport, and in modulation of glucose and lipid metabolism in the CNS. Similarly, FLNA has a crucial role in the nervous system, especially in the functioning of synaptic network. Therefore, both APOA4, and FLNA proteins represent good potential for candidate biomarkers for the diagnosis and prognosis of the intellectual disability. Overall, serum proteome of ID patients provides valuable information of proteins/pathways that are altered during ID progression.

Oncogenic role of RNA-binding protein GNL2 in glioma: Promotion of tumor development through enhancing protein synthesis.

RNA-binding proteins (RBPs) are aberrantly expressed in various diseases, including glioma. In the present study, the role and mechanism of RBPs in glioma were investigated. Differentially expressed genes (DEGs) in glioma were screened from public databases and overlapping genes between DEGs and RBPs were selected in a bioinformatics analysis to identify the hub gene. Next, evaluation of expression, survival analysis and cell experiments were performed to examine the impact of the hub gene on glioma. Through bioinformatics analysis, G protein nucleolar 2 (GNL2), programmed cell death 11 (PDCD11) and ribosomal protein S6 (RPS6) were identified as potential biomarkers in glioma prognosis and GNL2 was chosen as the hub gene for further investigation. GNL2 was increased in glioma tissues and related to poor survival outcomes. Cell experiments revealed that GNL2 knockdown inhibited glioma cell growth, migration and invasion. In addition, GNL2 was found to affect the overall protein synthesis of ribosomal protein L11 in glioma cells. In conclusion, GNL2, PDCD11 and RPS6 may serve as potential biomarkers in glioma prognosis. Importantly, GNL2 acts as an oncogene in glioma and it enhances protein synthesis to promote the development of brain glioma.

Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine.

Cancer cell growth, metastasis, and drug resistance are major challenges in treating liver hepatocellular carcinoma (LIHC). However, the lack of comprehensive and reliable models hamper the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) strategy in managing LIHC. Leveraging seven distinct patterns of mitochondrial cell death (MCD), we conducted a multi-omic screening of MCD-related genes. A novel machine learning framework was developed, integrating 10 machine learning algorithms with 67 different combinations to establish a consensus mitochondrial cell death index (MCDI). This index underwent rigorous evaluation across training, validation, and in-house clinical cohorts. A comprehensive multi-omics analysis encompassing bulk, single-cell, and spatial transcriptomics was employed to achieve a deeper insight into the constructed signature. The response of risk subgroups to immunotherapy and targeted therapy was evaluated and validated. RT-qPCR, western blotting, and immunohistochemical staining were utilized for findings validation. Nine critical differentially expressed MCD-related genes were identified in LIHC. A consensus MCDI was constructed based on a 67-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. MCDI correlated with immune infiltration, Tumor Immune Dysfunction and Exclusion (TIDE) score and sorafenib sensitivity. Findings were validated experimentally. Moreover, we identified PAK1IP1 as the most important gene for predicting LIHC prognosis and validated its potential as an indicator of prognosis and sorafenib response in our in-house clinical cohorts. This study developed a novel predictive model for LIHC, namely MCDI. Incorporating MCDI into the PPPM framework will enhance clinical decision-making processes and optimize individualized treatment strategies for LIHC patients. The online version contains supplementary material available at 10.1007/s13167-024-00362-8.

Abstract PO3-24-07: The role of Hepatitis A Virus Cellular Receptor 1 (HAVCR1) in breast cancer and the impact on penetration of blood brain barrier

Abstract Background: Hepatitis A Virus Cellular Receptor 1 (HAVCR1) is associated with the biological behaviour of several cancers, and has been shown to regulate junctional complexes. However, its role in breast cancer remains unexplored. This study aimed to investigate the effects of HAVCR1 on human breast cancer. Methods: We explored the UALCAN web portal, which is linked to the TCGA database, to determine the expression of HAVCR1 in breast cancer and the Kaplan-Meier plotter to evaluate the correlation with the survival of the patients. HAVCR1 siRNA was used to knock down the HAVCR1 expression in MCF-7 and MDA-MB-231 cell lines. In vitro cell growth, wounding healing, and electric cell impedance sensing (ECIS for assessing cellular proliferation, migration and adhesion) assays were used. Transepithelial resistance (TEER) and paracellular permeability (PCP) were assessed to determine changes in the barrier function of human breast cancer cells. The expression of HAVCR1 and prospective interactive binding molecules of HAVCR1 protein was assessed using quantitative polymerase chain reaction (qPCR). Cellular response to docetaxel was evaluated and shown (IC50). The invasiveness of breast cancer cells through the human cerebral microvessel endothelial cells (hCMEC/D3) cell layers was measured using an in vitro transwell cell invasion assay. Results: HAVCR1 gene expression levels were significantly lower (P< 0.001) in breast cancer tissue compared with normal tissues. Patients with high expression of HAVCR1 had a significantly better relapse-free survival than low expression (P< 0.001). There was no significant difference in overall survival (OS) between the HAVCR1 high and the low expression groups (P=0.22). However, in subgroup analysis, high HAVCR1 expression was associated with better OS in luminal A (P=0.04). Knockdown (KD) HAVCR1 in breast cancer cells influence cell function by enhanced adhesion, proliferation, and migration compared to wild type (WT) cell lines. It was noted that loss of HAVCR1 rendered both MCF-7 and MDA-MB-231 cells resistant to docetaxel (IC50 for WT and HAVCR1 KD respectively being 0.86nM vs 1.75nM for MCF-7 and 1.35nM vs 15.48nM for MDA-MB-231). HAVCR1 KD increase adhesion to hCMEC/D3 cells (53.14±8.23 vs ±99.37±8.97 for MCF-7, P< 0.001; 109.5±97.56 vs 147.1±96.63 for MDA-MB-231, P=0.228, WT and HAVCR1 KD). In the cerebral endothelial cell invasion assay, we found that HAVCR1 KD resulted in a significantly increased invasion of the breast cancer cells through the endothelium (19.27±8.74 vs 33.58±16.81 for MDA-MB-231, P=0.0114, WT and HAVCR1 KD). For the barrier function, the knockdown led to a decrease in TEER and an increase in PCP when compared with WT cells in both cell lines. HAVCR1 KD cells showed decreased barrier function, together with reduced expression of Claudin-1/8/10, occludin, MarvelD3, Tricellulin and ZO1. Conclusions: HAVCR1 is a potential biomarker for breast cancer prognosis. HAVCR1 influences the integrity of barrier function by influence the gene expression of tight junction in breast cancer, and influence the penetration to blood brain barrier. Together, it suggests that HAVCR1 may be a potential therapeutic target in breast cancer. Citation Format: Xiaoshan Cao, Binbin Cong, Wen Jiang, Tracey Martin. The role of Hepatitis A Virus Cellular Receptor 1 (HAVCR1) in breast cancer and the impact on penetration of blood brain barrier [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-07.

Significance of NKX2-1 as a biomarker for clinical prognosis, immune infiltration, and drug therapy in lung squamous cell carcinoma.

This study was performed to determine the biological processes in which NKX2-1 is involved and thus its role in the development of lung squamous cell carcinoma (LUSC) toward improving the prognosis and treatment of LUSC. Raw RNA sequencing (RNA-seq) data of LUSC from The Cancer Genome Atlas (TCGA) were used in bioinformatics analysis to characterize NKX2-1 expression levels in tumor and normal tissues. Survival analysis of Kaplan-Meier curve, the time-dependent receiver operating characteristic (ROC) curve, and a nomogram were used to analyze the prognosis value of NKX2-1 for LUSC in terms of overall survival (OS) and progression-free survival (PFS). Then, differentially expressed genes (DEGs) were identified, and Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) were used to clarify the biological mechanisms potentially involved in the development of LUSC. Moreover, the correlation between the NKX2-1 expression level and tumor mutation burden (TMB), tumor microenvironment (TME), and immune cell infiltration revealed that NKX2-1 participates in the development of LUSC. Finally, we studied the effects of NKX2-1 on drug therapy. To validate the protein and gene expression levels of NKX2-1 in LUSC, we employed immunohistochemistry(IHC) datasets, The Gene Expression Omnibus (GEO) database, and qRT-PCR analysis. NKX2-1 expression levels were significantly lower in LUSC than in normal lung tissue. It significantly differed in gender, stage and N classification. The survival analysis revealed that high expression of NKX2-1 had shorter OS and PFS in LUSC. The multivariate Cox regression hazard model showed the NKX2-1 expression as an independent prognostic factor. Then, the nomogram predicted LUSC prognosis. There are 51 upregulated DEGs and 49 downregulated DEGs in the NKX2-1 high-level groups. GO, KEGG and GSEA analysis revealed that DEGs were enriched in cell cycle and DNA replication.The TME results show that NKX2-1 expression was positively associated with mast cells resting, neutrophils, monocytes, T cells CD4 memory resting, and M2 macrophages but negatively associated with M1 macrophages. The TMB correlated negatively with NKX2-1 expression. The pharmacotherapy had great sensitivity in the NKX2-1 low-level group, the immunotherapy is no significant difference in the NKX2-1 low-level and high-level groups. The analysis of GEO data demonstrated concurrence with TCGA results. IHC revealed NKX2-1 protein expression in tumor tissues of both LUAD and LUSC. Meanwhile qRT-PCR analysis indicated a significantly lower NKX2-1 expression level in LUSC compared to LUAD. These qRT-PCR findings were consistent with co-expression analysis of NKX2-1. We conclude that NKX2-1 is a potential biomarker for prognosis and treatment LUSC. A new insights of NKX2-1 in LUSC is still needed further research.