Valuable Prognostic Biomarker Research Articles

Analysis of the differential expression and prognostic relationship of DEGs in AML based on TCGA database

BackgroundAcute myeloid leukemia (AML) is a common and lethal hematological malignant hyperplastic disease originating from hematopoietic stem cells. The purpose of this study is to obtain the key differentially expressed gene (DEG) related to the survival of AML by The Cancer Genome Atlas (TCGA) database and to verify these genes by a clinical follow-up investigation, in order to identify valuable predictive and prognostic biomarkers for early diagnosis of AML and predict the survival rates.MethodsThe RNA sequencing (RNA-Seq) data and clinical information of TCGA-LAML were downloaded from the TCGA database. After that we (1) screened the survival-related DEGs by Cox regression analysis, (2) selected the cytogenetics risk-related DEGs by DESeq2 R package, and (3) filtrated the genes in the top10 pathways of up-regulated and down-regulated of Normalization Enrichment Score (NES) by Gene Set Enrichment Analysis (GSEA). Finally, we focused the intersectional genes of above three parts as the key gene of the present study. The following Multivariate.

Circulatory miR-411-5p as a Novel Prognostic Biomarker for Major Adverse Cardiovascular Events in Patients with Atrial Fibrillation.

The risk stratification of patients with atrial fibrillation (AF) for subsequent cardiovascular events could help in guiding prevention strategies. In this study, we aimed at investigating circulating microRNAs as prognostic biomarkers for major adverse cardiovascular events (MACE) in AF patients. We conducted a three-stage nested case-control study within the framework of a prospective registry, including 347 AF patients. First, total small RNA-sequencing was performed in 26 patients (13 cases with MACE) and the differential expression of microRNAs was analyzed. Seven candidate microRNAs with promising results in a subgroup analysis on cardiovascular death were selected and measured via using RT-qPCR in 97 patients (42 cases with cardiovascular death). To further validate our findings and investigate broader clinical applicability, we analyzed the same microRNAs in a subsequent nested case-control study of 102 patients (37 cases with early MACE) by using Cox regression. In the microRNA discovery cohort (n = 26), we detected 184 well-expressed microRNAs in circulation without overt differential expression between the cases and controls. A subgroup analysis on cardiovascular death revealed 26 microRNAs that were differentially expressed at a significance level < 0.05 (three of which with an FDR-adjusted p-value <0.05). We, therefore, proceeded with a nested case-control approach (n = 97) focusing on patients with cardiovascular death and selected, in total, seven microRNAs for further RT-qPCR analysis. One microRNA, miR-411-5p, was significantly associated with cardiovascular death (adjusted HR (95% CI): 1.95 (1.04-3.67)). Further validation (n = 102) in patients who developed early MACE showed similar results (adjusted HR (95% CI) 2.35 (1.17-4.73)). In conclusion, circulating miR-411-5p could be a valuable prognostic biomarker for MACE in AF patients.

Prognostic Significance of Serum Albumin Level and Albumin-Based Mono- and Combination Biomarkers in Patients with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies.

Prognostic-Related Biomarkers in Pancreatic Ductal Adenocarcinoma Correlating with Immune Infiltrates Based on Proteomics.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) accounts for 85% of pancreatic carcinoma cases. Patients with PDAC have a poor prognosis. The lack of reliable prognostic biomarkers makes treatment challenging for patients with PDAC. Using a bioinformatics database, we sought to identify prognostic biomarkers for PDAC. MATERIAL AND METHODS Using proteomic analysis of the Clinical Proteomics Tumor Analysis Consortium (CPTAC) database, we were able to identify core differential proteins between early and advanced pancreatic ductal adenocarcinoma tissue, and then we used survival analysis, Cox regression analysis, and area under the ROC curves to screen for more significant differential proteins. Additionally, the Kaplan-Meier plotter database was utilized to determine the relationship between prognosis and immune infiltration in PDAC. RESULTS We identified 378 differential proteins in early (n=78) and advanced stages (n=47) of PDAC (P<0.05). PLG, COPS5, FYN, ITGB3, IRF3, and SPTA1 served as independent prognostic factors of patients with PDAC. Patients with higher COPS5 expression had shorter overall survival (OS) and recurrence-free survival, and those with higher PLG, ITGB3, and SPTA1, and lower FYN and IRF3 expression had shorter OS. More importantly, COPS5, IRF3 were negatively associated with macrophages and NK cells, but PLG, FYN, ITGB3, and SPTA1 were positively related to the expression of CD8+ T cells and B cells. COPS5 affected the prognosis of PDAC patients by acting on B cells, CD8+ T cells, macrophages, and NK cells immune infiltration, while PLG, FYN, ITGB3, IRF3, and SPTA1 affected PDAC patient prognosis through some immune cells. CONCLUSIONS PLG, COPS5, FYN, IRF3, ITGB3 and SPTA1 could be potential immunotherapeutic targets and valuable prognostic biomarkers of PDAC.

FOXP3 and SQSTM1/P62 correlate with prognosis and immune infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common highly malignant tumours worldwide. FOXP3 and SQSTM1/P62 have been shown to be abnormally expressed in tumour cells, but their function in different tumours remains controversial. The present study was designed to evaluate the expression of FOXP3 and P62 in HCC and their prognostic value as well as their relationship with immune infiltration in HCC patients. The Gene Expression Omnibus (GEO) database and TNMplot.com platform were used to analyse the expression of FOXP3 and P62. The Cancer Genome Atlas (TCGA) database and Kaplan-Meier plotter were used to assess the impacts of FOXP3 and P62 on clinical prognosis. In addition, TCGA database was also used to examine the correlation between the expression of FOXP3 and P62 and tumour immune infiltration using the CIBERSORT algorithm. Finally, immunohistochemistry (IHC) was used to determine expression levels of FOXP3 and P62 in 89 HCC and adjacent normal liver tissues, and their effects on clinicopathological features and prognosis were verified. FOXP3 expression was downregulated in HCC tissues, while P62 expression was upregulated. FOXP3 underexpression and P62 overexpression were closely related to decreased overall survival (OS) in HCC patients. Additionally, the abnormal expression of FOXP3 and P62 was closely related to the infiltration levels of 12 types of immune cells, including regulatory T cells (Tregs), M2 macrophages, M0 macrophages, and CD8 T cells. Notably, in the validation model, abnormal FOXP3 and P62 expression was significantly associated with adverse clinicopathological factors in HCC patients, including elevated α-fetoprotein (AFP) levels, poor tumour differentiation, and increased Ki67 levels. Furthermore, low FOXP3 and high P62 expression were independent risk factors for predicting OS prognosis in HCC patients. FOXP3 and P62 have been shown to be important prognostic factors in HCC patients and are associated with immune cell infiltration in HCC. These findings suggest that FOXP3 and P62 may be valuable prognostic biomarkers and potential therapeutic targets for HCC treatment.

KRT17 serves as an oncogene biomarker of poor survival in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death from worldwide. Thus, it is imperative to clarify valuable diagnostic and prognostic biomarkers for early-stage HCC. The expression of Keratin 17 (KRT17) has been reported to be associated with certain cancer types previously. However, its role in the development of HCC has not been fully clarified. Here, we assessed the expression of KRT17 in the cancer genome atlas liver hepatocellular carcinoma (TCGA LIHC) database and in 44 pairs of samples collected from patients with HCC. In addition, Kaplan-Meir curves were used to assess the prognostic relevance of KRT17. The essential cancer- and KRT17-related biological processes were defined through gene set enrichment analysis (GSEA). Finally, the functional association between KRT17 expression and tumor cell proliferation/survival was evaluated and the signaling pathways associated with KRT17 expression in HCC were identified. Overall, we found that increased KRT17 levels were associated with lower survival, more aggressive disease, and altered immune cell infiltration in HCC patients. KRT17 may potentially act as a prognostic biomarker in HCC.

PLT Counts as a Predictive Marker after Plasma Exchange in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

The platelet (PLT) value in hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is not sufficiently understood. The present study aimed to evaluate the prognostic effect of PLT on the prediction of HBV-ACLF outcomes after plasma exchange (PE). HBV-ACLF patients treated with PE between January 2017 and August 2021 were followed up for at least 6 months. Cox regression was performed to develop the predictive model, and the model's performance was analyzed using the receiver operating characteristic curve (ROC). A total of 170 patients were included. The overall survival rate within 180 days was 75.88%. Age, PLT, total bilirubin (TBil), and the iMELD scores were independent risk factors affecting the prognosis of HBV-ACLF patients after PE. According to the Cox regression results, the new model was calculated: R = 0.142 × iMELD-0.009 × PLT. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.758 (95% CI 0.678-0.838), and patients with lower PLT-iMELD scores (<4.50) had a better prognosis (p < 0.001). PLT is a valuable prognostic biomarker for HBV-ACLF patients after PE. The modified iMELD model incorporating PLT has a better sensitivity and efficacy in predicting the prognosis of patients.

Comprehensive analysis of the prognosis and immune infiltrates for the BET protein family reveals the significance of BRD4 in glioblastoma multiforme.

Background: Glioblastoma multiforme (GBM) is the most common and invasive primary central nervous system tumor. The prognosis after surgery, radiation and chemotherapy is very poor. Bromodomain (BRD) proteins have been identified in oncogenic rearrangements, and play a key role in the development of multiple cancers. However, the relationship between BET proteins and prognosis of GBM are still worth exploring, and the distinct functions of BET proteins and tumor immunology in GBM have not been fully elucidated. Therefore, it is particularly important to develop effective biomarkers to predict the prognosis of GBM patients. Methods: Metascape, David, Kaplan-Meier Plotter, Oncomine, GEPIA, TCGA, TIMER, and LinkedOmics databases were used to assess the expression and prognosis for BET proteins in GBM. ROC analysis of risk model was established to identify the correlation between BET genes and overall survival in GBM patients. TIMER and GEPIA databases were used to comprehensively investigate the correlation between BET genes and tumor immune infiltration cells. Moreover, the image of immunohistochemistry staining of BET proteins in normal tissue and tumor tissue were retrived from the HPA database. In addition, differential analysis and pathway enrichment analysis of BRD4 gene expression profile were also carried out. Finally, immune-fluorescence and Western blot were used to clarify the expression of BRD4 in GBM cells. Results: Bioinformatics analysis showed that the expression levels of BET genes in GBM may play an important role in oncogenesis. Specifically, bioinformatic and immunohistochemistry analysis showed that BRD4 protein was more highly expressed in tumor tissues than that in normal tissues. The high expression of BRD4 was associated with poor prognosis in GBM. The expression of BET genes were closely related to the immune checkpoint in GBM. The correlation effect of BRD4 was significantly higher than other BET genes, which represented negative correlation with immune checkpoint. The expression of BRD4 was positively associated with tumor purity, and negatively associated with immune infiltration abundance of macrophage, neutrophil and CD8+ T-cell, respectively. Cox analysis showed that the model had good survival prediction and prognosis discrimination ability. In addition, the expression levels of BRD4 protein was significantly higher in U-251MGcells than that in normal cells, which was consistent with the results of bioinformatics data. Conclusion: This study implied that BRD4 could be hopeful prognostic biomarker in GBM. The increased expression of BRD4 may act as a molecular marker to identify GBM patients with high-risk subgroups. BRD4 may be a valuable prognostic biomarker, and a potential target of precision therapy against GBM.

SPOCK1 and POSTN are valuable prognostic biomarkers and correlate with tumor immune infiltrates in colorectal cancer

BackgroundImmune cells and stromal cells in the tumor microenvironment play a vital role in the progression of colorectal cancer (CRC). The study aimed to screen valuable prognostic biomarkers in CRC based on stromal and immune scores.MethodThe ESTIMATE algorithm was used to calculate the immune and stromal scores of CRC samples in TCGA. Then samples were divided into high and low score groups based on the median value of the scores. Differentially expressed genes (DEGs) associated with immune and stromal scores were screened. WGCNA and univariate COX regression analysis were performed to further identify key prognostic genes. Analysis of scRNA-seq for CRC was used for verifying the main source of the key genes. The prognostic value of they was validated based on The Gene Expression Profiling Interactive Analysis and GSE17536 dataset. TIMER and CIBERSORT algorithms were applied to analyze the correlations among key genes and tumor-infiltrating immune cells. Several pairs of colon cancer tissue were used to be proven.Result1314 upregulated and 4 downregulated genes were identified, which were significantly enriched in immune-related biological processes and pathways. Among these DEGs, SPOCK1 and POSTN were identified as key prognostic genes and mainly expressed in cancer-associated fibroblasts for CRC. High expression of SPCOK1 and POSTN was associated with advanced clinical stage, T stage, N stage, and poor prognosis of CRC. The results from CIBERSORT and TIMER revealed that SPOCK1 and POSTN were associated with tumor-infiltrating immune cells, especially macrophages and neutrophils. Meanwhile, in several pairs of human colorectal tissue samples, SPOK1 and POSTN were found to be significantly overexpressed in colorectal tissue compared with para-cancer tissue, and macrophage surface markers CD68 (co-expressed by M1 and M2 macrophages) and CD206 (M2-specific macrophage expression) were also overexpressed in cancer tissue. Besides, SPOCK1 and POSTN expression were positively correlated with the expression of immune checkpoints.ConclusionCollectively, our results indicate that SPOCK1 and POSTN associated with CAF may be novel prognostic biomarkers in CRC and correlate with immune infiltrates.

Proximal Femur Fractures in the Elderly-A Novel Modality to Predict Mortality: The Neutrophil-to-Lymphocyte Ratio.

Background: The assessment and identification of elderly patients with proximal femur fractures (PFF) who are at high risk of postoperative mortality may influence the treatment decision-making process. The purpose of this study was to determine whether the neutrophil-to-lymphocyte ratio (NLR) could be used to predict postoperative mortality in the elderly population. Methods: A four-year retrospective cohort study of electronic medical records was conducted at a single tertiary care hospital between 2015 and 2018. Data from 1551 patients aged 65 years and older who underwent surgical treatment for PFF were collected and analyzed. The data included complete blood counts at admission, demographic information, underlying illnesses, type of surgery, and postoperative mortality and complications during the first year of follow-up. A survival analysis model was utilized. Results: The mean age was 90.76 ± 1.88 years, 1066 (68.7%) women. Forty-four (2.8%) patients experienced postoperative infection. A higher NLR0 was independently associated with higher all-cause mortality rates in patients who underwent surgical treatment for PFF (p = 0.041). Moreover, the mean NLR0 value was higher when the death occurred earlier after surgery (p < 0.001). Conclusions: When combined with other clinical and laboratory findings, NLR0 levels may serve as a potentially valuable, inexpensive, and reliable prognostic biomarker to improve risk stratification for elderly patients who are candidates for PFF surgery. Furthermore, with additional research, we could potentially develop a treatment algorithm to identify patients at high risk of postoperative mortality.

Increased serum pannexin-1 concentrations reflect illness severity and predict a poor prognosis after acute supratentorial intracerebral hemorrhage: A prospective longitudinal cohort study

BackgroundPannexin-1 is a nonselective, large pore and voltage gated channel protein, whose activation may aggravate acute brain injury. We ascertained the clinical significance of serum pannexin-1 as a prognostic biomarker of acute intracerebral hemorrhage (ICH). MethodsIn this prospective, observational study of 124 acute supratentorial ICH patients and 124 healthy controls, serum pannexin-1 concentrations were determined. Admission National Institutes of Health Stroke Scale (NIHSS) score and hematoma volume were used for assessment of hemorrhagic severity, post-stroke 6-month modified Rankin scale (mRS) score was registered to reflect clinical outcome and early neurologic deterioration (END) and 6-month poor outcome (mRS score of 3–6) were regarded as the 2 prognostic parameters. Their associations with serum pannexin-1 concentrations were investigated using multivariate analysis. The predictive performance was evaluated in terms of area under receiver operating characteristic curve (AUC). ResultsIn comparison to controls, significantly increased serum pannexin-1 concentrations after ICH (median, 6.8 vs. 2.7 mg/ml) were independently correlative with NIHSS score (β, 0.193; 95% CI: 0.086–0.300), hematoma volume (β, 0.641; 95% CI: 0.423–0.859) and mRS score (β, 0.199; 95% CI: 0.065–0.174), were independently predictive of END (OR, 1.176; 95% CI: 1.081–1.280) and poor outcome (odds ratio, 1.218; 95% CI: 1.059–1.400), as well as were efficiently discriminative of END (AUC, 0.764; 95% CI: 0.663–0.864) and poor 6-month outcome (AUC, 0.790; 95% CI: 0.711–0.870). Serum pannexin-1 combined with NIHSS score and hematoma volume (AUC, 0.908; 95% CI: 0.857–0.960) displayed significantly higher predictive ability for poor 6-month outcome than NIHSS score and hematoma volume alone (both P < 0.05). ConclusionRising serum pannexin-1 concentrations following ICH, in strong correlation with hemorrhagic severity, independently distinguish the risk of END and 90-day poor outcome. Assumably, serum pannexin-1 may represent a valuable prognostic biomarker of ICH.

The development of a tumor-associated autoantibodies panel to predict clinical outcomes for immune checkpoint inhibitor-based treatment in patients with advanced non-small-cell lung cancer.

Immune checkpoint inhibitors (ICIs) have become one important therapeutic strategy for advanced non-small-cell lung cancer (NSCLC). It remains imperative to identify reliable and convenient biomarkers to predict both the efficacy and toxicity of immunotherapy, and tumor-associated autoantibodies (TAAbs) are recognized as one of the promising candidates for this. This study enrolled 97 advanced NSCLC patients with ICI-based immunotherapy treatment, who were divided into a training cohort (n=48) and a validation cohort (n=49), and measured for the serum level of 35 TAAbs. According to the statistical association between the serum positivity and clinical outcome of each TAAb in the training cohort, a TAAb panel was developed to predict the progression-free survival (PFS), and further examined in the validation cohort andin different subgroups. Similarly, another TAAb panel was derived to predict the occurrence of immune-related adverse events (irAEs). In the training cohort, a 7-TAAb panel composed of p53, CAGE, MAGEA4, GAGE7, UTP14A, IMP2, and PSMC1 TAAbs was derived to predict PFS (median PFS [mPFS] 9.9 vs. 4.3months, p=0.043). The statistical association between the panel positivity and longer PFS was confirmed in the validation cohort (mPFS 11.1 vs. 4.8months, p=0.015) and in different subgroups of patients. Moreover, another 4-TAAb panel of BRCA2, MAGEA4, ZNF768, and PARP TAAbs was developed to predict the occurrence of irAEs, showing higher risk in panel-positive patients (71.43% vs. 28.91%, p=0.0046). Collectively, our study developed and validated two TAAb panels as valuable prognostic biomarkers for immunotherapy.

Inflammatory Markers in Lung CancerA Comparative Cross-sectional Study

Introduction: Lung cancer is the most common cause of cancer mortality worldwide, principally because of its late diagnosis. Chronic inflammation plays a significant role in tumour growth and progression via increasing the levels of inflammatory markers in blood. Inflammatory markers are expected to be valuable prognostic biomarkers in cancer. Markers like Absolute Neutrophil Count (ANC), Absolute Lymphocyte Count (ALC), platelet count, Neutrophil Lymphocyte Ratio (NLR) and Platelet Lymphocyte Ratio (PLR) may aid in assessing prognosis of lung cancer. Aim: To study the inflammatory markers (ANC, ALC, Platelet count, NLR and PLR) in lung cancer and correlate these markers with cancer stage and histopathological type. Materials and Methods: A hospital-based cross-sectional study was conducted in lung cancer patients at Institute of Respiratory Diseases, SMS Medical College, Jaipur, Rajasthan, India. Sixty patients with lung cancer and sixty controls were included. The clinical characteristics, ANC, ALC, platelet count, NLR and PLR of cases and controls were assessed and compared. Also, the comparison of these inflammatory markers with Tumor, Nodes and Metastases (TNM) staging and histopathological type of lung cancer were documented and results were interpreted. The data analysis was done with the use of Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, (Ver.) 26. Results: Mean age (years) of the case and control groups was 60.17 and 61.03, respectively. Distribution of gender in cases and controls was comparable. The major histology of lung cancer was Non-Small Cell Lung Cancer (NSCLC, 81.66%) out of which squamous cell carcinoma constituted 55.00% and adenocarcinoma 21.67%, followed by small cell carcinoma at 18.33%. Overall, 46.67% of the patients belonged to TNM staging IVA followed by IIIB (25.00%). The levels of ANC, platelet count, NLR and PLR were significantly elevated and ALC was decreased in cases as compared to control. There was no statistically significant association between the inflammatory markers ANC, ALC, platelet counts, NLR and PLR with the histopathological type of lung cancer. Mean ANC, platelet count, NLR and PLR were found to be significantly elevated in late stages of lung cancer, whereas, ALC had no such association with the stages of lung cancer. Conclusion: Inflammatory markers (ANC, platelet count, NLR, PLR, ALC) can serve as valuable prognostic biomarkers in lung cancer and can easily be used in resource-limited areas.

Comprehensive Analysis of Prognostic Value and Immune Infiltration of TFAP2 Family Members in Bladder Cancer from Database and FFPE Sample.

Background: Bladder cancer (BLCA) is one of the common malignant tumors worldwide. Recent studies have shown that Transcription factor activating protein-2(TFAP2) family proteins plays a bidirectional regulatory role in the process of tumorigenesis versus evolution by regulating the expression of tumor associated genes. However, little is known about the function of distinct TFAP2s proteins in patient with BLCA. Methods: Formalin-fixed paraffin-embedded (FFPE) sample tissues and clinical data of 240 patients with bladder cancer were collected for immunohistochemical analysis. The Human Protein Atlas, Gene Expression Profiling Interactive Analysis (GEPIA), Shiny Methylation Analysis Resource Tool (SMART), Kaplan-Meier plotter, cBioPortal, Metascape, LinkedOmics, TIMER and CIBERSORT were utilized to analyze differential expression, prognostic value, genetic alteration and immune cell infiltration of TFAP2 family in patients with BLCA. Results: Our study found that TFAP2 family proteins are generally expressed higher in BLCA tissues than in normal tissues. However, they show different trends in the growth, metastasis and survival prognosis of BLCA. TFAP2A and TFAP2C was associated with worse clinical stage and prognosis in BLCA patients, while TFAP2B, TFAP2D and TFAP2E showed the opposite trend. Importantly, the functions of the differentially expressed TFAP2s were primarily related to the developmental process, reproductive process, response to stimulus and immune system process, etc. Moreover, TFAP2 family was significantly correlated with the infiltration of six immune cell types and might regulate TAM polarization. Conclusion: TFAP2 family might be an important regulator of immune cell infiltration and a valuable prognostic biomarker in patients with BLCA.

Serum galectin-3 levels predict poor prognosis in sepsis and septic shock patients.

Sepsis and septic shock are clinical conditions with high mortality and an ever-increasing prevalence, and early diagnosis is of great importance in treating these diseases. Increase in serum Galectin-3 protein in septic patients is associated with increased inflammation, which in turn is associated with mortality. This study aimed to investigate the diagnostic importance of serum Galectin-3 levels and its relationship with in-hospital mortality in sepsis and septic shock patients. This prospective cohort study included 44 sepsis and 44 septic shock patients. Sequential Organ Failure Assessment score and Acute Physiology and Chronic Health Evaluation 2 score were calculated. In addition, routine clinical and laboratory parameters along with serum Galectin-3 were evaluated. Serum Galectin-3 levels were significantly higher in the septic shock group [4.1 (0.1-10.2) vs. 6.0 (0.1-11.3) ng/mL, respectively; p=0.01]. Moreover, patients with a Galectin-3 level <6.94 ng/mL were associated with longer survival [31.4 vs. 23.1 days; hazards ratio, 1.85; 1.03-3.34, p=0.03]. More importantly, the need for mechanical ventilation, the duration of mechanical ventilation, and serum Galectin-3 levels were independent prognostic factors and predicted poor in-hospital survival in both sepsis and septic shock patients. These findings suggest that Galectin-3 levels are higher in septic shock patients and predict mortality. In addition, high serum Galectin-3 levels, together with mechanical ventilation requirement and mechanical ventilation duration, are closely associated with poor in-hospital survival. Therefore, Galectin-3 may be a valuable diagnostic and prognostic biomarker in these patients.

Differential expression analysis in epithelial ovarian cancer using functional genomics and integrated bioinformatics approaches

BackgroundEpithelial Ovarian Cancer (EOC) has remained the most frequent and leading cause of death among gynecologic malignancies, with a remarkably elevated and alarming global mortality rate and a poor prognosis. As a result of its asymptomatic characteristics in the early stages, the disease is typically diagnosed at advanced stages, with extensive dissemination. Therefore, it is of great importance to explore more reliable diagnostic and prognostic biomarkers. The present study intended to design an integrative bioinformatics approach to investigate robust differentially expressed genes (DEGs) associated with EOC progression as valuable diagnostic and prognostic biomarkers, providing inspiring insights into cancer mechanisms. Materials and methodsThree mRNA (GSE40595, GSE14407, and GSE18520) expression profiles related to EOC were retrieved from Gene Expression Omnibus (GEO) database. Significant DEGs were screened out following raw data quality assessment, preprocessing, and statistical computing. Gene ontology and pathway enrichment analyses were performed on candidate DEGs. Next, the interactions between genes were visualized by constructing their networks, and subsequently, a list of hub genes was extracted through the estimation of their connections, which were subjected to further evaluations for validation and survival analysis. ResultsWe identified 241 overlapping DEGs (20 up- and 221 down-regulated) between 3 mRNA datasets. After evaluating the protein-protein interactions, validation, and survival analysis, five hub genes including four up-regulated (AURKA, CD24, CDCA3, CENPF) and one down-regulated (PGR) were eventually selected as potential biomarkers of EOC. GO and Enriched pathways related to selected genes compromised cell growth, actin filament organization, enzyme inhibitor, peptidase regulator, and receptor protein kinase activities, glycosaminoglycan binding, glycine, serine, and threonine metabolism pathways, proteoglycans, and EGFR tyrosine kinase inhibitor resistance. ConclusionIn summary, these findings will shed further light on the molecular mechanisms underlying EOC. In addition, the candidate genes, related metabolites, and signaling pathways could serve as promising prognostic, diagnostic, or even potential drug targets.

Evaluation of TET Family Gene Expression and 5-Hydroxymethylcytosine as Potential Epigenetic Markers in Non-small Cell Lung Cancer.

DNA methylation is the most studied epigenetic modification in cancer. Ten-eleven translocation enzymes (TET) catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in the DNA. In the current research, we aimed to evaluate the role of 5-hmC and TET enzymes in non-small cell lung cancer (NSCLC) patients and their possible association with outcomes. ELISA was used to measure the 5-hmC levels in genomic DNA and qRT-PCR was used to evaluate TET1, TET2, and TET3 mRNAs expression levels in NSCLC tissues and their paired normal controls. The levels of 5-hmC were significantly lower in NSCLC tissues than in normal tissues, with a mean ±SD of 0.28±0.37 vs. 1.84±0.58, respectively (t=22.77, p<0.0001), and this reduction was correlated with adverse clinical features. In addition, all TET genes were significantly down-regulated in NSCLC tissues in comparison to their matched normal tissues. The mean±SD level of TET1-mRNA was 38.48±16.38 in NSCLC vs. 80.65±11.25 in normal tissues (t=21.33, p<0.0001), TET2-mRNA level in NSCLC was 5.25±2.78 vs. 9.52±1.01 in normal tissues (t=14.48, p<0.0001), and TET3-mRNA level in NSCLC was 5.21±2.8 vs. 9.51±0.86 in normal tissues (t=14.75, p<0.0001). Downregulation of TET genes was correlated with poor clinical features. 5-HmC levels as well as TET1, TET2, and TET3 mRNA levels were reduced in NSCLC tissues. The reduced levels of 5-hmC and TET mRNAs were associated with adverse clinical features, suggesting that the level of 5-hmC may serve as a valuable prognostic biomarker for NSCLC.

HS3ST3A1 and CAPN8 Serve as Immune-Related Biomarkers for Predicting the Prognosis in Thyroid Cancer.

Thyroid cancer (TC) tends to be a common malignancy worldwide and results in various outcomes due to its different subtypes. The tumor microenvironment (TME) was demonstrated to play crucial roles in various malignancies, including thyroid cancer. This study combined the ESTIMATE and CIBERSORT algorithms, identified four TME-related genes, and evaluated their correlation with clinical characteristics. These findings revealed the malignant performance of TME in TC, and the TME-related DEGs might serve as prognostic biomarkers, which can be utilized for the prediction of immunotherapy effects in patients with TC. The clinical and gene expression profiles of TC patients were collected from the TCGA dataset. The ESTIMATE algorithm was utilized to estimate stromal and immune scores and predict the level of stromal and immune cell infiltration. The differential expressed genes related to TME were filtered by the "limma" package in R, and the PPI network was constructed by a string website. KEGG pathway and GO analyses were performed to investigate the biological progression and molecular functions of TME-related DEGs. Then, univariate Cox regression analysis was employed to screen four genes correlated with clinical characteristics. GSEA was conducted to assess their roles in the TME of TC. To further investigate the association between TME-related genes and tumor-infiltrating immune cells (TIICs), the CIBERSORT algorithm was performed. Finally, the malignancy behaviors of the two genes were verified by RT-qPCR, IHC, MTT, colony formation, and transwell assays. Four TME-related DEGs, LRRN4CL, HS3ST3A1, PCOLCE2, and CAPN8, were identified and were significantly predictive of poor overall survival. KEGG and GO pathway analysis established that the TME-related DEGs were involved in immune responses and pathways in cancer. Furthermore, the malignancy behaviors of HS3ST3A1 and CAPN8 were verified by cellular functional experiments. These results revealed that the TME-related genes HS3ST3A1 and CAPN8 were able to serve as predictors of prognosis in patients with TC. HS3ST3A1 and CAPN8 may serve as valuable prognostic biomarkers and TME indicators, which can be utilized for the prediction of immunotherapy effects and provide novel treatment strategies for patients with TC.

1542. MR-proADM Biomarker Predicts COVID-19 Clinical Outcomes: a US-based Cohort Study

Abstract Background Mid-regional proadrenomedullin (MR-proADM) is a biomarker released following endothelial damage. Our study aimed to investigate baseline MR-proADM as a predictor of a wider range of clinical outcomes of varying severity in patients admitted with COVID-19 from a US-based multicenter trial. Outcomes Within 28 days Stratified by Binary MR-proADM (Cutoff 0.87 Nmol/L), Number of Events (percentage) Values expressed as percentages (%) indicate either the proportion of the total population or the respective MR-proADM stratum. Statistical significance between MR-proADM strata was determined by the chi-square test or the Fisher's exact test when applicable. P-Values were not corrected for multiple testing. Methods Data from the Boston Area COVID-19 Consortium Bay Tocilizumab Trial (NCT04356937) was used in this study. Patients with biomarker determinations, and not admitted to the intensive care unit (ICU) on admission, were included. MR-proADM cutoff of 0.87 nmol/L was assessed in predicting clinical outcomes. Results Out of 182 patients, 11.0% were mechanically ventilated or dead within 28 days. Of patients with MR-proADM &amp;gt;0.87 nmol/L, 21.1% were mechanically ventilated or dead within 28 days, versus 4.5% of those ≤0.87 nmol/L (p&amp;lt; 0.001). The sensitivity, specificity, NPV, and PPV of MR-proADM cut-off of 0.87 nmol/L in predicting mechanical ventilation or death were 75%, 65%, 95%, and 21% respectively, with an AUC of 0.76, outperforming other biomarkers. Specifically, MR-proADM outperformed plasma IL-6 in predicting mechanical ventilation and death.MR-proADM was independently associated with mechanical ventilation or death, ICU admission, prolonged hospitalization beyond day 4, and worsening on the COVID-19 ordinal scale. Conclusion MR-proADM functions as a valuable prognostic biomarker in predicting clinical outcomes of patients with COVID-19, outperforming other commonly utilized biomarkers. Disclosures Michael Mansour, MD, PhD, ThermoFisher Scientific: Grant/Research Support.

Nox5 in Human Peripheral Blood Mononuclear Cells: A Promising Biomarker for Unstable Diabetic Vascular Disease

BackgroundHuman NADPH oxidase 5 (NOX5) is expressed and functionally active in peripheral blood mononuclear cells (PBMCs). Increased NOX5 expression has been demonstrated in atherosclerotic plaques of diabetic patients with associated coronary artery disease (CAD) and within diabetic kidney biopsies. We postulate that NOX5 expression in circulating PBMCs is particularly increased in diabetic patients with comorbid unstable CAD and chronic kidney disease (CKD). Methods64 males aged 33-85 years underwent elective or emergency coronary angiography/angioplasty at the Alfred Hospital Catheter Laboratory. PBMCs from whole blood were processed for flow-cytometry to measure NOX5 protein. In parallel, NOX5 gene expression was measured in PBMCs by qPCR. ResultsNOX5 protein expression in PBMCs was primarily driven by expression in monocytes (CD 45+/CD14+ cells) and was increased in diabetic patients with CKD versus without CKD (29.0±3.5 vs 12.8±2.3 AU; p=0.0007). CAD with acute presentation was associated with increased NOX5 expression versus elective presentation (24.7±2.7 vs 16.3±2.0 AU; p=0.013), especially in diabetic patients presenting acutely versus electively (28.2±3.5 vs 15.3±2.9 AU; p=0.0070). NOX5 expression was increased in diabetic patients with both CKD and acute presentation versus non-diabetic patients without CKD presenting electively (36.1±4.3 vs 11.9±3.4 AU; p=0.0003). A 3-fold upregulation of NOX5 gene was observed in diabetic patients with CAD and CKD versus diabetic patients with CAD but without CKD (p=0.044). ConclusionUnstable CAD and CKD appear to be key factors for increased NOX5 expression in circulating PBMC in patients with clustering diabetic complications. Measurement of NOX5 in PBMCs may serve as a valuable prognostic biomarker and therapeutic target.