Novel Biomarker For Prognosis Research Articles

Identification of VRK1 as a Novel Potential Biomarker for Prognosis and Immunotherapy in Hepatocellular Carcinoma.

Research has indicated that VRK1 is essential for the tumor cell cycle. However, its prognostic and immunotherapeutic predictive significance has not been documented in hepatocellular carcinoma (HCC). The TCGA, ICGC, and GSE14520 datasets were used to investigate VRK1 expression and its predictive significance of survival outcomes. The qRT-PCR and immunohistochemistry (IHC) were used to confirm the findings. The immunotherapeutic response of VRK1 was anticipated by the IMvigor210 cohort. Lastly, the association between immune infiltration, m6A modification, and functional enrichment of differentially expressed genes (DEGs) was investigated in connection to VRK1 expression. VRK1 expression was markedly elevated on both the mRNA and protein levels in HCC. In HCC patients, a high expression of VRK1 was linked to a poor prognosis. Furthermore, there was a substantial positive correlation seen between increased VRK1 expression and the response rate to anti-PD-L1 immunotherapy. Relationships between VRK1 and m6A-related genes as well as different immune cells were shown by correlation studies. Lastly, enrichment analysis revealed a tight relationship between VRK1 and important biological functions, including DNA replication, cell cycle control, and fatty acid metabolism. Our research reveals the potential of VRK1 as a novel biomarker for prognosis and immunotherapy response in HCC patients.

Bioinformatic analysis and experimental validation of cuproptosis-related LncRNA as a novel biomarker for prognosis and immunotherapy of oral squamous cell carcinoma

BackgroundThe novel form of regulatory cell death, cuproptosis, is characterized by proteotoxicity, which ultimately leads to cell death. Its targeting has emerged as a promising therapeutic approach for oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) participate in epigenetic regulation and have been linked to the progression, prognosis, and treatment of OSCC. Thus, this study aimed to identify new cuproptosis-related lncRNAs (CRLs), establish predictive models for clinical prognosis, immune response, and drug sensitivity, and provide novel insights into immune escape and tumor drug resistance.MethodsThe present study screened eight CRLs (THAP9-AS1, STARD4-AS1, WDFY3-AS2, LINC00847, CDKN2A-DT, AL132800.1, GCC2-AS1, AC005746.1) using Lasso Cox regression analysis to develop an eight-CRL prognostic model. Patients were categorized into high- and low-risk groups using risk scores. To evaluate the predictive ability of the model, Kaplan-Meier analysis, ROC curves, and nomograms were employed. Furthermore, the study investigated the differences in immune function and anticancer drug sensitivity between the high- and low-risk groups. To validate the expression of CRLs in the model, OSCC cell lines were subjected to quantitative real-time fluorescence PCR (qRT-PCR).ResultsThe results of the study showed that the high-risk group had a shorter overall survival (OS) time in OSCC patients. Cox regression analysis demonstrated that the high-risk score was an independent risk factor for a poor prognosis. The validity of the model was confirmed using ROC curve analysis, and a nomogram was developed to predict the prognosis of OSCC patients. Furthermore, patients in the high-risk group with high TMB had a poorer prognosis. Patients in the low-risk group responded better to immunotherapy than those in the high-risk group. Additionally, the risk scores were significantly associated with drug sensitivity in OSCC patients. Finally, the findings of qRT-PCR supported the reliability of the proposed risk model.ConclusionThe study identified and established the 8-CRL model, which represents a novel pathway of lncRNA regulation of cuproptosis in OSCC. This model provides guidance for the prognosis and treatment of OSCC and offers a new insight into immune escape and tumor drug resistance.

Identification of enhancer RNA AC005515.1 as a novel biomarker for prognosis in esophageal cancer and predictors of immunotherapy response.

The enhancer RNA (eRNA) signature shows excellent promise in the prognostic role of many malignancies, but its value has not been fully explored in esophageal cancer (ESCA). We comprehensively analyzed 33 oncogene expression matrices and clinical data from The Cancer Genome Atlas (TCGA) and identified ESCA prognostic-related key eRNAs by Kaplan-Meier and co-expression analysis. We also investigated the prognostic role of the key eRNA using a series of bioinformatics approaches, including immune infiltration, immune function, immune subtypes, and the tumor microenvironment. Finally, the tumor immune dysfunction and exclusion (TIDE) score was used to predict the immune response to immune checkpoint blockade (ICB) therapy. We identified eRNA AC005515.1, AC012368.1, AP003469.2, Clorf61, and WDFY3-AS2 were associated with the prognosis of ESCA. AC005515.1 is a critical prognostic-related eRNA in ESCA and was significantly co-expressed with immune checkpoint genes (CTLA4, CD274, etc.). In the pan-cancer analysis, AC005515.1 was also associated with the prognosis of seven cancers, including kidney renal papillary cell carcinoma and low-grade brain glioma. It was also found to be co-expressed with immune checkpoint genes in these tumors. Moreover, high expression of AC005515.1 was associated with CD8+ T cells and M1 macrophages infiltration, and the AC005515.1 high-expression group had a higher TIDE score in ESCA. Overall, eRNA AC005515.1 is associated with the local immune environment of ESCA and may become a new biomarker of ESCA prognosis and immunotherapy response.

TSPO is a novel biomarker for prognosis that regulates cell proliferation through influencing mitochondrial functions in HCC

The disorder of mitochondrial functions plays a key role in oncogenesis. It is known that TSPO (18-kDa translocator protein) lies in a peculiar location at the interface between the mitochondria and the cytosol. TSPO is found in many types of tissues and is associated with multiple cellular processes, including apoptosis, cell proliferation and the regulation of mitochondria. However, the involvement of TSPO in hepatocellular carcinoma (HCC) remains unclear. In this study, we found that TSPO is upregulated in HCC tissue and is associated with poor differentiation and poor survival. Multivariate analyses showed that TSPO was an independent predictive factor for poor prognosis in HCC patients. For the first time, we provided evidence that TSPO knockdown suppressed HCC cell proliferation in vitro. Hence, TSPO knockdown-induced apoptosis by disturbing mitochondrial function by enhancing the formation of reactive oxygen species (ROS) and decreasing the mitochondrial membrane potential (ΔΨm). An assay exploring the underlying mechanism revealed that TSPO knockdown modulated apoptotic regulatory proteins by regulating the ERK signaling pathway. Through a functional assay and an in vivo mouse model, the anti-cancer effect of PK11195, a specific ligand of TSPO, on HCC was revealed. In summary, TSPO may potentially serve as a prognostic biomarker, and TSPO might be a potential therapeutic target for HCC.

AARS2 as a novel biomarker for prognosis and its molecular characterization in pan-cancer.

The mitochondrial alanyl-tRNA synthetase 2 (AARS2) as one of aminoacyl-tRNA synthases (ARSs) performs amino acid transportation and involves protein synthesis. However, its role in cancer remains largely unexplored. In this study, more than 10,000 samples were enrolled to explore genomic alterations, biological function, prognosis, and clinical treatment based on AARS2 across pan-cancer. The molecular characterization of AARS2 was confirmed in hepatocellular carcinoma (HCC) using proteomics analysis, quantitative real-time PCR, western blotting, immunohistochemical staining, and cell experiments. For genomic landscape, the AARS2 was dramatically upregulated in multiple cancers, which might be mainly caused by copy number alteration rather than mutation and methylation. The abnormal expression of AARS2 was prominently associated with activity of cancer pathways and performed oncogenic roles in most cancers. Systematic experiments invitro substantiated the elevated expression of AARS2, and the deficiency of it inhibited cell proliferation and cell migration in HCC. Meanwhile, our findings suggested that AARS2 could serve as a novel promising and stable biomarker for assessing prognosis and immunotherapy. Moreover, a variety of therapeutic drugs and targeted pathways were proposed for cancer treatment, which might enhance clinical efficacy. The AARS2 could serve as a new oncogenic gene that promotes cell proliferation and migration in HCC. The comprehensive investigations increased the understanding of AARS2 across human cancers and generated beginning insights of AARS2 in genomic landscape, molecular biological function, prognosis, and clinical treatment.

Systematic analysis of markers for T‐cell differentiation revealing CD95 as a novel biomarker for prognosis and immunotherapeutic efficacy in colon cancer

Systematic analysis of markers for T‐cell differentiation revealing CD95 as a novel biomarker for prognosis and immunotherapeutic efficacy in colon cancer

OCLN as a novel biomarker for prognosis and immune infiltrates in kidney renal clear cell carcinoma: an integrative computational and experimental characterization.

Occludin (OCLN) is an important tight junction protein and has been reported to be abnormally expressed in the development of malignant tumors. However, its biomarker and carcinogenic roles in kidney renal clear cell carcinoma (KIRC) are less investigated. The Cancer Genome Atlas database and Human Protein Atlas database were used to analyze the expression of OCLN in KIRC. UALCAN database and methylation-specific PCR assay were used to evaluate the methylation level of OCLN in KIRC. Univariate and multivariate Cox regression analyses were performed to model the prognostic significance of OCLN in KIRC patient cohorts. The correlation between OCLN expression and the immune cell infiltration, immune-related function and immune checkpoints were explored. Finally, EdU, scratch assay and transwell experiments were conducted to validate the role of OCLN in KIRC development. The expression of OCLN was significantly downregulated in KIRC, compared with normal renal tissues (p<0.001). Patients with low OCLN expression showed a worse prognosis and poorer clinicopathological characteristics. Functional enrichment analysis revealed that OCLN was mainly involved in biological processes such as immune response, immunoglobulin complex circulating and cytokine and chemokine receptor to mediate KIRC development. Immune-related analysis indicated that OCLN could potentially serve as a candidate target for KIRC immunotherapy. OCLN overexpression inhibited proliferation, migration and invasion of KIRC cells in vitro. OCLN was validated as a candidate prognostic biomarker and therapeutic target of KIRC based both on computational and experimental approaches. More in vivo experiments will be conducted to decode its molecular mechanism in KIRC carcinogenesis in the future work.

Lactate dehydrogenase D serves as a novel biomarker for prognosis and immune infiltration in lung adenocarcinoma

BackgroundLung cancer is reported to be the leading cause of death in males and females, globally. Increasing evidence highlights the paramount importance of Lactate dehydrogenase D (LDHD) in different types of cancers, though it’s role in lung adenocarcinoma (LUAD) is still inadequately explored. In this study, we aimed to investigate and determine the relationship between LDHD and LUAD.MethodsThe collection of the samples was guided by The Cancer Genome Atlas (TCGA) datasets and Gene Expression Omnibus (GEO). To ascertain various aspects around LDHD function, we analyzed different expression genes (DEGs), functional enrichment, and protein–protein interaction (PPI) networks. The predictive values for LDHD were collectively determined using the Kaplan–Meier method, Cox regression analysis, and a nomogram. Evaluation of the immune infiltration analysis was completed using Estimate and ssGSEA. The prediction of the immunotherapy response was based on TIDE and IPS. The LDHD expression levels in LUAD were validated through Western blot, qPCR, and immunohistochemistry methods. Wound healing and transwell assays were also performed to illustrate the aggressive features in LUAD cell lines.ResultsThe results showed that LDHD was generally downregulated in LUAD patients, with the low LDHD group presenting a decline in OS, DSS, and PFI. Enriched pathways, which include pyruvate metabolism, central carbon metabolism, and oxidative phosphorylation were observed through KEGG analysis. It was also noted that the expression of LDHD expression was inversely related to immune cell infiltration and typical checkpoints. The high LDHD group’s response to immunotherapy was remarkable, particularly in CTAL4 + /PD1- therapy. In vitro studies revealed that the overexpression of LDHD caused tumor migration and invasion to be suppressed.ConclusionIn conclusion, our study revealed that LDHD might be an effective predictor of prognosis and immune filtration, possibly leading to better choices for immunotherapy.

IDENTIFICATION OF NEW BIOMARKERS AND PROMISING NEURO IMAGING OF DIFFUSE AXONAL INJURY: AN OBSERVATIONAL STUDY

Objective: To determine the clinical patterns of the newly identified novel biomarkers of prognosis among adult patients with traumatic brain injury (TBI), diffuse axonal injury (DAI) and ophthalmic injury (OI) and micro bleeds in the Brain. Methods: According to the online search engine from the databases of PubMed, Embase, Ovid Science Direct, and the way of sciences of the original contribution articles which are providing with the essential information about outcome in patients with DAI in general, DAI vs. non-DAI, related to magnetic resonance imaging (MRI) classification , related to lesion and their specific , Specific location/load and their future outcomes. We have gone through the major references and checked their quality control (QC) assessments performed through International standard protocol/guidelines and our own experiences. Results: A total of 585 articles were included. TBI patients with DAI patients favorable outcomes are (75-90 %). The risk associated unfavorable outcome (RAUO) is in TBI with DAI was three to four times higher than in TBI without DAI in our Asian Indian patients.The Odds ratio (OR) for their unfavorable outcome was 2.7 as per increase of DAI grade on the MRI findings. Lesions are located in the area of the corpus callosum (CC) associated with an unfavorable outcomes reported frequently (85-95%). Conclusions: DAI patients management through MRI and patients with with TBI results unfavorable outcome are increasing in larger in numbers day by day in trauma care. MRI grading, locations, pattern of diffuse (POD) and axonal injury rates (AIR) are increasing in their three to four fold with every grade. Associated Lesions in the corpus callosum (CC) are associated with an unfavorable outcomes are those frequently associated with the DAI patients in TBI. Need appropriate diagnosis and management for DAI. Our newly developed biomarkers are quite useful for DAI patients associated within the TBI patients management and follow-up.

The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer.

The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. The median values of the sarcopenia index (cm2/m2)±standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4±1.0, 1.7±0.6 and 12.6±3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29-5.97, P=0.009) and overall survival (hazard ratio=3.13, 95% confidence interval = 1.18-8.26, P=0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio=3.74, 95% confidence interval = 1.31-10.72, P=0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P=0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio=2.06, P=0.045) in multivariate analysis and recurrence-free survival (P=0.009) in patients with advanced stage. The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

Integrative analyses identify CD73 as a prognostic biomarker and immunotherapeutic target in intrahepatic cholangiocarcinoma

BackgroundCD73 promotes progression in several malignancies and is considered as a novel immune checkpoint. However, the function of CD73 in intrahepatic cholangiocarcinoma (ICC) remains uncertain. In this study, we aim to investigate the role of CD73 in ICC.MethodsMulti-omics data of 262 ICC patients from the FU-iCCA cohort were analyzed. Two single-cell datasets were downloaded to examine the expression of CD73 at baseline and in response to immunotherapy. Functional experiments were performed to explore the biological functions of CD73 in ICC. The expression of CD73 and HHLA2 and infiltrations of CD8 + , Foxp3 + , CD68 + , and CD163 + immune cells were evaluated by immunohistochemistry in 259 resected ICC samples from Zhongshan Hospital. The prognostic value of CD73 was assessed by Cox regression analysis.ResultsCD73 correlated with poor prognosis in two ICC cohorts. Single-cell atlas of ICC indicated high expression of CD73 on malignant cells. TP53 and KRAS gene mutations were more frequent in patients with high CD73 expression. CD73 promoted ICC proliferation, migration, invasion, and epithelial-mesenchymal transition. High CD73 expression was associated with a higher ratio of Foxp3 + /CD8 + tumor-infiltrating lymphocytes (TILs) and CD163 + /CD68 + tumor-associated macrophages (TAMs). A positive correlation between CD73 and CD44 was observed, and patients with high CD73 expression showed elevated expression of HHLA2. CD73 expression in malignant cells was significantly upregulated in response to immunotherapy.ConclusionsHigh expression of CD73 is associated with poor prognosis and a suppressive tumor immune microenvironment in ICC. CD73 could potentially be a novel biomarker for prognosis and immunotherapy in ICC.

Abstract P4-09-08: AI-based quantitation of cancer cell and fibroblast nuclear morphology reflects transcriptomic heterogeneity and predicts survival in breast cancer

Abstract Background: Morphological features of cancer cell nuclei are routinely used to assess disease severity and prognosis, and cancer nuclear morphology has been linked to genomic alterations. Quantitative analyses of the nuclear features of cancer cells and other tumor-resident cell types, such as cancer-associated fibroblasts (CAFs), may reveal novel biomarkers for prognosis and treatment response. Here, we applied a pan-cancer nucleus detection and segmentation algorithm and a cell classification model to hematoxylin and eosin (H&amp;E)-stained whole slide images (WSIs) of breast cancer specimens, enabling the measurement of morphological features of nuclei of multiple cell types within a tumor. Methods: Convolutional Neural Network models for 1) nucleus detection and segmentation and 2) cell classification were deployed on H&amp;E-stained WSIs from The Cancer Genome Atlas (TCGA) breast cancer dataset (primary surgical resections; N=890). Separate models were trained to segment regions of stromal subtypes, such as inflamed and fibroblastic stroma. Nuclear features (area, axis length, eccentricity, color, and texture) were computed and aggregated across each slide to summarize slide-level nuclear morphology for each cell type. Next-generation sequencing-based metrics of genomic instability (N=774) and gene expression (N=868) were acquired and paired with TCGA WSIs. Gene set enrichment analysis was performed using the Molecular Signatures Database. Spearman correlation compared nuclear features to genomic instability metrics. Linear regression was used to assess the relationship between nuclear features and bulk gene expression. Multivariable Cox regression with age and ordinal tumor stage as covariates was used to find association between overall survival (OS) and nuclear features. All reported results were significant (p&amp;lt; 0.05) when adjusted for false discovery rate via the Benjamini-Hochberg procedure. Results: Variation in cancer cell nuclear area, a quantitative metric related to pathologist-assessed nuclear pleomorphism, was calculated by the standard deviation of the nuclear area of cancer cells across a WSI. This feature was associated with genomic instability, as measured by aneuploidy score (r=0.448) and homologous recombination deficiency score (r=0.382), and reduced OS. In contrast, the variability in fibroblast and lymphocyte nuclear areas did not correlate with either metric of genomic instability (all r&amp;lt; 0.1, p&amp;gt;0.05). Furthermore, an association between variation in cancer cell nuclear area with the expression of cell cycle and proliferation pathway genes was observed, suggesting that increased nuclear size heterogeneity may indicate a more aggressive cancer phenotype. Features quantifying CAF nuclear morphology were also assessed, revealing that CAF nucleus shape (larger minor axis length) was associated with lower OS, as well as the expression of gene sets involved in extracellular matrix remodeling and degradation. Conclusions: The nuclear morphologies of breast cancer cells and CAFs reflect underlying genomic and transcriptomic properties of the tumor and correlates with patient outcome. The application of digital pathology analysis of breast cancer histopathology slides enables the integrative study of genomics, transcriptomics, tumor morphology, and overall survival to support research into disease biology research and biomarker discovery. Citation Format: John Abel, Christian Kirkup, Filip Kos, Ylaine Gerardin, Sandhya Srinivasan, Jacqueline Brosnan-Cashman, Ken Leidal, Sanjana Vasudevan, Deepta Rajan, Suyog Jain, Aaditya Prakash, Harshith Padigela, Jake Conway, Neel Patel, Benjamin Trotter, Limin Yu, Amaro Taylor-Weiner, Emma L. Krause, Matthew Bronnimann, Laura Chambre, Ben Glass, Chintan Parmar, Stephanie Hennek, Archit Khosla, Murray Resnick, Andrew H. Beck, Michael Montalto, Fedaa Najdawi, Michael G. Drage, Ilan Wapinski. AI-based quantitation of cancer cell and fibroblast nuclear morphology reflects transcriptomic heterogeneity and predicts survival in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-09-08.

TRIM27 expression is associated with poor prognosis in sinonasal mucosal melanoma.

Tripartite motif-containing 27 (TRIM27) has been implicated in the progression of various cancers. However, the role of TRIM27 in sinonasal mucosal melanoma (SNMM) remains poorly understood. We retrospectively examined 28 patients with SNMM treated with between 2003 and 2021. We undertook immunohistochemical analysis of TRIM27, Ki-67, and p-Akt1 expression in SNMM tissues. We also investigated the relationship between TRIM27 expression and clinical characteristics, prognosis, Ki-67 as a tumor growth potential marker, and p-Akt1 as one of the prognostic factors in mucosal melanoma. TRIM27 expression was significantly higher in T4 disease than in T3 disease and was higher in stage IV than in stage III. Patients with high-TRIM27 SNMM had a significantly poorer prognosis in terms of overall survival (OS) and disease-free survival.There was also a significantly higher rate of distant metastasis. Univariate analysis for OS revealed that TRIM27 and T classification were significant poor prognostic factors. In addition, the Ki-67 positive score and the p-Akt1 total staining score were significantly higher in the high-TRIM27 group than in the low-TRIM27 group. High TRIM27 expression in SNMM was associated with advanced T classification, poor prognosis and distant metastasis. We suggest that TRIM27 has potential as a novel biomarker for prognosis in SNMM.

A human pan-cancer system analysis of regulator of chromatin condensation 2

Regulation of chromosome condensation 2 (RCC2) is associated with the cell cycle and is a crucial regulator of the chromatin condensation 1 (RCC1) family. The members of this family were normally regulators in the process of DNA replication and nucleocytoplasmic transport. RCC2 overexpression may lead to tumor formation and poor prognosis in some tumors including breast cancer and lung adenocarcinoma. However, the possible role of RCC2 in tumor formation and its prognostic function remains unclear. In this study, expression analysis from databases including The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were combined to perform the first integrative and comprehensive analysis of RCC2 in human pan-cancer. RCC2 was highly expressed in most tumors which may lead to a poor prognosis. RCC2 expression was associated with immune/stromal infiltration, immune checkpoints, tumor mutational burden, and microsatellite instability. Thus, RCC2 could be a novel biomarker for prognosis and a promising cancer therapy target.

Identification of key proteins as potential biomarkers associated with post-infarction complications in diabetics.

Background: The ability of transcriptome analysis to identify dysregulated pathways and outcome-related genes following myocardial infarction in diabetic patients remains unknown. The present study was designed to detect possible biomarkers associated with the incidence of post-infarction complications in diabetes to assist thedevelopment of novel treatments for this condition.Methods: Two gene expression datasets, GSE12639 and GSE6880, were downloaded from the Gene Expression Omnibus (GEO) database, and then differentially expressed genes (DEGs) were identified between post-infarction diabetics and healthy samples from the left ventricular wall of rats. These DEGs were then arranged into a protein-protein interaction (PPI) network, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were performed to explore the functional roles of these genes.Results: In total, 30 DEGs (14 upregulated and 16 downregulated) were shared between these two datasets, as identified through Venn diagram analyses. GO analyses revealed these DEGs to be significantly enriched in ovarian steroidogenesis, fatty acid elongation, biosynthesis of unsaturated fatty acids, synthesis and degradation of ketone bodies, and butanoate metabolism. The PPI network of the DEGs had 14 genes and 70 edges. We identified two key proteins, 3-hydroxymethylglutaryl-CoA synthase 2 (Hmgcs2) and Δ3, Δ2-Enoyl-CoA Delta Isomerase 1 (ECI1), and the upregulated gene Hmgcs2 with the highest score in the MCC method. We generated a co-expression network for the hub genes and obtained the top ten medications suggested for infarction with diabetes.Conclusion: Taken together, the findings of these bioinformatics analyses identified key hub genes associated with the development of myocardial infarction in diabetics. These hub genes and potential drugs may become novel biomarkers for prognosis and precision treatment in the future.

The LncRNA signature associated with cuproptosis as a novel biomarker of prognosis in immunotherapy and drug screening for clear cell renal cell carcinoma.

Cuproptosis is a new form of cell death, the second form of metal ion-induced cell death defined after ferroptosis. Recently, cuproptosis has been suggested to be associated with tumorigenesis. However, the relationship between cuproptosis and patient prognosis in clear cell renal cell carcinoma (ccRCC) in the context of immunotherapy remains unknown. The aim of this study was to investigate the correlation between cuproptosis-related long non-coding RNA (lncRNA) and ccRCC in terms of immunity as well as prognosis. Clinical information on lncRNAs associated with differences in cuproptosis genes in ccRCC and normal tissues was collected from The Cancer Genome Atlas (TCGA) dataset. Univariate Cox regression was used to screen lncRNAs. A total of 11 lncRNAs closely associated with cuproptosis were further screened and established using the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression, and the samples were randomly divided into training and test groups. A risk prognostic model was constructed using the training group, and the model was validated using the test group. We investigated the predictive ability of the prognostic risk model in terms of clinical prognosis, tumor mutation, immune escape, immunotherapy, tumor microenvironment, immune infiltration levels, and tumor drug treatment of ccRCC. Using the median risk score, patients were divided into low and high-risk groups. Kaplan-Meier curves showed that the overall survival (OS) of patients in the high-risk group was significantly worse than low-risk group (p < 0.001). Receiver operating characteristic (ROC) curves further validated the reliability of our model. The model consistently and accurately predicted prognosis at 1, 3, and 5years, with an AUC above 0.7. Tumor cell genes generally precede morphological abnormalities; therefore, the model we constructed can effectively compensate for the traditional method of evaluating the prognosis of patients with renal cancer, and our model was also clinically meaningful in predicting ccRCC staging. In addition, lower model risk scores determined by mutational load indicated a good chance of survival. The high-risk group had greater recruitment of immune cells, while the anti-immune checkpoint immunotherapy was less efficacious overall than that of the low-risk group. Tumor and immune-related pathways were enriched, and anti-tumor agents were selected to improve the survival of ccRCC. This prognostic risk model is based on the levels of cuproptosis-associated lncRNAs and provides a new perspective in the clinical assessment and precise treatment of ccRCC.

Integration of proteomic and metabolomic characterization in atrial fibrillation-induced heart failure

BackgroundThe exact mechanism of atrial fibrillation (AF)-induced heart failure (HF) remains unclear. Proteomics and metabolomics were integrated to in this study, as to describe AF patients’ dysregulated proteins and metabolites, comparing patients without HF to patients with HF.MethodsPlasma samples of 20 AF patients without HF and another 20 with HF were analyzed by multi-omics platforms. Proteomics was performed with data independent acquisition-based liquid chromatography-tandem mass spectrometry (LC-MS/MS), as metabolomics was performed with LC-MS/MS platform. Proteomic and metabolomic results were analyzed separately and integrated using univariate statistical methods, multivariate statistical methods or machine learning model.ResultsWe found 35 up-regulated and 15 down-regulated differentially expressed proteins (DEPs) in AF patients with HF compared to AF patients without HF. Moreover, 121 up-regulated and 14 down-regulated differentially expressed metabolites (DEMs) were discovered in HF patients compared to AF patients without HF. An integrated analysis of proteomics and metabolomics revealed several significantly enriched pathways, including Glycolysis or Gluconeogenesis, Tyrosine metabolism and Pentose phosphate pathway. A total of 10 DEPs and DEMs selected as potential biomarkers provided excellent predictive performance, with an AUC of 0.94. In addition, subgroup analysis of HF classification was performed based on metabolomics, which yielded 9 DEMs that can distinguish between AF and HF for HF classification.ConclusionsThis study provides novel insights to understanding the mechanisms of AF-induced HF progression and identifying novel biomarkers for prognosis of AF with HF by using metabolomics and proteomics analyses.

Fc receptor-like 1 (FCRL1) is a novel biomarker for prognosis and a possible therapeutic target in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, which can involve various types of mature B-cells. Considering that the incidence of DLBCL has increased, additional research is required to identify novel and effective prognostic and therapeutic molecules. Fc receptor-like 1 (FCRL1) acts as an activation co-receptor of human B-cells. Aberrant expression of this molecule has been reported in a number of B-cell-related disorders. Moreover, the clinical significance and prognosis value of FCRL1 in DLBCL are not completely identified. In this study, the expression levels of FCRL1 were determined in thirty patients with DLBCL and 15 healthy controls (HCs). In addition, the correlation between FCRL1 expressions with clinicopathological variables of DLBCL patients were examined. Then, the potential roles of FCRL1 in proliferation, apoptosis, and cell cycle distribution of B-cells from DLBCL patients were determined using flow cytometry analysis, after knockdown of this marker using retroviral short hairpin RNA interference. Quantitative real time-PCR, western blotting, and enzyme-linked immunosorbent assay were also used to identify the possible effects of FCRL1 knockdown on the expression levels of BCL-2, BID, BAX, intracellular signaling pathway PI3K/p-Akt, and p65 nuclear factor-kappa B (NF-κB) in the B-cells of DLBCL. Statistical analysis revealed higher levels of FCRL1 expression in the B-cells of DLBCL patients compared to HCs at both protein and mRNA levels. A positive correlation was observed between the FCRL1 expression and some clinicopathological parameters of DLBCL patients. In addition, FCRL1 knockdown significantly decreased cell proliferation and stimulated apoptosis as well as G1 cell cycle arrest in the B-cells of DLBCL patients. The levels of p65 NF-κB and PI3K/p-Akt expressions were markedly reduced after knockdown of FCRL1 expression. These results suggested that FCRL1 could be a potential novel biomarker for prognosis and/or a possible effective therapeutic target for treatment of patients with DLBCL.

A Novel Ferroptosis-Related Signature for Prediction of Prognosis, Immune Profiles and Drug Sensitivity in Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC) is a malignant disease with an increasing incidence and a high mortality rate. Ferroptosis, a novel type of cell death, has been reported to be closely associated with the progression of HCC. The aim of our study was to construct a novel ferroptosis-related signature (nFRGs) for prediction of prognosis, immune features and drug sensitivity of HCC patients. Data were obtained from the TCGA, ICGC, GSE104580, CCLE and IMvigor210 datasets, and the least absolute shrinkage and selection operator (LASSO) was used to construct nFRGs. In addition, the analyses involved in prognoses, molecular function, stemness indices, somatic mutation, responses to immunologic therapy, efficacy of transcatheter arterial chemoembolization (TACE) therapy and drug sensitivity were performed using diverse packages of R 4.1.3 between the low- and high-risk groups. The nFRGs included seven ferroptosis-related genes. Our results showed that nFRGs was an independent risk factor for prognoses of HCC patients, and HCC patients in the high-risk group presented with worse prognosis. Compared with the results of other studies, nFRGs was superior to other promising signatures in predicting prognoses of patients with HCC. In addition, most of the enriched pathways of differentially expressed genes (DEGs) between these subgroups were related to immune features. The molecular functions, genetic mutation and mRNAsi were varied between the high- and low-risk groups. Moreover, we observed significant immunosuppression state in the high-risk group. Patients in the high-risk group might benefit from immunotherapy, whereas patients in the low-risk group may be susceptible to TACE therapy. Finally, five sensitive drugs and four sensitive drugs were screened for patients in the high- and low-risk groups, respectively. nFRGs may served as a novel biomarker of prognosis and aid in personalized therapeutic strategies for patients with HCC.

A novel prognostic biomarker CD3G that correlates with the tumor microenvironment in cervical cancer

Cervical cancer (CESC) is the fourth most common and death-causing gynecological cancer, mostly induced by infection of human papillomavirus (HPV). Multiple components of the tumor microenvironment (TME), such as tumor infiltrating immune cells, could be targets of immunotherapy for HPV-related CESC. However, little is known about the TME of CESC until now. Here, we aimed to uncover the pathogenesis as well as to identify novel biomarkers to predict prognosis and immunotherapy efficacy for CESC. Combining the transcriptomic data and clinical characteristics, we identified differentially expressed genes in CESC samples from TCGA database by comparing the two groups with different ImmuneScore and StromalScore. Next, we detected ten key genes based on the PPI network and survival analyses with the univariate Cox regression model. Thereafter, we focused on CD3G, the only gene exhibiting increased RNA and protein expression in tumors by multiple analyses. Higher CD3G expression was associated with better survival; and it was also significantly associated with immune-related pathways through GSEA analysis. Furthermore, we found that CD3G expression was correlated with 16 types of TICs. Single cell RNA-sequencing data of CD3G in lymphocytes subgroup indicated its possible role in HPV defense. Hence, CD3G might be a novel biomarker in prognosis and immunotherapy for CESC patients.