Potential Biomarker For Prognosis Research Articles

Identification of autophagy and angiogenesis modulators in colorectal cancer based on bioinformatics analysis

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death worldwide. The purpose of this study was to discover novel molecular pathways and potential prognosis biomarkers. To achieve this, we acquired five microarray datasets from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes between CRC and adjacent normal tissue samples and further validated them using The Cancer Genome Atlas (TCGA) database. Using various analytical approaches, including the construction of a competing endogenous RNA (ceRNA) network, Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway analyses, as well as survival analysis, we identified key genes and pathways associated with the diagnosis and prognosis of CRC. We obtained a total of 185 differentially expressed genes, comprising 17 lncRNAs, 30 miRNAs, and 138 mRNAs. The ceRNA network consisted of 17 lncRNAs, 25 miRNAs, and 7 mRNAs. Among the 7 mRNAs involved in the ceRNA network, SLC7A5 and KRT80 were found to be upregulated, while ADIPOQ, CCBE1, KCNB1, CADM2, and CHRDL1 were downregulated in CRC. Further analysis revealed that ADIPOQ and SLC7A5 are involved in the AMPK and mTOR signaling pathway, respectively. In addition, survival analysis demonstrated a statistically significant relationship between ADIPOQ, SLC7A5, and overall survival rates in CRC patients. In conclusion, our findings suggest that downregulation of ADIPOQ and upregulation of SLC7A5 in tumor cells lead to increased mTORC1 activity, reduced autophagy, enhanced angiogenesis, and ultimately contribute to cancer progression and decreased survival in CRC patients.

Endogenous retrovirus group FRD member 1 is a potential biomarker for prognosis and immunotherapy for kidney renal clear cell carcinoma.

The activation of endogenous retroviral (ERV) genes in kidney renal clear cell carcinoma (KIRC) suggests the necessity for further research on their functions. In this study, KIRC and healthy cohorts were obtained from TGGA and GEO datasets. Subsequently, differential analysis and functional annotation were conducted using GO, KEGG, and GSEA. Clinical outcomes were then observed and utilized in the development of a nomogram. We observed the general low expression of ERVFRD-1 in KIRC tumors compared to normal tissue (P < 0.001) across multiple cohorts. Differential analysis and functional annotation using GO, KEGG, GSEA analysis revealed significant involvement of ERVFRD-1 in tumor immunoregulation: a close relation to the infiltration levels of mast cells and Treg cell (P < 0.001) and occurrence with a variety of immune markers. Methylation status was then applied to uncover potential mechanisms of ERVFRD-1 in KIRC. Notably, higher expression levels of ERVFRD-1 were associated with extended overall survival, disease-specific survival, and progression-free survival. Finally, based on Cox regression analysis, we constructed a nomogram incorporating ERVFRD-1, pathologic T, and age, which exhibited promising predictive power in assessing the survival outcomes of KIRC patients. To sum up, our study suggests that ERVFRD-1 plays a role in regulating immunological activity within the tumor microenvironment and is associated with overall survival in KIRC patients. ERVFRD-1 may therefore be a sensitive biomarker for diagnosis, immunotherapy, and prognosis assessment of KIRC.

Diagnostic Value of DAPK Methylation for Nasopharyngeal Carcinoma: Meta-Analysis.

Methylation of DAPK has been reported to play a key role in the initiation and progression of nasopharyngeal cancer. However, there are differences between the studies on it. This meta-analysis was performed to evaluate the diagnostic value of DAPK promoter methylation for NPC. The study method involves the systematic research of eligible studies based on criteria. The frequency, odds ratios (OR), sensitivity as well as specificity with the corresponding 95% confidence intervals (CIs) were used to assess the effect sizes. A total of 13 studies, including 1048 NPC samples and 446 non-cancerous samples, were used for the meta-analysis. The overall frequencies of DAPK methylation were 56.94% and 9.28% in NPC samples and non-cancerous samples, respectively. The association between DAPK methylation and risk of NPC was also confirmed by calculating the OR value which was 13.13 (95%CI = 54.24-40.72) based on a random-effect model (Q = 64.74; p < 0.0001; I2 = 81.47% with 95%CI for I2 = 69.39-88.78). Additionally, the study results suggest that testing for DAPK methylation in tissue samples or brushing may provide a promising method for diagnosing NPC. This is the first meta-analysis that provided scientific evidence that methylation of the DAPK gene could serve as a potential biomarker for diagnosis, prognosis, and early screening of NPC patients.

Integrative analysis identifies AKAP8L as an immunological and prognostic biomarker of pan-cancer.

A-kinase anchoring protein 8L (AKAP8L) belong to the A-kinase anchoring protein (AKAP) family. Recent studies have proved that AKAP8L is associated with the progression of various tumors. To establish a more complete understanding of the significance of AKAP8L across various types of cancers, we conducted a detailed analysis of multiple histological datasets, including the level of gene expression in pancancer, biological function, molecular characteristics, as well as the diagnostic and prognostic value of AKAP8L in pancancer. Furthermore, we focused on renal clear cell carcinoma (KIRC), and of explored the correlation of AKAP8L with clinical characteristics, prognosis of distinct patient subsets, co-expression genes and differentially expressed genes (DEG). We also performed the immunohistochemical staining and semi-quantitative verification of the monoclonal antibody established by AKAP8L. Our findings indicate that AKAP8L expression varied significantly not only across most cancer types, but also across different cancer molecules and immune subtypes. In addition, the robust ability to accurately predict cancer and its strong correlation with the prognosis of cancer strongly suggest that AKAP8L may be a potential biomarker for cancer diagnosis and prognosis. Furthermore, the high expression levels of AKAP8L were related to the worse overall survival (OS), disease-specific survival (DSS) as well as progression-free interval (PFI) of KIRC with statistical significance, especially among distinct clinical subgroups of KIRC. To sum up, AKAP8L has the potential to serve as a critical molecular biomarker for the diagnosis and prognosis of pancancer, an independent prognostic risk factor of KIRC, and a novel molecular target for cancer therapies.

Comprehensive analysis of P2Y family genes expression, immune characteristics, and prognosis in pan-cancer

BackgroundP2Y receptors are a family of G protein-coupled receptor genes that have an important function in cancer development and metastasis. However, systematic studies have not been conducted on human tumors. This study attempted to explore the role of P2Y family genes (P2Ys) in pan-cancer. MethodsGene expression and clinical data were downloaded from The Cancer Genome Alas dataset. Gene differential expression, mutation, prognosis, tumor microenvironment (TME) (containing immune cells infiltration, Estimate/immune/stromal scores, immune checkpoints, immune and molecular subtypes, DNA repair genes and methyltransferase), clinical correlation, protein-protein interaction network and functional enrichment analysis were performed. In addition, experiments such as western blots were performed for validation. ResultsEight P2Ys were differentially expressed in most tumor and normal tissues, and their abnormal expression in a variety of cancers could significantly reduce the survival rate of patients. Expression levels of P2Ys, especially P2Y6, P2Y12, P2Y13, P2Y14, were correlated significantly with immune cells, immune checkpoint genes, immune and molecular subtypes and Estimate/immune/stromal scores in a variety of cancers such as uveal melanoma, liver hepatocellular carcinoma, stomach adenocarcinoma, colorectal cancer (CRC), prostate adenocarcinoma, breast invasive carcinoma and uterine corpus endometrial carcinoma (all p < 0.05). P2Ys play an important role in TME and are involved in immune regulation. In addition, enrichment analysis and western blots showed that the levels of P2Y2 and P2Y6 expression regulate the Akt/GSK-3β/β-catenin pathway in CRC, thereby affecting epithelial-to-mesenchymal transition. ConclusionP2Ys may be used as potential pan-cancer biomarkers in prognosis and immunology. They may also be new targets for tumor immunotherapy, which has wide clinical implications.

Peripheral α-synuclein isoforms are potential biomarkers for diagnosis and prognosis of isolated REM sleep behavior disorder

IntroductionIsolated REM sleep behavior disorder (IRBD) represents an early manifestation of the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Aggregation of abnormal α-synuclein and its increased expression in the brain is crucial in the development of the synucleinopathies. Whereas α-synuclein gene (SNCA) transcripts are overexpressed in brain, a concomitant reduction occurs in blood of DLB patients. We assessed whether this decrease is also detectable in IRBD. Methods108 IRBD patients and 149 controls were included of which 29 IRBD and 32 control cases were available for expression studies. Expression of SNCAtv1, SNCAtv2, SNCAtv3 and SNCA126 isoforms, and GBA were determined by real-time PCR. Genotype distribution of SNCA SNPs, rs356219 and rs2736990, and correlation with SNCA expression was analyzed. ResultsExpression of all SNCA transcripts was reduced in IRBD blood whereas GBA expression did not change. SNCAtv3 expression correlated inversely with IRBD duration, being lower in patients with longer follow-up. Rs356219-AA genotype frequency was increased in IRBD patients who later developed PD and DLB. Rs2736990-CC frequency was increased among IRBD cases who remained disease-free. No correlation was observed between rs356219 and rs2736990 genotypes and SNCA transcript levels. ConclusionSNCA transcript expression is decreased in blood in IRBD, and levels decrease with IRBD duration. Our findings indicate that changes in SNCA expression occur in the earliest stages of the synucleinopathies before motor and cognitive symptoms become apparent.

Comprehensive pan-cancer analysis of expression profiles and prognostic significance for NUMB and NUMBL in human tumors.

NUMB has been initially identified as a critical cell fate determinant that modulates cell differentiation via asymmetrical partitioning during mitosis, including tumor cells. However, it remains absent that a systematic assessment of the mechanisms underlying NUMB and its homologous protein NUMBLIKE (NUMBL) involvement in cancer. This study aimed to investigate the prognostic significance for NUMB and NUMBL in pan-cancer. In this study, using the online databases TIMER2.0, gene expression profiling interactive analysis, cBioPortal, the University of ALabama at Birmingham CANcer data analysis Portal, SearchTool for the Retrieval of Interacting Genes/Proteins, and R software, we focused on the relevance between NUMB/NUMBL and oncogenesis, progression, mutation, phosphorylation, function and prognosis. This study demonstrated that abnormal expression of NUMB and NUMBL were found to be significantly associated with clinicopathologic stages and the prognosis of survival. Besides, genetic alternations of NUMB and NUMBL focused on uterine corpus endometrial carcinoma, and higher genetic mutations of NUMBL were correlated with more prolonged overall survival and disease-free survival in different cancers. Moreover, S438 locus of NUMB peptide fragment was frequently phosphorylated in 4 cancer types and relevant to its phosphorylation sites. Furthermore, endocytosis processing and neurogenesis regulation were involved in the functional mechanisms of NUMB and NUMBL separately. Additionally, the pathway enrichment suggested that NUMB was implicated in Hippo, Neurotrophin, Thyroid hormone, and FoxO pathways, while MAPK, Hippo, Rap1, mTOR, and Notch pathways were related to the functions of NUMBL. This study highlights the predictive roles of NUMB and NUMBL in pan-cancer, suggesting NUMB and NUMBL might be served as potential biomarkers for diagnosis and prognosis in various malignant tumors.

MiR-628-5p is a Potential Novel Prognosis Biomarker, Associated with Immune Infiltration in Bladder Urothelial Carcinoma.

microRNA-628-5p (miR-628-5p) has a significant impact on certain types of cancer. The precise function of miR-628-5p in the context of bladder urothelial carcinoma (BLCA) remains ambiguous. We aimed to investigate the role of miR-628-5p in BLCA. The samples were collected from The Cancer Genome Atlas (TCGA). Statistics were employed to evaluate the correlation and predictive significance of miR-628-5p. We analyzed the target genes and regulatory network of miR-628-5p and the correlation between miR-628-5p and immune infiltration. The expression of miR-628-5p in BLCA cells was confirmed by quantitative reverse-transcription PCR (qRT-PCR). miR-628-5p exhibited differential expression across various types of cancer. There was a significant association between high expression of miR-628-5p and primary therapy outcome (p < 0.05). High expression of miR-628-5p was observed to be associated with poorer overall survival (HR: 1.42; 95% CI: 1.06-1.90; p = 0.02), progress free survival (HR: 1.57; 95% CI: 1.17-2.11; p = 0.003), and disease specific survival (HR: 1.83; 95% CI: 1.28-2.62; p = 0.001) in BLCA. miR-628-5p was an independent prognostic factor in BLCA and may be involved in the development of the disease through various pathways, including focal adhesion, ECM-receptor interaction, PI3K-Akt signaling pathway, and MAPK signaling pathway, and among others. miR-628-5p expression was significantly correlated with immune infiltration in BLCA patients. Compared to normal bladder epithelial cells, BLCA cell lines exhibited a significant upregulation of miR-628-5p. It is possible that miR-628-5p could serve as a hopeful therapeutic target and prognostic biomarker for individuals with BLCA.

An Uncharacterised lncRNA Coded by the ASAP1 Locus Is Downregulated in Serum of Type 2 Diabetes Mellitus Patients.

Diabetes mellitus (DM) is a complex and multifactorial disease characterised by high blood glucose. Type 2 Diabetes (T2D), the most frequent clinical condition accounting for about 90% of all DM cases worldwide, is a chronic disease with slow development usually affecting middle-aged or elderly individuals. T2D represents a significant problem of public health today because its incidence is constantly growing among both children and adults. It is also estimated that underdiagnosis prevalence would strongly further increase the real incidence of the disease, with about half of T2D patients being undiagnosed. Therefore, it is important to increase diagnosis accuracy. The current interest in RNA molecules (both protein- and non-protein-coding) as potential biomarkers for diagnosis, prognosis, and treatment lies in the ease and low cost of isolation and quantification with basic molecular biology techniques. In the present study, we analysed the transcriptome in serum samples collected from T2D patients and unaffected individuals to identify potential RNA-based biomarkers. Microarray-based profiling and subsequent validation using Real-Time PCR identified an uncharacterised long non-coding RNA (lncRNA) transcribed from the ASAP1 locus as a potential diagnostic biomarker. ROC curve analysis showed that a molecular signature including the lncRNA and the clinicopathological parameters of T2D patients as well as unaffected individuals showed a better diagnostic performance compared with the glycated haemoglobin test (HbA1c). This result suggests that the application of this biomarker in clinical practice would help to improve the diagnosis, and therefore the clinical management, of T2D patients. The proposed biomarker would be useful in the context of predictive, preventive, and personalised medicine (3PM/PPPM).

Global comparative transcriptomes uncover novel and population-specific gene expression in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) has a poor prognosis and is one of the deadliest gastrointestinal malignancies. Despite numerous transcriptomics studies to understand its molecular basis, the impact of population-specific differences on this disease remains unexplored.AimsThis study aimed to investigate the population-specific differences in gene expression patterns among ESCC samples obtained from six distinct global populations, identify differentially expressed genes (DEGs) and their associated pathways, and identify potential biomarkers for ESCC diagnosis and prognosis. In addition, this study deciphers population specific microbial and chemical risk factors in ESCC.MethodsWe compared the gene expression patterns of ESCC samples from six different global populations by analyzing microarray datasets. To identify DEGs, we conducted stringent quality control and employed linear modeling. We cross-compared the resulting DEG lists of each populations along with ESCC ATLAS to identify known and novel DEGs. We performed a survival analysis using The Cancer Genome Atlas Program (TCGA) data to identify potential biomarkers for ESCC diagnosis and prognosis among the novel DEGs. Finally, we performed comparative functional enrichment and toxicogenomic analysis.ResultsHere we report 19 genes with distinct expression patterns among populations, indicating population-specific variations in ESCC. Additionally, we discovered 166 novel DEGs, such as ENDOU, SLCO1B3, KCNS3, IFI35, among others. The survival analysis identified three novel genes (CHRM3, CREG2, H2AC6) critical for ESCC survival. Notably, our findings showed that ECM-related gene ontology terms and pathways were significantly enriched among the DEGs in ESCC. We also found population-specific variations in immune response and microbial infection-related pathways which included genes enriched for HPV, Ameobiosis, Leishmaniosis, and Human Cytomegaloviruses. Our toxicogenomic analysis identified tobacco smoking as the primary risk factor and cisplatin as the main drug chemical interacting with the maximum number of DEGs across populations.ConclusionThis study provides new insights into population-specific differences in gene expression patterns and their associated pathways in ESCC. Our findings suggest that changes in extracellular matrix (ECM) organization may be crucial to the development and progression of this cancer, and that environmental and genetic factors play important roles in the disease. The novel DEGs identified may serve as potential biomarkers for diagnosis, prognosis and treatment.

Identification of hub genes and drug-gene interactions for targeted breast cancer treatment by integrated bioinformatics analysis

Breast cancer (BC) is one of the most common cancer types in women. In addition to conventional methods for BC diagnosis, applying methods for a fast and accurate prognosis at the early stage of cancer is very meaningful for the treatment of the disease. To date, the most advanced methods are molecular diagnostics and bioinformatics. In this study, bioinformatics is applied to genetic testing for BC diagnosis; namely the R programming language combined with the bioinformatics toolkit was used to analyze gene expression levels between normal and tumor tissues in three gene expression profiles (GSE29431, GSE42568, GSE21422). The bioinformatics approaches included identification of differentially expressed genes (DEGs) and hub genes, Gen Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) analyses, the construction of a protein-protein interaction (PPI) network, and module analysis. Following the completion of the hub gene selection process, coexpression and survival analysis were carried out. Finally, the GEPIA2 and DGIdb databases were utilized to verify the expression levels of hub genes and select the candidate drugs for BC, respectively. A total of 1369 DEGs was identified, including 400 upregulated DEGs and 969 downregulated DEGs. Thereafter, 10 hub genes (CDK1, CCNA2, CCNB1, CCNB2, TOP2A, KIF11, RRM2, BUB1B, CDC20, and NCAPG) were identified as potential biomarkers for BC diagnosis, prognosis, and therapy. Six screened small molecules, dexrazoxane, teniposide, amsacrine, etoposide, mitoxantrone and daunorubicin, were determined to be the new targeted drugs for BC treatment.

Expression and clinical significance of RBBP4 gene in lower-grade glioma: An integrative analysis

This study investigated the expression pattern of retinoblastoma binding protein 4 (RBBP4) gene in glioma and explored its associations with clinicopathologic characteristics and prognosis of patients. Data retrieved from the GEPIA, CGGA, HPA and TIMER databases were processed to analyze RBBP4 expression in glioma and investigate its relationship with clinicopathologic characteristics, tumor immune infiltration and prognosis in glioma patients. Immunohistochemistry was applied to determine the expression of RBBP4 protein in glioma tissue. Additionally, the Coexpedia database was visited to identify co-expressed genes for RBBP4 gene, while the Cytoscape software was run to visualize the enriched GO entries and KEGG pathways of these co-expressed genes. The expression levels of RBBP4 in lower-grade glioma (LGG) and glioblastoma (GBM) tissues were markedly elevated when compared to normal tissues (both p < 0.05). The up-regulation of RBBP4 expression was associated with an increase in WHO grade (II-IV), wild-type IDH, and 1p/19q non-codeletion (all p < 0.05). Multi-variate Cox regression analysis showed that both increased abundance of infiltrating macrophages and up-regulated RBBP4 expression independently predicted poor survival outcomes in LGG patients (both p < 0.05). Furthermore, RBBP4 expression exhibited significant positive correlations with the abundance of infiltrating B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell in LGG (all p < 0.05). Functional enrichment analyses indicated that the co-expressed genes associated with RBBP4 were highly involved in pathways such as the p53 signaling pathway, cell cycle, DNA replication, glutathione metabolism, as well as biological processes including cell cycle process, DNA replication, and DNA repair. High levels of RBBP4 are predictive for the poor survival outcome of LGG patients. RBBP4 gene, therefore, is expected to be a potential biomarker for prognosis of LGG and a target for immunotherapy.

Pan-cancer analysis and experimental validation revealed the m6A methyltransferase KIAA1429 as a potential biomarker for diagnosis, prognosis, and immunotherapy.

KIAA1429, also known as VIRMA (vir-like m6A methyltransferase associated), plays a crucial role in tumorigenesis by modulating the level of m6A methylation. Previous studies have reported the prevalent overexpression of KIAA1429 in multiple cancers, related to a poor prognosis. Nevertheless, the precise role of KIAA1429 in tumor progression and its impact on the immune response remains unclear. A differential analysis of KIAA1429 expression was performed across cancers using data from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We evaluated the role of KIAA1429 in the diagnosis, prognosis, and immunotherapy of tumor patients using bioinformatics methods. In addition, we also analyzed the associations between KIAA1429 and DNA methylation, immunotherapy. RT-qPCR was used to study the expression levels of KIAA1429 mRNA in 11 cell lines. KIAA1429 is found to be overexpressed in 28 cancer types, but its expression is relatively low in patients with acute myeloid leukemia (LAML) and ovarian serous cystadenocarcinoma (OV). Moreover, KIAA1429 demonstrates a positive correlation with advanced stages of multiple cancers. Kaplan-Meier (KM) analysis suggested that patients with elevated KIAA1429 expression had shorter survival. Furthermore, KIAA1429 shows strong associations with DNA methylation, tumor-infiltrating immune cells (TIICs), and the tumor microenvironment (TME). RT-qPCR results indicated significantly higher expression of KIAA1429 in tumor cells compared to matched-normal cells. In summary, our work illustrates that KIAA1429 expression is positively connected with poor prognosis in multiple cancers. Moreover, KIAA1429 could serve as a diagnostic factor and a predictor of immune response for specific tumor types.

Unraveling Acute and Post-COVID Cytokine Patterns to Anticipate Future Challenges.

The aims of this study were to analyze cytokine profiles in patients with COVID-19, gain insights into the immune response during acute infection, identify cytokines associated with disease severity and post-COVID complications, and explore potential biomarkers for prognosis and therapeutic targets. Using a multiplex analysis, we studied the cytokine pattern in 294 acute COVID-19 and post-COVID patients with varying severities of infection. Our findings revealed that disease severity was associated with elevated levels of IL-15, IL-8, and fractalkine. Severe/extremely severe forms in comparison with mild/moderate disease were associated with MCP-1, IFNa2, IL-7, IL-15, EGF, IP-10, IL-8, Eotaxin, FGF-2, GROa, sCD40L, and IL-10. The key cytokines of post-COVID are FGF-2, VEGF-A, EGF, IL-12(p70), IL-13, and IL-6. By the sixth month after recovering from a coronavirus infection, regardless of disease severity, some patients may develop complications such as arterial hypertension, type 2 diabetes mellitus, glucose intolerance, thyrotoxicosis, atherosclerosis, and rapid progression of previously diagnosed conditions. Each complication is characterized by distinct cytokine profiles. Importantly, these complications can also be predicted during the acute phase of the coronavirus infection. Understanding cytokine patterns can aid in predicting disease progression, identifying high-risk patients, and developing targeted interventions to improve the outcomes of COVID-19.

Cell-in-cell: a potential biomarker of prognosis and a novel mechanism of drug resistance in cancer.

The cell-in-cell (CIC) phenomenon has received increasing attention over recent years because of its wide existence in multiple cancer tissues. The mechanism of CIC formation is considerably complex as it involves interactions between two cells. Although the molecular mechanisms of CIC formation have been extensively investigated, the process of CIC formation remains ambiguous. Currently, CIC is classified into four subtypes based on different cell types and inducing factors, and the underlying mechanisms for each subtype are distinct. Here, we investigated the subtypes of CIC and their major mechanisms involved in cancer development. To determine the clinical significance of CIC, we reviewed several clinical studies on CIC and found that CIC could serve as a diagnostic and prognostic biomarker. The implications of CIC on the clinical management of cancers also remain largely unknown. To clarify this aspect, in the present review, we highlight the findings of recent investigations on the causal link between CIC and cancer treatment. We also indicate the existing issues that need to be resolved urgently to provide a potential direction for future research on CIC.

Metabolic fingerprinting of systemic sclerosis: a systematic review.

Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Methods: Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Results: Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. Discussion: The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.

Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.

Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.

PTERT C250T mutation: A potential biomarker of poor prognosis in metastatic melanoma

Melanoma is the most aggressive form of skin cancer and the leading cause of death from cutaneous tumors. Several studies have associated alterations in the TERT promoter region (pTERT) with gene overexpression, aggressiveness and poor prognosis of the disease. The aim of this study was to clarify the role of pTERT molecular status in paired samples of primary melanoma and metastasis using tissue and plasma to establish a correlation with disease progression and survival.A total of 88 FFPE tissue samples from 53 patients with advanced melanoma were analyzed. Of these, 35 had paired samples. We also examined cfDNA samples from plasma of 25 patients. We detected a good correlation between primary tumors and metastases in pTERT mutation and methylation status. We were also able to identify pTERT mutations in plasma samples that correlated with mutational status in tissue samples. Interestingly, the C250T mutation was associated with worse survival and higher TERT mRNA expression, compared to the other most common mutation: C228T. In addition, hyper-methylation of the promoter region seems to be related to the progression of pTERT wild type (WT) patients. These results suggest that TERT gene alterations plays an important role during tumor progression, with the detection of the C250T mutation in tissue and plasma as a potential biomarker of poor prognosis in patients with advanced melanoma.

Circulating exosomal microRNA-4497 as a potential biomarker for metastasis and prognosis in non-small-cell lung cancer.

Circulating exosomal microRNAs (miRNAs) have shown great potential for the diagnosis, prognosis, and treatment monitoring of patients with non-small-cell lung cancer (NSCLC). Our main purpose was to determine the clinical value of serum exosomal miR-4497 as a new non-invasive biomarker for NSCLC. The exoRNeasy Kit (QIAGEN, Hilden, Germany) was used to isolate exosomes and exoRNA from the serum of 84 patients with NSCLC (NSCLC group), 30 patients with benign lung lesion (BLL group), and 47 healthy controls. Six serum exosomal miRNAs (Let-7b-5p, miR-122-5p, miR-155-5p, miR-223-3p, miR-320c, and miR-4497) were selected as candidate miRNAs and analyzed using real-time qPCR, among which miR-4497 displayed the most striking differences. Exosomal miR-4497 expressed significantly lower in NSCLC than in BLL patients and healthy controls (P < 0.001). Further investigation showed that miR-4497 was negatively correlated with the malignant characteristics of tumors (tumor size, tumor-node-metastasis [TNM] stage, and distant metastasis) and was an independent tumor suppressor (P < 0.05). According to receiver operating characteristic (ROC) analysis, exosomal miR-4497 independently exhibited excellent diagnostic efficacy, which could be improved by combining it with traditional markers (for identifying tumor size, the area under the curve [AUC] = 0.761; TNM stage, AUC = 0.878; distant metastasis, AUC = 0.895; all P < 0.001). Moreover, longitudinal analysis revealed that exosomal miR-4497 levels increased after chemoradiotherapy (P < 0.001). According to the survival analysis, poor overall survival (OS) and disease-free survival (DFS) were associated with low exosomal miR-4497 levels (P < 0.05). Moreover, exosomal miR-4497 was an independent protective factor affecting DFS (hazard ratio = 0.190, P = 0.009) in the Cox proportional hazards model. Therefore, serum exosomal miR-4497 can be used as a potential biomarker to identify NSCLC and healthy individuals or BLL patients for early screening or as a biomarker for staging and grading, prognosis, and monitoring recurrence, metastasis, and the therapeutic effects in patients with NSCLC.

Cytokines as Prognostic Biomarkers in Osteosarcoma Patients: A Systematic Review and Meta-analysis.

Osteosarcoma is the most prevalent type of primary bone malignancy in children and adolescents. The effect of cytokines on osteosarcoma prognosis has been studied and reported. This meta-analysis aimed to assess the prognostic value of cytokines as osteosarcoma biomarkers. Databases including PubMed, Embase, and Cochrane Library were searched for studies on the prognostic value of cytokines in osteosarcoma. From the eligible studies, data on overall survival (OS), disease-free survival, and metastasis-free survival (MFS) were extracted. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A total of 11 studies involving 755 patients were included in this analysis. High macrophage migration inhibitory factor (MIF) expression in tumors was significantly associated with shortened OS (HR = 2.01, 95% CI: 1.18-3.42, P = 0.010) and MFS (HR = 2.51, 95% CI: 1.47-4.01, P = 0.001). Elevated T cell immunoglobulin and mucin domain-3 (Tim-3) levels in serum correlated with increased risk of disease progression in patients with osteosarcoma (HR = 3.14, 95% CI: 2.88-3.03, P < 0.001). However, interleukin 6 (IL-6) and tumor necrosis factor were not substantially associated with osteosarcoma prognosis. Owing to a paucity of research, other relevant cytokines [interferon-α/β receptor, tissue factor, macrophage inhibitory cytokine 1 (MIC-1), and IL-23] could not be combined. In conclusion, MIF levels in tumors and Tim-3 levels in serum can be potential biomarkers of poor prognosis in osteosarcoma. To confirm this finding and implement these biomarkers into clinical applications, additional large-scale, high-quality studies are needed.