Expression Levels In Patients Research Articles

Comparison of microRNA expression levels in patients with schizophrenia before and after electroconvulsive therapy.

Exploring the role of microRNAs in the antipsychotic efficacy of electroconvulsive therapy (ECT) will contribute to understanding the underlying mechanism through which ECT exerts its therapeutic effects. The primary objective of this study was to identify microRNA alterations before and after ECT in patients with schizophrenia. We compared microarray-based microRNA profiles in peripheral blood from eight patients with schizophrenia before and after ECT and eight healthy controls. Then, we aimed to validate selected differentially expressed microRNAs in 30 patients with schizophrenia following a course of ECT, alongside 30 healthy controls by using quantitative real-time PCR (qRT-PCR). Microarray-based expression profiling revealed alterations in 681 microRNAs when comparing pre- and post-ECT samples. Subsequent qRT-PCR analysis of the selected microRNAs (miR-20a-5p and miR-598) did not reveal any statistical differences between pre- and post-ECT samples nor between pre-ECT samples and those of healthy controls. As neuroepigenetic studies on ECT are still in their infancy, the results reported in this study are best interpreted as exploratory outcomes. Additional studies are required to explore the potential epigenetic mechanisms underlying the therapeutic efficacy of ECT.

Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

Predictive value of miR-7110-5p and miR-223-3p as biomarkers for sepsis secondary to pneumonia.

Investigating the secondary sepsis of pneumonia is of great significance for rapid diagnosis and early treatment of sepsis. This study aimed to investigate the predictive value of micro ribonucleic acids (miRNA) 7110-5p and miR-223-3p in sepsis secondary to pneumonia. A miRNA microarray was used to analyze the differences in miRNA expression between patients with pneumonia and those with sepsis secondary to pneumonia. The study included a total of 50 patients with pneumonia and 42 patients with sepsis secondary to pneumonia. Quantitative polymerase chain reaction analysis was conducted to measure the circulating miRNA expression levels in patients and assess their correlations with clinical characteristics and prognosis. In this study, nine miRNAs - hsa-miR-4689-5p, hsa-miR-4621-5p, hsa-miR-6740-5p, hsa-miR-7110-5p, hsa-miR-765, hsa-miR-940, hsa-miR-213-5p, hsa-miR-223-3p, and hsa-miR-122 - met the screening criteria of having a fold change ⩾ 2 or < 0.5; p< 0.01 indicated significant differences in the results. The expression levels of miR-7110-5p and miR-223-3p differed between the two patient groups, being up-regulated in the plasma of patients with sepsis secondary to pneumonia. miR-7110-5p and miR-223-3p showed higher expression levels in both patients with pneumonia and sepsis compared to healthy controls. Moreover, the receiver operating characteristic curve revealed that the areas under the curve for predicting pneumonia using miR-7110-5p were 0.781 while those for predicting sepsis secondary to pneumonia were 0.862. For miR-223-3p, the corresponding values for predicting pneumonia and sepsis secondary to pneumonia were 0.879 and 0.924, respectively. However, there were no significant differences in the levels of miR-7110-5p and miR-223-3p between the plasma of survived and deceased patients with sepsis. MiR-7110-5p and miR-223-3p have the potential to serve as biological indicators for predicting sepsis secondary to pneumonia.

C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina.

Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting loss of C9ORF72 function could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the adult female spinal cords revealed no appreciable neurodegenerative pathology such as loss of motor neurons or increased levels of neuroinflammation. However, detailed examination of adult female c9orf72-/- retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Analysis of rod and cone cells within the photoreceptor layer showed a disturbance in their outer segment structure and rhodopsin mislocalization from rod outer segments to their cell bodies and synaptic terminals. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.

Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

Prediction of the Ki-67 expression level in head and neck squamous cell carcinoma with machine learning-based multiparametric MRI radiomics: a multicenter study

BackgroundThis study aimed to develop and validate a machine learning (ML)-based fusion model to preoperatively predict Ki-67 expression levels in patients with head and neck squamous cell carcinoma (HNSCC) using multiparametric magnetic resonance imaging (MRI).MethodsA total of 351 patients with pathologically proven HNSCC from two medical centers were retrospectively enrolled in the study and divided into training (n = 196), internal validation (n = 84), and external validation (n = 71) cohorts. Radiomics features were extracted from T2-weighted images and contrast-enhanced T1-weighted images and screened. Seven ML classifiers, including k-nearest neighbors (KNN), support vector machine (SVM), logistic regression (LR), random forest (RF), linear discriminant analysis (LDA), naive Bayes (NB), and eXtreme Gradient Boosting (XGBoost) were trained. The best classifier was used to calculate radiomics (Rad)-scores and combine clinical factors to construct a fusion model. Performance was evaluated based on calibration, discrimination, reclassification, and clinical utility.ResultsThirteen features combining multiparametric MRI were finally selected. The SVM classifier showed the best performance, with the highest average area under the curve (AUC) of 0.851 in the validation cohorts. The fusion model incorporating SVM-based Rad-scores with clinical T stage and MR-reported lymph node status achieved encouraging predictive performance in the training (AUC = 0.916), internal validation (AUC = 0.903), and external validation (AUC = 0.885) cohorts. Furthermore, the fusion model showed better clinical benefit and higher classification accuracy than the clinical model.ConclusionsThe ML-based fusion model based on multiparametric MRI exhibited promise for predicting Ki-67 expression levels in HNSCC patients, which might be helpful for prognosis evaluation and clinical decision-making.

Prognostic Value of IGF2BP3 Gene Expression Levels in Patients with Acute Myeloid Leukemia

To investigate the relationship between IGF2BP3 gene expression and prognosis in patients with acute myeloid leukemia (AML). High throughput transcriptome sequencing was performed on bone marrow primary leukemia cells from 27 patients with AML in our center, the relationship between IGF2BP3 expression levels and clinical characteristics were analyzed and verify the samples from patients with newly treated AML and refractory AML. The expression level of IGF2BP3 gene were analyzed in 20 healthy subjects and 26 patients with AML. The expression of IGF2BP3 in two anthracycline-resistant cell lines (HL60/ADR, K562/ADR) was detected by RT-qPCR and Western blot, and the expression difference of IGF2BP3 was compared with that in sensitive cells (HL60, K562). The relationship between the expression level of IGF2BP3 in patients with AML and prognostic were analyzed through data analysis of 746 patients with AML, and the prognostic value of IGF2BP3 in AML was analyzed by multivariate Cox regression analysis. In the bone marrow primary leukemia cells of 27 AML patients in our center, the expression level of IGF2BP3 in patients with refractory AML was significantly higher than that in chemotherapy sensitive patients (P =0.0343). The expression of IGF2BP3 in leukemia patients with extramedullary infiltration (EMI) was significantly higher than that in AML patients without extramedullary infiltration (P =0.0049). Compared with healthy subjects (n=20), IGF2BP3 expression in AML patients (n=26) was higher (P =0.0009). The expression of IGF2BP3 mRNA in the anthracycline resistant cell lines (HL60/ADR, K562/ADR) was significantly higher than that in the sensitive cell lines (K562/ADR vs K562,P =0.0430; HL60/ADR vs HL60, P =0.7369). Western blot results showed that the expression of IGF2BP3 protein in mycin resistant cells was significantly higher than that in sensitive cells (P < 0.001). qPCR results showed that the expression level of IGF2BP3 mRNA in refractory AML patients was significantly higher than that in patients with chemotherapy sensitive (P =0.002). High expression of IGF2BP3 was associated with poor prognosis in AML (P < 0.05) in 3 large sample cohorts of AML patients. Univariate and multivariate prognostic analyses demonstrated that high expression of IGF2BP3 was significantly associated with shorter event-free survival (EFS, HR=1.887, P =0.024) and overall survival (OS, HR=1.619, P =0.016). The high expression of IGF2BP3 gene may be an important factor in the poor prognosis of AML, suggesting that IGF2BP3 gene may be a new molecular marker for the clinical prognosis evaluation and treatment strategy of AML.

Construction and experimental validation of a novel ferroptosis-related gene signature for myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by morphological abnormalities and peripheral blood cytopenias, carrying a risk of progression to acute myeloid leukemia. Although ferroptosis is a promising target for MDS treatment, the specific roles of ferroptosis-related genes (FRGs) in MDS diagnosis have not been elucidated. MDS-related microarray data were obtained from the Gene Expression Omnibus database. A comprehensive analysis of FRG expression levels in patients with MDS and controls was conducted, followed by the use of multiple machine learning methods to establish prediction models. The predictive ability of the optimal model was evaluated using nomogram analysis and an external data set. Functional analysis was applied to explore the underlying mechanisms. The mRNA levels of the model genes were verified in MDS clinical samples by quantitative real-time polymerase chain reaction (qRT-PCR). The extreme gradient boosting model demonstrated the best performance, leading to the identification of a panel of six signature genes: SREBF1, PTPN6, PARP9, MAP3K11, MDM4, and EZH2. Receiver operating characteristic curves indicated that the model exhibited high accuracy in predicting MDS diagnosis, with area under the curve values of 0.989 and 0.962 for the training and validation cohorts, respectively. Functional analysis revealed significant associations between these genes and the infiltrating immune cells. The expression levels of these genes were successfully verified in MDS clinical samples. Our study is the first to identify a novel model using FRGs to predict the risk of developing MDS. FRGs may be implicated in MDS pathogenesis through immune-related pathways. These findings highlight the intricate correlation between ferroptosis and MDS, offering insights that may aid in identifying potential therapeutic targets for this debilitating disorder.

ACE2 and TMPRSS2 expression in patients before, during, and after SARS-CoV-2 infection.

During the SARS-CoV-2 pandemic angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were constantly under the scientific spotlight, but most studies evaluated ACE2 and TMPRSS2 expression levels in patients infected by SARS-CoV-2. Thus, this study aimed to evaluate the expression levels of both proteins before, during, and after-infection. For that, nasopharyngeal samples from 26 patients were used to measure ACE2/TMPRSS2 ex-pression via qPCR. Symptomatic patients presented lower ACE2 expression levels before and after the infection than those in asymptomatic patients; however, these levels increased during SARS-CoV-2 infection. In addition, symptomatic patients presented higher expression levels of TMPRSS2 pre-infection, which decreased in the following periods. In summary, ACE2 and TMPRSS2 expression levels are potential risk factors for the development of symptomatic COVID-19, and the presence of SARS-CoV-2 potentially modulates those levels.

Abstract 1208: Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy

Abstract Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with metastatic non-small cell lung cancer (NSCLC). However, clinical management is challenging. The PD-L1 biomarker does not optimally guide the choice between ICI monotherapy and combination ICI-chemotherapy, and there are currently no biomarkers to predict immune-related adverse events (irAEs). Here, we describe a versatile platform based on plasma proteomics and machine learning for generating predictive tools to support treatment decisions. Methods: Pre-treatment plasma samples were collected from 616 NSCLC patients receiving ICI-based therapy (NCT04056247). Clinical benefit (CB) data and irAEs were recorded. Proteomic profiling of plasma samples was performed using the SomaScan® assay, covering ~7000 proteins per sample. Proteins associated with Clinical Benefit (progression-free survival at 12 months) were classified as resistance-associated proteins (RAPs). Proteins associated with grade ≥3 irAEs occurring within the first 100 days of treatment were classified as toxicity-associated proteins (TAPs). RAPs and TAPs were integrated into two separate machine learning-based models, yielding CB and irAE probabilities, respectively. The CB model used a CB probability threshold to assign patients a PROphet-positive or PROphet-negative result. Bioinformatic analysis was performed on RAPs and TAPs. Results: CB and irAE models displayed strong predictive performance with a high correlation between predicted probability and observed CB or irAE rate (CB model: R2=0.98; p-value&amp;lt;0.0001; irAE model: R2= 0.92; p-value &amp;lt;0.0001). In the CB model, patients classified as PROphet-positive achieved significantly longer overall survival (OS) than PROphet-negative patients, with a median OS of 25.9 vs. 10.8 months (hazard ratio, HR = 0.51; p-value&amp;lt;0.001). Furthermore, patients with PD-L1 ≥50% tumors and a PROphet-negative result had significantly longer OS with ICI-chemotherapy in comparison to ICI monotherapy (HR=0.23, p-value = 0.0003), suggesting that combination therapy is preferable for such patients despite high PD-L1 levels. Bioinformatic analysis showed that RAPs related to immune regulation, angiogenesis, chemo-resistance, and other potential resistance mechanisms displayed higher expression levels in patients who did not benefit from treatment. Neutrophil- and inflammation-related proteins were significantly enriched in patients who experienced irAEs. Conclusions: We describe two machine-learning based predictive tools that may be used separately or in combination to inform treatment decisions based on the patient’s likelihood to benefit from ICI therapy and to develop serious irAEs. Our findings also provide biological insights related to treatment resistance and immune-related toxicity. Citation Format: Michal Harel, Petros Christopoulos, Igor Puzanov, Jair Bar, Iris Kamer, Niels Reinmuth, Ina Koch, Mor Moskovitz, Adva Levy-Barda, Alona Zer, Michal Lotem, David Farrugia, Rivka Katzenelson, Gillian Price, Abed Agbarya, Helen Cheley, Adam Hassani, Mahmoud Abu-Amna, Tom Geldart, Anirban Chatterjee, Andreas Polychronis, Maya Gottfried, Yanyan Lou, Tatiana Harkovsky, Alison Brewster, Ido Wolf, Ella Tepper, Ben Yellin, Itamar Sela, Coren Lahav, Yehonatan Elon, Raya Leibowitz, Adam P. Dicker, Young Kwang Chae, Ryan J. Sullivan, David Carbone, David Gandara, Jarushka Naidoo. Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1208.

Abstract 5183: Retrospective analysis of CCNG1 expression in tumors, a novel biomarker in development for partnering with DRG-101, a tumor targeted retrovector encoding a CCNG1 inhibitor gene

Abstract Background: CCNG1, a non-canonical cyclin, is a novel biomarker in development for partnering with DRG-101 (DeltaRex-G), a tumor targeted retrovector encoding a CCNG1 inhibitor gene. Expanded access using DRG-101 is currently open for an intermediate-size population of advanced pancreatic cancer, sarcoma and carcinoma of breast (NCT04091295). Therefore, it is important to identify patients who might respond favorably to DRG-101 gene therapy. Previously, we reported that CCNG1 expression is enhanced in sarcoma tumors (Ann Oncol 34, 1980P, 2023). In this report, we have expanded the analysis to 137 patients with all cancer types and describe patients with known CCNG1 expression levels who have been treated with DRG-101. Methods: Archived formalin-fixed paraffin-embedded (FFPE) tumor specimens (n=137) from patients who were followed at the Sarcoma Oncology Research Center were collected, processed, and subjected to RNA sequencing. Briefly, RNA-seq libraries were sequenced to generate 50 million reads, aligned using Kallisto v0.42.4 to GENCODE v23 transcripts with default parameters. Only protein-coding, IGH/K/L- and TCR-related transcripts were retained for downstream processing, resulting in 20,062 protein-coding genes. Gene expression levels in patients of the reference cohorts are categorized as low/medium/high, defined by Low = &amp;lt; 17%; Medium-high = 50%-83%; Medium-low = 17%-49%; High = &amp;gt;83%. Results: Seventy women and sixty-seven men, ranging in age from 16 to 87 years, were studied. All tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited high CCNG1 expression, 53 (39%) showed medium-high CCNG1 expression, 48 (35%) displayed medium-low CCNG1 expression, and six (4%) had low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. As a result of these findings, the FDA-CBER authorized the use of DRG-101 in an Expanded Access program as platform therapy upon which one or more FDA approved cancer drugs/immunotherapies may be added. Historically, one patient with metastatic pancreatic cancer, one with early stage, HR+ HER2+ invasive breast cancer and one with early stage triple negative breast cancer are alive 15, 3 and 2.5 years in sustained remission with DRG-101 therapy, and had 24%, 23% and 74% CCNG1 tumor expression levels respectively. Five patients with advanced pancreatic cancer, sarcoma and breast cancer and known CCNG1 expression levels are currently being treated with DRG-101. Conclusions:(1) 100% of tumors tested showed enhanced CCNG1 expression at varying levels, and (2) the use of DRG-101 in combination with FDA approved cancer drugs/immunotherapies is on-going for an intermediate size population of advanced pancreatic cancer, sarcoma and carcinoma of breast. Citation Format: Nadezhda Omelchenko, Vaishali Kumar, Samantha Jeffrey, Grace Haroun, Don Brigham, William H. Isacoff, Sant Chawla. Retrospective analysis of CCNG1 expression in tumors, a novel biomarker in development for partnering with DRG-101, a tumor targeted retrovector encoding a CCNG1 inhibitor gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5183.

Prognostic Significance of the Cribriform Pattern in Prostate Cancer: Clinical Outcomes and Genomic Alterations.

Given the diverse clinical progression of prostate cancer (PC) and the evolving significance of histopathological factors in its management, this study aimed to explore the impact of cribriform pattern 4 (CP4) on clinical outcomes in PC patients and examine its molecular characteristics. This retrospective study analyzed data from The Cancer Genome Atlas (TCGA) database and included PC patients who underwent radical prostatectomy (RP) and had pathology slides available for the assessment of CP4. A multivariable competing risk regression analysis was used to assess the association between CP4 and progression-free survival (PFS) while adjusting for established PC prognostic factors. The frequency of genomic alterations was compared between patients with and without CP4 using the Fisher's exact test. Among the 394 patients analyzed, 129 (32.74%) had CP4. After a median follow-up of 40.50 months (IQR: 23.90, 65.60), the presence of CP4 was significantly associated with lower PFS (AHR, 1.84; 95% CI, 1.08 to 3.114; p = 0.023) after adjusting for covariates. Seven hub genes-KRT13, KRT5, KRT15, COL17A1, KRT14, KRT16, and TP63-had significantly lower mRNA expression levels in patients with CP4 compared to those without. PC patients with CP4 have distinct genomic alterations and are at a high risk of disease progression following RP. Therefore, these patients may benefit from additional post-RP treatments and should be the subject of a prospective randomized clinical trial.

Machine learning models based on quantitative dynamic contrast-enhanced MRI parameters assess the expression levels of CD3+, CD4+, and CD8+ tumor-infiltrating lymphocytes in advanced gastric carcinoma.

To explore the effectiveness of machine learning classifiers based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting the expression levels of CD3+, CD4+, and CD8+ tumor-infiltrating lymphocytes (TILs) in patients with advanced gastric cancer (AGC). This study investigated 103 patients with confirmed AGC through DCE-MRI and immunohistochemical staining. Immunohistochemical staining was used to evaluate CD3+, CD4+, and CD8+ T-cell expression. Utilizing Omni Kinetics software, radiomics features (Ktrans, Kep, and Ve) were extracted and underwent selection via variance threshold, SelectKBest, and LASSO methods. Logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost) are the four classifiers used to build four machine learning (ML) models, and their performance was evaluated using 10-fold cross-validation. The model's performance was evaluated and compared using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. In terms of CD3+, CD4+, and CD8+ T lymphocyte prediction models, the random forest model outperformed the other classifier models in terms of CD4+ and CD8+ T cell prediction, with AUCs of 0.913 and 0.970 on the training set and 0.904 and 0.908 on the validation set, respectively. In terms of CD3+ T cell prediction, the logistic regression model fared the best, with AUCs on the training and validation sets of 0.872 and 0.817, respectively. Machine learning classifiers based on DCE-MRI have the potential to accurately predict CD3+, CD4+, and CD8+ tumor-infiltrating lymphocyte expression levels in patients with AGC.

Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder.

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the toll-like receptor signaling pathway. It is associated with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, the relationship between the functional single nucleotide polymorphisms (SNPs) of IRF5 and its mRNA expression level in patients with neuromyelitis optica spectrum disorder remains unclear. The present study aimed to investigate the relationship between polymorphisms and mRNA expression levels of the IRF5 gene with the incidence of neuromyelitis optica spectrum disorder (NMOSD) in northern Chinese Han people. Two loci of the IRF5 gene (rs2004640 and rs2280714) of 164 patients with NMOSD and 269 healthy subjects were genotyped using the multiple SNaPshot technique. The frequencies of alleles, genotypes, and haplotypes were compared. Stratified analysis was performed according to age, sex, AQP4 status, onset age, and Expanded Disability Status Scale (EDSS) score. The IRF5 mRNA levels in peripheral blood mononuclear cells (PBMCs) of 64 NMOSD patients (32 patients in the acute stage and 32 patients in the remission stage) and 35 healthy subjects were detected by real-time PCR. The association of SNP polymorphisms with the mRNA expression level was determined by nonparametric tests. Allele and genotype frequency distributions of rs2004640 showed significant differences between both groups. Compared to healthy controls, the frequency of rs2004640 T allele markedly increased in patients (OR = 1.51, 95% CI = 1.09-2.08, P = 0.005). Minor allele T and GT genotype of rs2004640 that significantly increases the risk of NMOSD were discovered using genetic inheritance models (codominant, dominant, and overdominant) and haplotype analyses. Subsequent haplotype analyses revealed that the major haplotype "T-A" containing the risk alleles (the SNP sequence of the alleles was rs2004640 and rs2280714) had adverse effects on NMOSD. Based on the stratification analysis according to the EDSS score, the GT genotype frequency in the EDSS ≥ 4 group (38.2%) was markedly lower than that in the EDSS < 4 group (61.8%) (OR = 0.32, 95% CI = 0.15-0.68, P = 0.0054), with a significant difference. The IRF5 mRNA expression level was increased in NMOSD patients compared to that in normal subjects. IRF5 gene polymorphisms may be tightly associated with the genesis and progression of NMOSD in northern Chinese Han people. IRF5 mRNA expression was increased in patients with NMOSD and significantly increased in patients with acute phase. Perhaps IRF5 expression levels can be used as a predictor of disease activity in the future.

Lung cancer, predictive factor and ERCC1

Introduction: Excision repair cross-complementing group 1 (ERCC1) counteracts the cytotoxic effect of cisplatin through its role in DNA repair, and its expression level is a crucial factor for sensitivity to this drug. The objective of this study was to assess the impact of ERCC1 on tumor response and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with a platinum-based regimen. Methods: Analysis of survival and tumor response based on the expression level of ERCC1 (detected by immunohistochemistry) in a cohort of NSCLC patients followed in a standard care setting. Results: Among the 77 cases of NSCLC included, ERCC1 expression was low in 64.9% of cases and high in 35.1% of cases. In the 52 patients treated with cisplatin, survival and tumor response were better in the low-expression group compared to the high-expression group: 14.35 months versus 9.49 months, p=0.022; Objective Response: 42.4% versus 0%, p=0.001. No significant difference was found based on protein expression level in patients treated with carboplatin. Conclusion: ERCC1 overexpression in patients treated with cisplatin predicts a poor tumor response and shorter survival.

METTL3-mediated m6A modification enhances ZDHHC16 expression in nonsmall- cell lung cancer patients, attenuating ferroptosis by suppressing CREB ubiquitination.

At present, the early diagnosis and treatment of non-small cell lung cancer (NSCLC) is still an urgent problem to be solved worldwide, including in China. The present work investigated the possible protective effect of ZDHHC16 in cell proliferation and metastasis of NSCLC and explored its possible mechanisms. ZDHHC16 expression level in patients with Non-Small-Cell Lung Cancer was up-regulation. ZDHHC16 gene is stabilized by m6A methylation. ZDHHC16 gene reduced ferroptosis of NSCLC by the rehabilitation of the mitochondrial structure. ZDHHC16 promoted CREB expression through the inhibition of CREB Ubiquitination. Confocalmicroscopy showed that ZDHHC16 reduced the CREB expression of NSCLC. ZDHHC16 up-regulation reduced CREB Ubiquitination, and down-regulation of ZDHHC16 promoted CREB Ubiquitination of NSCLC. CREB Agonists reduced the effects of ZDHHC16 on ferroptosis, not affecting the Warburg effect of NSCLC. CREB inhibitor reduced the effects of si-ZDHHC16 on ferroptosis, not affecting the Warburg effect of NSCLC. METTL3-mediated m6A modification increases ZDHHC16 stability. Our study revealed that the m6A-forming enzyme METTL3 upregulates ZDHHC16 expression in NSCLC patients, leading to the reduction of ferroptosis by inhibiting CREB ubiquitination.

Therapeutic role of miR-19a/b protection from influenza virus infection in patients with coronary heart disease

Patients with pre-existing medical conditions are at a heightened risk of contracting severe acute respiratory syndrome (SARS), SARS-CoV-2, and influenza viruses, which can result in more severe disease progression and increased mortality rates. Nevertheless, the molecular mechanism behind this phenomenon remained largely unidentified. Here, we found that microRNA-19a/b (miR-19a/b), which is a constituent of the miR-17-92 cluster, exhibits reduced expression levels in patients with coronary heart disease in comparison to healthy individuals. The downregulation of miR-19a/b has been observed to facilitate the replication of influenza A virus (IAV). miR-19a/b can effectively inhibit IAV replication by targeting and reducing the expression of SOCS1, as observed in cell-based and coronary heart disease mouse models. This mechanism leads to the alleviation of the inhibitory effect of SOCS1 on the interferon (IFN)/JAK/STAT signaling pathway. The results indicate that the IAV employs a unique approach to inhibit the host's type I IFN-mediated antiviral immune responses by decreasing miR-19a/b. These findings provide additional insights into the underlying mechanisms of susceptibility to flu in patients with coronary heart disease. miR-19a/b can be considered as a preventative/therapy strategy for patients with coronary heart disease against influenza virus infection.

HINT2 may be One Clinical Significance Target for Patient with Diabetes Mellitus and Reduced ROS-Induced Oxidative Stress and Ferroptosis by MCU.

The World Health Organization (WHO) predicted that patients with diabetes around the world will increase to 600 million by 2040, of which about 1/3 will develop diabetic nephropathy (DN). Therefore, the present study aimed to uncover therapeutic effect of HINT2 and determined its possible mechanisms. Patients with diabetes mellitus and normal volunteers were enrolled at our hospital. Male C57BL/6 mice were fed with a high fat diet and injected intraperitoneally with STZ for once (100 mg/kg body weight). Mouse podocytes (MPC5) cells were induced with 20 mmol/l D-glucose. Inhibition of HINT2 mRNA expression levels in patients with DN was observed, compared with normal group. The serum of HINT2 mRNA expression was negative in correlation with blood sugar, tubulo-interstitial damage, glomerular damage score or urine protein level in patients with DN. HINT2 expression in kidney tissue of mice with DN were downregulated. HINT2 presented reduced DN and inflammation and ROS-induced oxidative stress in model of DN. HINT2 promoted ferroptosis in model of DN by mitochondrial membrane potential. HINT2 suppressed MCU expression in model of DN. HINT2 protein combined with MCU protein increased MCU protein ubiquitination. HINT2 triggers mitochondrial Ca2+ influx to increase ROS production level by MCU. Taken together, these findings demonstrated that HINT2 reduced ROS-induced Oxidative stress and ferroptosis by MCU, suggesting that HINT2 may be a feasible strategy to treat DN.

M6A methylation of FKFB3 reduced pyroptosis of gastric cancer by NLRP3.

Gastric cancer is a kind of malignant tumor that seriously endangers human life and health. Its incidence rate and mortality rate are among the highest in the global malignant tumors. Therefore, this study explored the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the progression of gastric cancer and its underlying mechanism. Patients with gastric cancer were collected, and human GC cell lines (stomach gastric carcinoma 7901, stomach gastric carcinoma 823 , human gastric carcinoma cell line 803 and adenocarcinoma gastric stomach) were used in this study. We utilized glucose consumption, cell migration, and ELISA assay kits to investigate the function of GC. To understand its mechanism, we employed quantitative PCR (qPCR), western blot, and m6A methylated RNA immunoprecipitation assay. FKFB3 protein expression levels in patients with gastric cancer were increased. The induction of PFKFB3 mRNA expression levels in patients with gastric cancer or gastric cancer cell lines. Gastric cancer patients with high PFKFB3 expression had a lower survival rate. PFKFB3 high expression possessed the probability of pathological stage, lymph node metastasis or distant metastasis in patients with gastric cancer. PFKFB3 upregulation promoted cancer progression and Warburg effect progression of gastric cancer. PFKFB3 upregulation reduced pyroptosis and suppressed nucleotidebinding domain, leucinerich repeat containing protein 3-induced pyroptosis of gastric cancer. M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability. Taken together, the M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability and reduced pyroptosis in the model of gastric cancer through the Warburg effect. The PFKFB3 gene represents a potential therapeutic strategy for the treatment of gastric cancer.

LncRNA HOTAIR Inhibits miR-19a-3p to Alleviate Foam Cell Formation and Inflammatory Response in Atherosclerosis.

Background: Atherosclerosis, a chronic inflammatory disease, poses a significant risk for cardiovascular disorders. Meanwhile, emerging evidence suggests that long noncoding RNAs (lncRNAs) play pivotal roles in diverse cardiovascular conditions. Nonetheless, the functional implications of lncRNAs in atherosclerosis remain largely unexplored. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess lncRNA HOTAIR and miR-19a-3p expression levels in patients with atherosclerosis and macrophage-derived foam cells. The release of inflammatory factors was evaluated using enzyme-linked immunosorbent assay (ELISA), while lipid uptake by foam cells was assessed through Oil Red O staining. Additionally, the targeting relationship between lncRNA HOTAIR and miR-19a-3p was validated via a Luciferase reporter assay. Results: LncRNA HOTAIR exhibited downregulation in the plasma of atherosclerosis patients and was found to be inhibited by ox-LDL in human macrophage-derived foam cells. Overexpression of HOTAIR effectively reduced lipid uptake and suppressed the inflammatory response by downregulating the expression of TNF-α and IL-6 during foam cell formation. Mechanistically, HOTAIR mitigated foam cell formation by repressing the expression of miR-19a-3p. Conclusions: In conclusion, our findings, in conjunction with previous studies, elucidate the role of HOTAIR in atherosclerosis. Specifically, we demonstrate that HOTAIR plays a role in alleviating foam cell formation and suppressing the inflammatory response by inhibiting miR-19a-3p in the context of atherosclerosis. Our results suggest the involvement of the TNF-α/miR-19a/HBP1/MIF pathway in mediating these effects. These findings contribute to a better understanding of atherosclerosis's molecular mechanisms and highlight the potential therapeutic implications of targeting HOTAIR and its associated pathways.