High-dose vitamin C attenuates radiation-induced pulmonary fibrosis by targeting S100A8 and S100A9.

Radiation-induced pulmonary fibrosis (RIPF) is a frequently encountered late complication in patients undergoing radiation therapy, presenting a substantial risk to patient mortality and quality of life. The pathogenesis of RIPF remains unclear, and current treatment options are limited in efficacy. High-dose vitamin C has demonstrated potential when used in conjunction with other adjuvant therapies due to potent anticancer properties. However, the potential relationship between high-dose vitamin C and RIPF has not yet been explored in existing literature. In our study, the RIPF model and the LLC tumor model were used as two animal models to explore how high-dose vitamin C can improve RIPF without hampering the antitumour efficacy of radiotherapy. The impact of high-dose vitamin C on RIPF was assessed through various assays, including micro-CT, HE staining, Masson staining, and immunohistochemistry. Our results indicated that administering high-dose vitamin C 2 days before radiation and continuing for a duration of 6 weeks significantly inhibited the progression of RIPF. In order to explore the mechanism by which high-dose vitamin C attenuates RIPF, we utilized RNA-seq analysis of mouse lung tissue in conjunction with publicly available databases. Our findings indicated that high-dose vitamin C inhibits the differentiation of fibroblasts into myofibroblasts by targeting S100A8 and S100A9 derived from neutrophils. Additionally, the combination of high-dose vitamin C and radiation demonstrated enhanced inhibition of tumor growth in a murine LLC tumor model. These results revealed that the combination of radiotherapy and high-dose vitamin C may offer a promising therapeutic approach for the clinical management of thoracic tumors and the prevention of RIPF.

TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion.

Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, tankyrasel binding protein 1 (TNKS1BP1) was found to interact with tripartite motif containing 21 (TRIM21) and mediated the ubiquitination of CCR4-NOT transcription complex subunit 4 (CNOT4) at the K239 residue via K48 and K6 linkage, which was essential for its tumorigenesis function. Autophagy and lipid reprogramming were identified as two possible mechanisms underlying the pro-tumor effect of TNKS1BP1. Upregulated TNKS1BP1 inhibited autophagy while induced lipid accumulation by inhibiting the JAK2/STAT3 pathway upon the degradation of CNOT4 in HCC. Importantly, knocking down TNKS1BP1 synergized with anti-PD-L1 treatment by upregulating PD-L1 expression on tumor cells via the JAK2/STAT3 pathway, and remodeling the tumor microenvironment by increasing infiltration of tumor-infiltrating lymphocytes as well as augmenting the effect of cytotoxic T lymphocytes. In conclusion, this study identified TNKS1BP1 as a predictive biomarker for patient prognosis and a promising therapeutic target to overcome anti-PD-L1 resistance in HCC.

A comprehensive investigation on the receptor BSG expression reveals the potential risk of healthy individuals and cancer patients to 2019-nCoV infection.

BACKGROUND: Coronavirus disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a newly emerging coronavirus. BSG (basigin) is involved in the tumorigenesis of multiple tumors and recently emerged as a novel viral entry receptor for SARS-CoV-2. However, its expression profile in normal individuals and cancer patients are still unclear. METHODS: We performed a comprehensive analysis of the expression and distribution of BSG in normal tissues, tumor tissues, and cell lines via bioinformatics analysis and experimental verification. In addition, we investigated the expression of BSG and its isoforms in multiple malignancies and adjacent normal tissues, and explored the prognostic values across pan-cancers. Finally, we conducted function analysis for co-expressed genes with BSG. RESULTS: We found BSG was highly conserved in different species, and was ubiquitously expressed in almost all normal tissues and significantly increased in some types of cancer tissues. Moreover, BSG at mRNA expression level was higher than ACE2 in normal lung tissues, and lung cancer tissues. High expression of BSG indicated shorter overall survival (OS) in multiple tumors. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that BSG is mostly enriched in genes for mitochondria electron transport, oxidoreduction-driven active transmembrane transporter activity, mitochondrial inner membrane, oxidative phosphorylation, and genes involving COVID-19. CONCLUSIONS: Our present work emphasized the value of targeting BSG in the treatment of COVID-19 and cancer, and also provided several novel insights for understanding the SARS-CoV-2 pandemic.

Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA.

Endometrial cancer (EC) is a prevalent gynecological malignancy worldwide, and 5-methylcytosine (m5C) modification of mRNA is a crucial epigenetic modification associated with the development and occurrence of several cancers. However, the precise function of m5C modification in EC remains elusive. This study aimed to investigate the expression and clinical significance of the primary m5C modification writer, NSUN2, in EC. Our findings indicated that NSUN2 exhibited a substantial up-regulation in EC as a result of an epigenetic augmentation in H3K4me3 levels within the promoter region, which was triggered by the down-regulation of KDM5A. Moreover, gain- and loss-of-function experiments revealed the role of NSUN2 in enhancing m5C modification of mRNA, thereby promoting EC cell proliferation. RNA bisulfite sequencing and transcriptomic sequencing were employed to elucidate the involvement of NSUN2 in the regulation of ferroptosis. Subsequent in vitro experiments confirmed that the knockdown of NSUN2 significantly up-regulated the levels of lipid peroxides and lipid ROS in EC cells, thereby augmenting the susceptibility of EC to ferroptosis. Mechanistically, NSUN2 stimulated the m5C modification of SLC7A11 mRNA, and the m5C reader YBX1 exhibited direct recognition and binding to the m5C sites on SLC7A11 mRNA via its internal cold shock domain (CSD), leading to an increase in SLC7A11 mRNA stability and elevated levels of SLC7A11. Additionally, rescue experiments showed that NSUN2 functioned as a suppressor of ferroptosis, which was dependent on SLC7A11. Overall, targeting the NSUN2/SLC7A11 axis inhibited tumor growth by increasing lipid peroxidation and ferroptosis of EC cells both in vitro and in vivo. Therefore, our study provides new insight into the role of NSUN2, suggesting that NSUN2 may serve as a prognostic biomarker and therapeutic target in patients with EC.

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma.

BACKGROUND: Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied. METHODS: Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan-Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments. RESULTS: Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells. CONCLUSIONS: Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.

Comprehensive Pan-Cancer Analyses of Immunogenic Cell Death as a Biomarker in Predicting Prognosis and Therapeutic Response.

Immunogenic cell death (ICD), a form of regulated cell death, is related to anticancer therapy. Due to the absence of widely accepted markers, characterizing ICD-related phenotypes across cancer types remained unexplored. Here, we defined the ICD score to delineate the ICD landscape across 33 cancerous types and 31 normal tissue types based on transcriptomic, proteomic and epigenetics data from multiple databases. We found that ICD score showed cancer type-specific association with genomic and immune features. Importantly, the ICD score had the potential to predict therapy response and patient prognosis in multiple cancer types. We also developed an ICD-related prognostic model by machine learning and cox regression analysis. Single-cell level analysis revealed intra-tumor ICD state heterogeneity and communication between ICD-based clusters of T cells and other immune cells in the tumor microenvironment in colon cancer. For the first time, we identified IGF2BP3 as a potential ICD regulator in colon cancer. In conclusion, our study provides a comprehensive framework for evaluating the relation between ICD and clinical relevance, gaining insights into identification of ICD as a potential cancer-related biomarker and therapeutic target.

Characterization of the SARS-CoV-2 co-receptor NRP1 expression profiles in healthy people and cancer patients: Implication for susceptibility to COVID-19 disease and potential therapeutic strategy.

Neuropilin-1 (NRP1) is a transmembrane protein involved in many physiological and pathological processes, and it functions as a co-receptor to facilitate the entry of SARS-CoV-2 into host cells. Therefore, it is critical to predict the susceptibility to SARS-CoV-2 and prognosis after infection among healthy people and cancer patients based on expression of NRP1. In the current study, we analyzed the conservation and isoform of NRP1 using public databases. NRP1 expression landscape in healthy people, COVID-19 patients, and cancer patients at both bulk and single-cell RNA-seq level was also depicted. We also analyzed the relationship between tissue-specific NRP1 expression and overall survival (OS), as well as tumor immune environment at a pan-cancer level, providing a comprehensive insight into the relationship between the vulnerability to SARS-CoV-2 infection and tumorigenesis. In conclusion, we identified NRP1 as a potential biomarker in predicting susceptibility to SARS-CoV-2 infection among healthy people and cancer patients.

Identifying potential pharmacological targets and mechanisms of vitamin D for hepatocellular carcinoma and COVID-19.

Coronavirus disease 2019 (COVID-19) is a severe pandemic that has posed an unprecedented challenge to public health worldwide. Hepatocellular carcinoma (HCC) is a common digestive system malignancy, with high aggressiveness and poor prognosis. HCC patients may be vulnerable to COVID-19. Since the anti-inflammatory, immunomodulatory and antiviral effects of vitamin D, we aimed to investigate the possible therapeutic effects and underlying action mechanisms of vitamin D in COVID-19 and HCC in this study. By using a range of bioinformatics and network pharmacology analyses, we identified many COVID-19/HCC target genes and analyzed their prognostic significance in HCC patients. Further, a risk score model with good predictive performance was developed to evaluate the prognosis of HCC patients with COVID-19 based on these target genes. Moreover, we identified seven possible pharmacological targets of vitamin D against COVID-19/HCC, including HMOX1, MB, TLR4, ALB, TTR, ACTA1 and RBP4. And we revealed the biological functions, signaling pathways and TF-miRNA coregulatory network of vitamin D in COVID-19/HCC. The enrichment analysis revealed that vitamin D could help in treating COVID-19/HCC effects through regulation of immune response, epithelial structure maintenance, regulation of chemokine and cytokine production involved in immune response and anti-inflammatory action. Finally, the molecular docking analyses were performed and showed that vitamin D possessed effective binding activity in COVID-19. Overall, we revealed the possible molecular mechanisms and pharmacological targets of vitamin D for treating COVID-19/HCC for the first time. But these findings need to be further validated in actual HCC patients with COVID-19 and need further investigation to confirm.

Identification of a prognostic classifier based on EMT-related lncRNAs and the function of LINC01138 in tumor progression for lung adenocarcinoma.

Purpose: This study aimed to develop a prognostic indicator based on epithelial-mesenchymal transition (EMT)-related long noncoding RNAs (lncRNAs) and explore the function of EMT-related lncRNAs in malignant progression in lung adenocarcinoma (LUAD). Materials and methods: A LUAD dataset was acquired from The Cancer Genome Atlas (TCGA) to identify prognostic EMT-related lncRNAs via differential expression analysis and univariate Cox regression analysis. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis was utilized for variable selection and model construction. The EMT-related prognostic index (ERPI) was calculated according to the model and served as a classifier to divide LUAD individuals into high-ERPI and low-ERPI groups. A nomogram incorporating ERPI and clinicopathological variables was constructed. TCGA-LUAD, GSE50081, and GSE31210 were used to test the predictive capacity of the ERPI and nomogram. The characteristics of the tumor microenvironment (TME) were evaluated via the ESTIMATE, TIMER, and ssGSEA algorithms. Gene set variation analysis (GSVA) and ssGSEA were used to annotate the functions of the high-ERPI and low-ERPI groups. CCK8, transwell assay, wound-healing assay, and clone formation assay were conducted to clarify the biological functions of prognostic EMT-related lncRNAs. Results: Ninety-seven differentially expressed EMT-related lncRNAs were identified, 15 of which were related to overall survival (OS). A prognostic signature was constructed based on 14 prognostic EMT-related lncRNAs to calculate the ERPI of each patient, and the predictive ability of ERPI was verified in TCGA, GSE50081, and GSE31210. The low-ERPI group survived longer and had a lower percentage of patients in advanced stage than the high-ERPI group. The nomogram had the highest predictive accuracy, followed by ERPI and stage. Patients with low ERPI had higher infiltration degree of immune cells and stronger immune responses than those with high ERPI. A series of in vitro experiments demonstrated that knockdown of LINC01138 dampened variability, proliferation, and motility of A549 and H460 cells. Conclusion: Our study developed a prognostic classifier with robust prognostic performance and clarified the biological functions of LINC01138 in LUAD, aiding in making individual treatments for patients with LUAD and dissecting the mechanism of oncogenesis.

Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

A Novel Secreted Protein-Related Gene Signature Predicts Overall Survival and Is Associated With Tumor Immunity in Patients With Lung Adenocarcinoma.

Secreted proteins are important proteins in the human proteome, accounting for approximately one-tenth of the proteome. However, the prognostic value of secreted protein-related genes has not been comprehensively explored in lung adenocarcinoma (LUAD). In this study, we screened 379 differentially expressed secretory protein genes (DESPRGs) by analyzing the expression profile in patients with LUAD from The Cancer Genome Atlas database. Following univariate Cox regression and least absolute shrinkage and selection operator method regression analysis, 9 prognostic SPRGs were selected to develop secreted protein-related risk score (SPRrisk), including CLEC3B, C1QTNF6, TCN1, F2, FETUB, IGFBP1, ANGPTL4, IFNE, and CCL20. The prediction accuracy of the prognostic models was determined by Kaplan-Meier survival curve analysis and receiver operating characteristic curve analysis. Moreover, a nomogram with improved accuracy for predicting overall survival was established based on independent prognostic factors (SPRrisk and clinical stage). The DESPRGs were validated by quantitative real-time PCR and enzyme-linked immunosorbent assay by using our clinical samples and datasets. Our results demonstrated that SPRrisk can accurately predict the prognosis of patients with LUAD. Patients with a higher risk had lower immune, stromal, and ESTIMATE scores and higher tumor purity. A higher SPRrisk was also negatively associated with the abundance of CD8+ T cells and M1 macrophages. In addition, several genes of the human leukocyte antigen family and immune checkpoints were expressed in low levels in the high-SPRrisk group. Our results provided some insights into assessing individual prognosis and choosing personalized treatment modalities.

Integrative Analysis Constructs an Extracellular Matrix-Associated Gene Signature for the Prediction of Survival and Tumor Immunity in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) accounts for the majority of lung cancers, and the survival of patients with advanced LUAD is poor. The extracellular matrix (ECM) is a fundamental component of the tumor microenvironment (TME) that determines the oncogenesis and antitumor immunity of solid tumors. However, the prognostic value of extracellular matrix-related genes (ERGs) in LUAD remains unexplored. Therefore, this study is aimed to explore the prognostic value of ERGs in LUAD and establish a classification system to predict the survival of patients with LUAD. Methods: LUAD samples from The Cancer Genome Atlas (TCGA) and GSE37745 were used as discovery and validation cohorts, respectively. Prognostic ERGs were identified by univariate Cox analysis and used to construct a prognostic signature by Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. The extracellular matrix-related score (ECMRS) of each patient was calculated according to the prognostic signature and used to classify patients into high- and low-risk groups. The prognostic performance of the signature was evaluated using Kaplan-Meier curves, Cox regression analyses, and ROC curves. The relationship between ECMRS and tumor immunity was determined using stepwise analyses. A nomogram based on the signature was established for the convenience of use in the clinical practice. The prognostic genes were validated in multiple databases and clinical specimens by qRT-PCR. Results: A prognostic signature based on eight ERGs (FERMT1, CTSV, CPS1, ENTPD2, SERPINB5, ITGA8, ADAMTS8, and LYPD3) was constructed. Patients with higher ECMRS had poorer survival, lower immune scores, and higher tumor purity in both the discovery and validation cohorts. The predictive power of the signature was independent of the clinicopathological parameters, and the nomogram could also predict survival precisely. Conclusions: We constructed an ECM-related gene signature which can be used to predict survival and tumor immunity in patients with LUAD. This signature can serve as a novel prognostic indicator and therapeutic target in LUAD.

Paravertebral abscess and bloodstream infection caused by Burkholderia pseudomallei after acupuncture: a case report.

BACKGROUND: Various pathogenic bacterial infections caused by acupuncture have raised widespread concern, but paravertebral abscesses and bloodstream infections of Burkholderia pseudomallei (B.pseudomallei) after acupuncture have not been reported. CASE PRESENTATION: A 49-year-old man was admitted to hospital with recurrent back pain and fever for 1 month, along with the finding of undiagnosed diabetes. He was considered to have tuberculosis because of unrelieved high fever and pulmonary nodules. Bilateral blood culture suggested B.pseudomallei infection, MRI of the lumbar spine suggested paravertebral abscess, and the final diagnosis was paravertebral abscess and bloodstream infection after acupuncture combined with migrating lung infection. He was discharged after abscess debridement and intensive anti-infective therapy, but no further oral antibiotics were administered because of his poor adherence. More than 5 months later, he was readmitted with the urine culture findings of B.pseudomallei. No other abscess formation was observed and he received oral antibiotics for more than 3 months without recurrence. CONCLUSIONS: Acupuncture may lead to B.pseudomallei infection in high-risk groups, and inadequate treatment can lead to recurrent infections.

Construction of a Redox-Related Prognostic Model with Predictive Value in Survival and Therapeutic Response for Patients with Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) represents the most common histological subtype of lung cancer. Redox plays a significant role in oncogenesis and antitumor immunity. In this study, we aimed to investigate the prognostic redox-associated genes and construct a redox-based prognostic signature for LUAD. MATERIALS AND METHODS: A discovery cohort containing 479 LUAD samples from The Cancer Genome Atlas (TCGA) was analyzed. We identified prognostic redox-associated genes by weighted correlation network analysis (WGCNA) and univariate Cox regression analysis to construct a prognostic model via least absolute shrinkage and selection operator (LASSO)-multivariate Cox regression analyses. The performance of the redox-based model was validated in the TCGA cohort and an independent cohort of 456 samples by Cox regression analyses, log-rank test, and receiver operating characteristic (ROC) curves. Correlations of the model with clinicopathological variables and lymphocyte infiltration were assessed. Gene set enrichment analysis (GSEA) was used to clarify the underlying mechanism of the prognostic model. We constructed a nomogram based on the model and created calibration curves to show the accordance between actual survival and predicted survival of the nomogram. RESULTS: Stepwise analyses identified 6 prognostic redox-associated genes of LUAD and constructed a prognostic model that performed well in both the discovery and validation cohorts. The model was found to be associated with tumor stage, mutation of TP53 and EGFR, and lymphocyte infiltration. The model was mainly involved in the regulation of the cell cycle, DNA replication and repair, NADH metabolism, and the p53 signaling pathway. Calibration curves showed the high predictive accuracy of the nomogram. CONCLUSIONS: This study explored the role of redox-associated genes in LUAD and constructed a prognostic model of LUAD. The signature was also associated with tumor progression and therapeutic response to immunotherapy. These findings contributed to uncovering the underlying mechanism and discovering novel prognostic predictor of LUAD.

Comprehensive and Integrative Analysis of Two Novel SARS-CoV-2 Entry Associated Proteases CTSB and CTSL in Healthy Individuals and Cancer Patients.

More than 200 million people have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 4 million deaths have been reported worldwide to date. Cathepsin B/cathepsin L (CTSB/L) are SARS-CoV-2 entry-associated proteases and facilitate SARS-CoV-2 to infect host cells. However, the expressions of CTSB/L in healthy individuals and cancer patients remain not fully elucidated yet. Here, we comprehensively profiled the expressions and distributions of CTSB/L in human normal tissues, cancer tissues, and cell lines. Moreover, we compared CTSB/L expressions between various cancers and matched normal tissues, and investigated their genetic alteration and prognostic values in pan-cancer. Finally, we also explored the correlation between CTSB/L expressions and immune infiltration. We found that CTSB was highly expressed in most tissues, and CTSL was highly expressed predominantly in the digestive, urinary, and respiratory systems, such as the lungs, liver and gallbladder, and kidney tissues in the translational level. Moreover, cancer patients may be more susceptible to SARS-CoV-2 infection. Our data suggested that CTSB/L are overexpressed in aerodigestive and genitourinary cancers when compared with that in matched normal tissues, and their expressions were closely related to the prognosis of some cancer types. Interestingly, CTSB/L expressions were significantly correlated with immune cell infiltration in manifold cancer tissues and their corresponding normal tissues. In conclusion, our study shows a comprehensive bioinformatic analysis of two important SARS-CoV-2 entry-related proteases, which could provide a potential indication on prevention of SARS-CoV-2 infection.

Exploring the Prognostic Value, Immune Implication and Biological Function of H2AFY Gene in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is an extremely malignant cancer with poor survival. H2AFY gene encodes for a variant of H2A histone, and it has been found to be dysregulated in various tumors. However, the clinical value, biological functions and correlations with immune infiltration of H2AFY in HCC remain unclear. Methods: We analyzed the expression and clinical significance of H2AFY in HCC using multiple databases, including Oncomine, HCCDB, TCGA, ICGC, and so on. The genetic alterations of H2AFY were analyzed by cBioPortal and COSMIC databases. Co-expression networks of H2AFY and its regulators were investigated by LinkedOmics. The correlations between H2AFY and tumor immune infiltration were explored using TIMER, TISIDB databases, and CIBERSORT method. Finally, H2AFY was knocked down with shRNA lentiviruses in HCC cell lines for functional assays in vitro. Results: H2AFY expression was upregulated in the HCC tissues and cells. Kaplan-Meier and Cox regression analyses revealed that high H2AFY expression was an independent prognostic factor for poor survival in HCC patients. Functional network analysis indicated that H2AFY and its co-expressed genes regulates cell cycle, mitosis, spliceosome and chromatin assembly through pathways involving many cancer-related kinases and E2F family. Furthermore, we observed significant correlations between H2AFY expression and immune infiltration in HCC. H2AFY knockdown suppressed the cell proliferation and migration, promoted cycle arrest, and apoptosis of HCC cells in vitro. Conclusion: Our study revealed that H2AFY is a potential biomarker for unfavorable prognosis and correlates with immune infiltration in HCC.

Yi-Qi-Jian-Pi formula modulates the PI3K/AKT signaling pathway to attenuate acute-on-chronic liver failure by suppressing hypoxic injury and apoptosis in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute-on-chronic liver failure (ACLF) is a key complication of chronic hepatitis, with a relatively high mortality rate and limited treatment options, which dramatically threatens human lives. Yi-Qi-Jian-Pi formula (YQJPF) is a herbal compound commonly used to treat liver failure. AIM OF THE STUDY: The purpose of this research is to discuss the potential molecular biological effect and mechanism of YQJPF in ACLF. MATERIALS AND METHODS: In this study, we created a rat model of ACLF by CCl4-, LPS- and D-Galactosamine (D-Gal) and an in vitro model of LPS-induced hepatocyte damage. The specific components of YQJPF and potential mechanism were explored based on bioinformatics analyses. Furthermore, we verified the effect of YQJPF on ACLF using immunohistochemistry, RT-qPCR, western blotting, and flow cytometry. RESULTS: Our research demonstrated that, after YQJPF treatment, hepatocyte injury in rats was relieved. Bioinformatics analysis showed that PI3K/AKT, HIF-1, mitochondrial apoptosis pathways played prominent roles. YQJPF promoted HIF-1α protein expression and exerted protective effects against hypoxic injury, simultaneously reducing mitochondrial ROS production, suppressing hepatocyte apoptosis. Furthermore, we showed that YQJPF accelerates PI3K/AKT pathway activation, a known broad-spectrum inhibitor of PI3K. LY294002, which was used for reverse verification, suppressed the effect of YQJPF on hypoxic injury and ROS-mediated hepatocyte apoptosis. CONCLUSIONS: YQJPF ameliorates liver injury by suppressing hypoxic injury and ROS-mediated hepatocyte apoptosis by modulating the PI3K/AKT pathway.

A Novel Prognostic Signature for Survival Prediction and Immune Implication Based on SARS-CoV-2-Related Genes in Kidney Renal Clear Cell Carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a common aggressive malignancy of the urinary system. COVID-19, a highly infectious and severe disease caused by SARS-CoV-2, has become a significant challenge for global public health. Cancer patients have been reported to be more vulnerable to SARS-CoV-2 infection and have a higher risk for serious complications than the general population. However, the correlation between KIRC and COVID-19 remains incompletely elucidated. In this study, we comprehensively investigated the expression and prognostic significance of 333 SARS-CoV-2 infection-related genes in KIRC using the TCGA dataset and identified 31 SARS-CoV-2-related differently expressed genes between KIRC and normal renal tissues. Based on these genes, we constructed and validated a 5-gene prognostic signature (including ACADM, CENPF, KDELC1, PLOD2, and TRMT1) to distinguish low- and high-risk KIRC patients of poor survival in TCGA and E-MTAB-1980 cohorts. Gene set enrichment analysis (GSEA) showed that some inflammatory/immune-related pathways were significantly enriched in the high-risk group. The ESTIMATE analysis indicated that patients in the high-risk group had higher stromal and immune cell scores, therefore lower tumor purity. Moreover, they presented higher proportions of macrophages M0, regulatory T cells (Tregs), and T follicular helper cells and higher expression of immune checkpoints CTLA-4, LAG-3, TIGIT, and PDCD1 than low-risk patients. Besides, we also developed a nomogram to expand clinical applicability, which exhibits excellent predictive accuracy for survival. In conclusion, we identified a novel prognostic signature and nomogram based on SARS-CoV-2-related genes as reliable prognostic predictors for KIRC patients and provided potential therapeutic targets for KIRC and COVID-19.

Skull-femoral traction after posterior release for correction of adult severe scoliosis: efficacy and complications.

BACKGROUND: It is a great challenge for spine surgeons to correct severe rigid scoliosis. We developed a three- staged correction (one stage posterior release and screw placement, two stage skull-femoral traction and three stage posterior instrumentation) for adult severe scoliosis. The objective of this study is to investigate safety and efficacy of a three- staged correction for adult severe scoliosis. METHODS: A retrospective review was performed for patients with severe scoliosis receiving three- staged correction (one stage posterior release and screw placement, two stage skull-femoral traction and three stage posterior instrumentation) from June 2001 to October 2014. The inclusion criteria were as follows: [1] age more than 18 years; [2] main curve larger than 90°; [3] a minimum 2-year follow-up. Patients were excluded if they had a history of surgery or anterior release or receiving three column osteotomies. RESULTS: A total of 63 patients were included (37 female and 26 male), with a mean age of 22.7 years (range: 18-30 years) and follow-up of 42.6 months (range: 24-108 months). The aetiology was congenital in 27 patients, neuromuscular in 18, idiopathic in 11, neurofibromatosis-1 in 4 and Marfan syndrome in 3. The mean traction weight was 28.4 kg (range: 18-32 kg), equal to 57.2% of patients' body weight (range: 42.7-72.3%). The mean traction time was 22.7 days (range: 12-44 days). Postoperative correction rate was 55% (range: 38-78%) for scoliosis and 51% (range: 32-75%) for kyphosis. Contribution of traction to correction was 51% (range: 36-70%) for scoliosis and was 43% (range: 34-55%) for kyphosis. CONCLUSIONS: Three- staged correction (one stage posterior release and screw placement, two stage skull-femoral traction and three stage posterior instrumentation) could effectively correct adult severe scoliosis. The incidence of complications of skull-femoral traction was not low, but transient and could be successfully managed.

Comparison of Complications and Surgical Outcomes of Adolescent Idiopathic Scoliosis Between Junior Attending Surgeons and Senior Attending Surgeons.

BACKGROUND: To our knowledge, few studies have compared complications and surgical outcomes of adolescent idiopathic scoliosis (AIS) between junior attending surgeons and senior attending surgeons. OBJECTIVES: To compare surgical strategies, complications, and outcomes of posterior corrective surgery for AIS between junior attending surgeons and senior attending surgeons. METHODS: According to experience level of operation surgeons, the patients were assigned to 2 groups. Group A was the "junior surgeon" group. Group B was the "senior surgeon" group. The following parameters were compared between the 2 groups: age, sex, diagnosis, hospital of record, surgeon experience level, type of instrumentation, type of screws, estimated blood loss, duration of surgery, length of fusion, correction techniques, main curve correction, and thoracic kyphosis correction. RESULTS: A total of 132 patients with AIS were included in group A, whereas 207 were in group B. The translational technique was used more often in group A (P < 0.05). whereas the derotation technique was used more often in group B (P < 0.05). Senior surgeons used more monoaxial screws than junior surgeons (P < 0.05). The junior group had significantly greater estimated blood loss than the senior group (P < 0.05). The senior group had significant better correction rates of severe main curve (>70°) and thoracic kyphosis than the junior group (P < 0.05). CONCLUSIONS: Senior attending surgeons outperformed junior surgeons in blood loss control, thoracic kyphosis correction, and correction of severe curves.